{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","name":"Research Synthesis: Alpha-ketoglutarate — full paper","doi":"10.17605/OSF.IO/84YSJ","doi_status":"minted","osf_url":"https://osf.io/84ysj/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_dfb61cdfc5da412e/chain","content_hash":"sha256:259fc5c5201345c13b9fef14f0b856e34339657122e85c238bac7b91bb4b1d3d","provenance_passport":{"publication_id":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","submission_id":"5e389f1a-19f8-469e-b6ec-4f1e60c38dc4","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:259fc5c5201345c13b9fef14f0b856e34339657122e85c238bac7b91bb4b1d3d","persistent_identifiers":{"doi":"10.17605/OSF.IO/84YSJ","osf_url":"https://osf.io/84ysj/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":{"recommendation":"unavailable","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null,"status":"unavailable"},"provenance":{"dw_artifact_id":"claim_dfb61cdfc5da412e","dw_chain_url":"https://provenance.researka.org/artifacts/claim_dfb61cdfc5da412e/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","object_type":"publication","parent_object_id":"5e389f1a-19f8-469e-b6ec-4f1e60c38dc4","title":"Research Synthesis: Alpha-ketoglutarate — full paper","body_markdown":"# Research Synthesis: Alpha-ketoglutarate — full paper\n\n## Abstract\n\nEvidence-honesty note: 46/53 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.\n\nThis paper synthesizes evidence on Alpha-ketoglutarate across 53 accepted source papers and 2847 high-confidence extracted claims.\n\nThe evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 45 adjacent clinical sources, and 8 mechanistic or model-system sources, with 1 cross-study disagreement across the evidence base.\n\nPositive study-level signals are summarized in the safety and comorbidity outcome class, null signals in the contextual adjacent evidence, cardiometabolic and mechanism outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that Alpha-ketoglutarate remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.\n\n## Methods\n\n### Review type and protocol\nThis manuscript is reported as a Evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-alpha_ketoglutarate_akg-v06-DAILY-2026-06-20T04-00-35Z`.\n\n### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-20.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `alpha-ketoglutarate AND aging AND human`\n- `calcium alpha-ketoglutarate AND biological age`\n- `AKG AND longevity AND trial`\n- `alpha ketoglutarate AND epigenetic clock`\n- `Ca-AKG AND safety AND human`\n\n### Eligibility criteria\n- Sources whose primary content addresses alpha ketoglutarate akg.\n- Sources with extractable quantitative or qualitative findings.\n- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.\n- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).\n\n### Selection of sources of evidence\nThe synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 188 records in the receipt-candidate union, 68 were classified as source candidates and 53 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.\n\n### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 188 |\n| Classified source candidates | 68 |\n| No extractable claims | 32 |\n| None-only claim binding | 5 |\n| Mixed partial-or-none claim-binding candidates | 62 |\n| Partial-only claim-binding candidates | 15 |\n| Strict high-confidence sources | 6 |\n| Admitted final sources | 53 |\n\n### Exclusion reasons\n- No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.\n\n### Data items\nThe following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.\n\n### Risk-of-bias appraisal\nPer-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses).\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, immune and inflammation, immune and inflammation, mechanism, mortality and survival, muscle function, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.\n\n### AI-use disclosure\nSource retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.\n\n### Accountability\nAccountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.\n\n## Results\n| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=33; claims=1572 | no extracted directional signal in 31/33 sources | 30 indirect; 1 protocol; 2 review | limited corpus depth in this outcome class |\n| Immune and Inflammation | n=4; claims=305 | unclear signal in 2/4 sources | 4 indirect | limited corpus depth in this outcome class |\n| Mechanism | n=4; claims=302 | no extracted directional signal in 3/4 sources | 4 mechanistic | limited corpus depth in this outcome class |\n| Cardiometabolic | n=3; claims=162 | no extracted directional signal in 3/3 sources | 1 indirect; 2 mechanistic | limited corpus depth in this outcome class |\n| Muscle Function | n=3; claims=139 | no extracted directional signal in 2/3 sources | 3 indirect | limited corpus depth in this outcome class |\n| Safety and Comorbidity | n=2; claims=215 | positive signal in 1/2 sources | 2 mechanistic | limited corpus depth in this outcome class |\n| Skeletal, Fracture, and Bone | n=2; claims=98 | no extracted directional signal in 2/2 sources | 2 indirect | limited corpus depth in this outcome class |\n| Deficiency Prevalence | n=1; claims=10 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Mortality and Survival | n=1; claims=44 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n\n**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.\n\nThis evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.\n\n### Contextual Adjacent Evidence Outcomes\n\n33 included sources were assigned to this outcome class. Directional coding: null=31, unclear=2. Directness coding: indirect=30, protocol=1, review=2.\n\n### Mechanism Outcomes\n\n4 included sources were assigned to this outcome class. Directional coding: mixed=1, null=3. Directness coding: mechanistic=4.\n\n### Cardiometabolic Outcomes\n\n3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=1, mechanistic=2.\n\n### Immune Inflammation Outcomes\n\n3 included sources were assigned to this outcome class. Directional coding: null=1, unclear=2. Directness coding: indirect=3.\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\nEvidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.\n\n### Muscle Function Outcomes\n\n3 included sources were assigned to this outcome class. Directional coding: null=2, unclear=1. Directness coding: indirect=3.\n\n### Safety Comorbidity Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=1, positive=1. Directness coding: mechanistic=2.\n\n### Skeletal Fracture Bone Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.\n\n### Deficiency Prevalence Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\n### Mortality Survival Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\n## Limitations\n\n**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.\n\nAdditional corpus sources included animal/preclinical evidence; the most consequential scope gap is the near-absence of long-term, hard-outcome randomized evidence in non-diabetic, community-dwelling adults. Consequently, every human claim in this synthesis that is anchored to a clinical event — whether survival in flap surgery (Huang 2025), aneurysm progression (Liu 2022), or diabetic cardiomyopathy (Dhat 2023) — is supported only by indirect, indirect-directness sources, and the headline conclusions cannot be transported to general adult populations without a dedicated long-term mortality RCT, of which the corpus contains none.\n\nSeveral clinically relevant claims rest on a single source and therefore cannot be internally replicated within the corpus. Because no second source in the curated set re-tests any of these endpoints, none of these single-study findings can be confirmed, refuted, or meta-analyzed at the synthesis level, and any effect size drawn from them should be treated as hypothesis-generating rather than confirmatory.\n\nThe enrolled populations are heavily skewed toward animal models, livestock, and cell-line systems, which constrains the external validity of every claim framed in human terms.\n\nFinally, the corpus contains a mechanism-to-clinic gap for the most clinically relevant claim, namely that αKG influences cardiovascular, skeletal, and longevity outcomes in humans. Mechanistic plausibility is densely documented: PI3K/Akt/HIF-1α angiogenesis in skin flaps (Huang 2025), PHD1-dependent NF-κB suppression in osteoclastogenesis (Tian 2023b), epigenetic H3K27me3 reduction in periodontal regeneration (Hasegawa 2026), histone methylation rescue in age-related osteoporosis (Wang 2020), and Tnfrsf12a/Fn14 histone-modification protection against cancer cachexia (Ruiz 2023). However, each of these sources is either preclinical (An 2021, Iwaniak 2022, Bayliak 2017, Kalawaj 2020), mechanistic-only (Iniguez 2022, Cai 2016, Qiu 2025, Sekita 2021, Wu 2018, Burdyliuk 2017, Showalter 2017, Fiehn 2016), or review/protocol-level (Sandalova 2023, Lamichhane 2023, Doroftei 2024, Wu 2016). The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. Pending further trials, the intervention should not be used off-label for geroprotection or anti-aging purposes outside clinical-trial settings given current evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.\n\n## What This Synthesis Adds\n\nThis synthesis maps 53 included sources on Alpha Ketoglutarate Akg across 10 outcome classes and 1 cross-study disagreement. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.\n\nAcross 53 curated reference papers, the evidence base for Alpha shows a context-dependent profile. Positive signals appear in: safety comorbidity. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Alpha anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.\n\nIn animal/preclinical evidence, the strongest unresolved contrast is the null vs positive between An 2021 and Iwaniak 2022 on safety and comorbidity, which defines the boundary condition future studies must test rather than smooth over.\n\nThis synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.\n\n### Boundary-Condition Matrix\n\n| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| cardiometabolic | 0 | 3 | null | direct interventional hard-endpoint gap |\n| muscle function | 0 | 3 | null, unclear | direct interventional hard-endpoint gap |\n| immune and inflammation | 0 | 1 | null | direct interventional hard-endpoint gap |\n| mechanism | 0 | 4 | mixed, null | direct interventional hard-endpoint gap |\n| safety and comorbidity | 0 | 2 | null, positive | conflict-resolution gap |\n| contextual adjacent evidence | 0 | 33 | null, unclear | direct interventional hard-endpoint gap |\n| deficiency prevalence | 0 | 1 | null | direct interventional hard-endpoint gap |\n| immune and inflammation | 0 | 3 | null, unclear | direct interventional hard-endpoint gap |\n| mortality and survival | 0 | 1 | null | direct interventional hard-endpoint gap |\n| skeletal, fracture, and bone | 0 | 2 | null | direct interventional hard-endpoint gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null |\n| P2 | muscle function: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null, unclear |\n| P3 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null |\n| P4 | mechanism: direct interventional hard-endpoint gap | 0 direct and 4 indirect sources; direction profile: mixed, null |\n| P5 | safety and comorbidity: conflict-resolution gap | 0 direct and 2 indirect sources; direction profile: null, positive |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Alpha Ketoglutarate Akg should target the **cardiometabolic** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.\n\n## Evidence Snapshot\n\nThe manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.\n\n### Load-Bearing Included Studies\n\n- Additional corpus sources included animal/preclinical evidence; Greilberger 2023; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.\n- Greilberger 2022; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.\n- Greilberger 2021; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.\n- Wu 2022; tier=B2; directness=indirect; endpoint=immune inflammation; direction=unclear; representative statistic=P < 0.05.\n- Tomaszewska 2020; tier=B2; directness=indirect; endpoint=muscle function; direction=null.\n- Wu 2021; tier=B2; directness=indirect; endpoint=immune inflammation; direction=unclear; representative statistic=P < 0.05.\n- Dhat 2023; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.\n- Tian 2023; tier=B2; directness=indirect; endpoint=skeletal fracture bone; direction=null; representative statistic=P > 0.05.\n- Chen 2018; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P = 0.013.\n- Chen 2019; tier=B2; directness=indirect; endpoint=muscle function; direction=null; representative statistic=P > 0.05.\n\n### Source Classification Map\n\nEach retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.\n\n- Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=466.\n- Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=335.\n- Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=188.\n- Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio ): outcome=immune inflammation; directness=indirect; tier=B2; direction=unclear; claims=155.\n- Alpha-Ketoglutarate: An Effective Feed Supplement in Improving Bone Metabolism and Muscle Quality of Laying Hens: A Preliminary Study: outcome=muscle function; directness=indirect; tier=B2; direction=null; claims=80.\n- Evaluation of Alpha-Ketoglutarate Supplementation on the Improvement of Intestinal Antioxidant Capacity and Immune Response in Songpu Mirror Carp ( Cyprinus carpio ) After Infection With Aeromonas hydrophila: outcome=immune inflammation; directness=indirect; tier=B2; direction=unclear; claims=79.\n- Epigenetic modifier alpha-ketoglutarate modulates aberrant gene body methylation and hydroxymethylation marks in diabetic heart: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=57.\n- Dietary Alpha-Ketoglutarate Supplementation Improves Bone Growth, Phosphorus Digestion, and Growth Performance in Piglets: outcome=skeletal fracture bone; directness=indirect; tier=B2; direction=null; claims=54.\n- Alpha-Ketoglutarate in Low-Protein Diets for Growing Pigs: Effects on Cecal Microbial Communities and Parameters of Microbial Metabolism: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=50.\n- Effects of Dietary Supplementation of Alpha-Ketoglutarate in a Low-Protein Diet on Fatty Acid Composition and Lipid Metabolism Related Gene Expression in Muscles of Growing Pigs: outcome=muscle function; directness=indirect; tier=B2; direction=null; claims=46.\n- Effects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=46.\n- Effects of Long-Term Cultivation on Medium with Alpha-Ketoglutarate Supplementation on Metabolic Processes of Saccharomyces cerevisiae: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=45.\n- Alpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway: outcome=mortality survival; directness=indirect; tier=B2; direction=null; claims=44.\n- Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations: outcome=skeletal fracture bone; directness=indirect; tier=B2; direction=null; claims=44.\n- Glutaminase 1 regulates the release of extracellular vesicles during neuroinflammation through key metabolic intermediate alpha-ketoglutarate: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=42.\n- Replication Study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=41.\n- Alpha-ketoglutarate ameliorates abdominal aortic aneurysm via inhibiting PXDN/HOCL/ERK signaling pathways: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=36.\n- Elevation of Intracellular Alpha-Ketoglutarate Levels Inhibits Osteoclastogenesis by Suppressing the NF-κB Signaling Pathway in a PHD1-Dependent Manner: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=30.\n- Alpha-ketoglutarate enhances adipose-derived stem cells survival in wound healing by hypoxia-inducible factor 1-alpha-mediated redox homeostasis and glycogen-dependent bioenergetics: outcome=immune; directness=indirect; tier=B2; direction=null; claims=29.\n- Alpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=28.\n- Administration of alpha-ketoglutarate improves epithelial restitution under stress injury in early-weaning piglets: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=26.\n- Development and First-in-Human Translation of Hyperpolarized [1- 13 C]Alpha-Ketoglutarate MR Spectroscopy in the Brain: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=26.\n- Effects of Alpha-Ketoglutarate Supplementation on Growth Performance, Diarrhea Incidence, Plasma Amino Acid, and Nutrient Digestibility in Weaned Piglets: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=25.\n- Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=21.\n- Cholesterol Content, Fatty Acid Profile and Health Lipid Indices in the Egg Yolk of Eggs from Hens at the End of the Laying Cycle, Following Alpha-Ketoglutarate Supplementation: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=18.\n- Effects of Dietary Alpha-Ketoglutarate Supplementation on Diarrhea Incidence and Nutrient Digestibility in Weaned Piglets Fed Low-Protein Diets: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=14.\n- Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways: outcome=muscle function; directness=indirect; tier=B2; direction=unclear; claims=13.\n- Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=13.\n- Alpha-Ketoglutarate: A Potential Inner Mitochondrial and Cytosolic Protector against Peroxynitrite and Peroxynitrite-Induced Nitration?: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=12.\n- Lack of association of the alpha-ketoglutarate-dependent dioxygenase (FTO) gene polymorphisms with pulmonary tuberculosis risk: a systematic review and meta-analysis: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=11.\n- AKT signaling is associated with epigenetic reprogramming via the upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=11.\n- The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=10.\n- Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=null; claims=10.\n- Foliar application of alpha-ketoglutarate plus nitrogen improves drought resistance in soybean ( Glycine max L. Merr. ): outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=9.\n- Alpha Ketoglutarate Downregulates the Neutral Endopeptidase and Enhances the Growth Inhibitory Activity of Thiorphan in Highly Aggressive Osteosarcoma Cells: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=8.\n- Repurposing FDA-approved drugs to find a novel inhibitor of alpha-ketoglutarate-dependent dioxygenase FTO to treat esophageal cancer: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=8.\n- A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=8.\n- D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=6.\n- Comparative Study of Various Delivery Methods for the Supply of Alpha-Ketoglutarate to the Neural Cells for Tissue Engineering: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=5.\n- Alpha-Ketoglutarate Drives an Osteogenic and Extracellular Matrix Gene Program in Periodontal Ligament Fibroblasts via Selective Reduction of H3K27me3: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=2.\n\n### Classification Criteria\n\n- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\n- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.\n- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.\n- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.\n\n### Load-Bearing Tensions\n\n- In animal/preclinical evidence, severity 4 null vs positive: An 2021 vs Iwaniak 2022; An 2021 (positive on safety comorbidity) vs Iwaniak 2022 (null on safety comorbidity) — partial conflict\n\n## Conclusion\n\nAdditional corpus sources included animal/preclinical evidence; additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Takemura 2025, Sun 2025, Khamineh 2026, Dilimulati 2026, He 2017, Kim 2026, He 2017b, Sun 2025b, Tomaszewska 2021, Sun 2025c, Demidenko 2021, Greilberger 2021b, Soreze 2013, Csaban 2021, Gai 2022, Mohammadi 2025, Stuart 2014, Mizerska-Kowalska 2022, Lin 2015, Vishnoi 2013, Zhang 2020, Studenski 2011, Perera 2006, ADA 2024, WHO 2000, Cruz-Jentoft 2019, Ioannidis 2005.\n\n## References\n\n- **Greilberger 2023.** _Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF._ Current Issues in Molecular Biology, 2023. DOI: 10.3390/cimb45080410. PMID: 37623229.\n- **Greilberger 2022.** _Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways._ International Journal of Molecular Sciences, 2022. DOI: 10.3390/ijms23169034. PMID: 36012295.\n- **Qiu 2025.** _Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice._ Frontiers in Pharmacology, 2025. DOI: 10.3389/fphar.2025.1656473. PMID: 41181587.\n- **Greilberger 2021.** _Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells._ Antioxidants, 2021. DOI: 10.3390/antiox10111804. PMID: 34829675.\n- **Wu 2022.** _Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )._ Frontiers in Immunology, 2022. DOI: 10.3389/fimmu.2022.915657. PMID: 35720284.\n- **An 2021.** _Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice._ Redox Biology, 2021. DOI: 10.1016/j.redox.2021.102088. PMID: 34364218.\n- **Tomaszewska 2020.** _Alpha-Ketoglutarate: An Effective Feed Supplement in Improving Bone Metabolism and Muscle Quality of Laying Hens: A Preliminary Study._ Animals : an Open Access Journal from MDPI, 2020. DOI: 10.3390/ani10122420. PMID: 33348724.\n- **Wu 2021.** _Evaluation of Alpha-Ketoglutarate Supplementation on the Improvement of Intestinal Antioxidant Capacity and Immune Response in Songpu Mirror Carp ( Cyprinus carpio ) After Infection With Aeromonas hydrophila._ Frontiers in Immunology, 2021. DOI: 10.3389/fimmu.2021.690234. PMID: 34220849.\n- **Iwaniak 2022.** _Dietary Alpha-Ketoglutarate Partially Abolishes Adverse Changes in the Small Intestine after Gastric Bypass Surgery in a Rat Model._ Nutrients, 2022. DOI: 10.3390/nu14102062. PMID: 35631203.\n- **Takemura 2025.** _Alpha-ketoglutarate supplementation improves hyperglycemia and attenuates the decrease in GLUT4 and PGC-1α proteins in adipose tissue of streptozotocin-high-fat diet-induced diabetic mice._ Journal of Nutritional Science, 2025. DOI: 10.1017/jns.2025.10059. PMID: 41496859.\n- **Sun 2025.** _Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia._ Nature Communications, 2025. DOI: 10.1038/s41467-025-64360-8. PMID: 41120320.\n- **Kalawaj 2020.** _Alpha Ketoglutarate Exerts In Vitro Anti-Osteosarcoma Effects through Inhibition of Cell Proliferation, Induction of Apoptosis via the JNK and Caspase 9-Dependent Mechanism, and Suppression of TGF-β and VEGF Production and Metastatic Potential of Cells._ International Journal of Molecular Sciences, 2020. DOI: 10.3390/ijms21249406. PMID: 33321940.\n- **Dhat 2023.** _Epigenetic modifier alpha-ketoglutarate modulates aberrant gene body methylation and hydroxymethylation marks in diabetic heart._ Epigenetics & Chromatin, 2023. DOI: 10.1186/s13072-023-00489-4. PMID: 37101286.\n- **Tian 2023.** _Dietary Alpha-Ketoglutarate Supplementation Improves Bone Growth, Phosphorus Digestion, and Growth Performance in Piglets._ Animals : an Open Access Journal from MDPI, 2023. DOI: 10.3390/ani13040569. PMID: 36830356.\n- **Chen 2018.** _Alpha-Ketoglutarate in Low-Protein Diets for Growing Pigs: Effects on Cecal Microbial Communities and Parameters of Microbial Metabolism._ Frontiers in Microbiology, 2018. DOI: 10.3389/fmicb.2018.01057. PMID: 29904374.\n- **Khamineh 2026.** _Effects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation._ Cells, 2026. DOI: 10.3390/cells15030281. PMID: 41677644.\n- **Chen 2019.** _Effects of Dietary Supplementation of Alpha-Ketoglutarate in a Low-Protein Diet on Fatty Acid Composition and Lipid Metabolism Related Gene Expression in Muscles of Growing Pigs._ Animals : an Open Access Journal from MDPI, 2019. DOI: 10.3390/ani9100838. PMID: 31640132.\n- **Burdyliuk 2017.** _Effects of Long-Term Cultivation on Medium with Alpha-Ketoglutarate Supplementation on Metabolic Processes of Saccharomyces cerevisiae._ Journal of Aging Research, 2017. DOI: 10.1155/2017/8754879. PMID: 29181198.\n- **Huang 2025.** _Alpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway._ Cell Regeneration, 2025. DOI: 10.1186/s13619-025-00264-8. PMID: 41428315.\n- **Wang 2020.** _Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations._ Nature Communications, 2020. DOI: 10.1038/s41467-020-19360-1. PMID: 33154378.\n- **Wu 2018.** _Glutaminase 1 regulates the release of extracellular vesicles during neuroinflammation through key metabolic intermediate alpha-ketoglutarate._ Journal of Neuroinflammation, 2018. DOI: 10.1186/s12974-018-1120-x. PMID: 29540215.\n- **Showalter 2017.** _Replication Study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate._ eLife, 2017. DOI: 10.7554/eLife.26030. PMID: 28653623.\n- **Liu 2022.** _Alpha-ketoglutarate ameliorates abdominal aortic aneurysm via inhibiting PXDN/HOCL/ERK signaling pathways._ Journal of Translational Medicine, 2022. DOI: 10.1186/s12967-022-03659-2. PMID: 36209172.\n- **Sandalova 2023.** _Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)—intervention study protocol._ GeroScience, 2023. DOI: 10.1007/s11357-023-00813-6. PMID: 37217632.\n- **Tian 2023b.** _Elevation of Intracellular Alpha-Ketoglutarate Levels Inhibits Osteoclastogenesis by Suppressing the NF-κB Signaling Pathway in a PHD1-Dependent Manner._ Nutrients, 2023. DOI: 10.3390/nu15030701. PMID: 36771407.\n- **Dilimulati 2026.** _Alpha-ketoglutarate enhances adipose-derived stem cells survival in wound healing by hypoxia-inducible factor 1-alpha-mediated redox homeostasis and glycogen-dependent bioenergetics._ World Journal of Stem Cells, 2026. DOI: 10.4252/wjsc.v18.i2.113694. PMID: 41808885.\n- **He 2017.** _Alpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway._ Oncotarget, 2017. DOI: 10.18632/oncotarget.16875. PMID: 29262538.\n- **Kim 2026.** _Development and First-in-Human Translation of Hyperpolarized [1-13 C]Alpha-Ketoglutarate MR Spectroscopy in the Brain._ Sensors (Basel, Switzerland), 2026. DOI: 10.3390/s26092753. PMID: 42122474.\n- **He 2017b.** _Administration of alpha-ketoglutarate improves epithelial restitution under stress injury in early-weaning piglets._ Oncotarget, 2017. DOI: 10.18632/oncotarget.20555. PMID: 29190890.\n- **Sun 2025b.** _Effects of Alpha-Ketoglutarate Supplementation on Growth Performance, Diarrhea Incidence, Plasma Amino Acid, and Nutrient Digestibility in Weaned Piglets._ Animals : an Open Access Journal from MDPI, 2025. DOI: 10.3390/ani15121723. PMID: 40564275.\n- **Ruiz 2023.** _Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia._ Genes, 2023. DOI: 10.3390/genes14091818. PMID: 37761958.\n- **Bayliak 2017.** _Growth on Alpha-Ketoglutarate Increases Oxidative Stress Resistance in the Yeast Saccharomyces cerevisiae._ International Journal of Microbiology, 2017. DOI: 10.1155/2017/5792192. PMID: 28154578.\n- **Tomaszewska 2021.** _Cholesterol Content, Fatty Acid Profile and Health Lipid Indices in the Egg Yolk of Eggs from Hens at the End of the Laying Cycle, Following Alpha-Ketoglutarate Supplementation._ Foods, 2021. DOI: 10.3390/foods10030596. PMID: 33799887.\n- **Sun 2025c.** _Effects of Dietary Alpha-Ketoglutarate Supplementation on Diarrhea Incidence and Nutrient Digestibility in Weaned Piglets Fed Low-Protein Diets._ Veterinary Sciences, 2025. DOI: 10.3390/vetsci12121163. PMID: 41472143.\n- **Iniguez 2022.** _Alpha-Ketoglutarate Promotes Goblet Cell Differentiation and Alters Urea Cycle Metabolites in DSS-Induced Colitis Mice._ Nutrients, 2022. DOI: 10.3390/nu14061148. PMID: 35334805.\n- **Cai 2016.** _Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways._ Scientific Reports, 2016. DOI: 10.1038/srep26802. PMID: 27225984.\n- **Demidenko 2021.** _Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test._ Aging (Albany NY), 2021. DOI: 10.18632/aging.203736. PMID: 34847066.\n- **Greilberger 2021b.** _Alpha-Ketoglutarate: A Potential Inner Mitochondrial and Cytosolic Protector against Peroxynitrite and Peroxynitrite-Induced Nitration?._ Antioxidants, 2021. DOI: 10.3390/antiox10091501. PMID: 34573133.\n- **Lamichhane 2023.** _Lack of association of the alpha-ketoglutarate-dependent dioxygenase (FTO) gene polymorphisms with pulmonary tuberculosis risk: a systematic review and meta-analysis._ Annals of Medicine and Surgery, 2023. DOI: 10.1097/MS9.0000000000001188. PMID: 37811091.\n- **Sekita 2021.** _AKT signaling is associated with epigenetic reprogramming via the upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation._ Stem Cell Research & Therapy, 2021. DOI: 10.1186/s13287-021-02578-1. PMID: 34563253.\n- **Soreze 2013.** _Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase._ Orphanet Journal of Rare Diseases, 2013. DOI: 10.1186/1750-1172-8-192. PMID: 24341803.\n- **Csaban 2021.** _The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease._ Life, 2021. DOI: 10.3390/life11040321. PMID: 33917565.\n- **Gai 2022.** _Foliar application of alpha-ketoglutarate plus nitrogen improves drought resistance in soybean ( Glycine max L. Merr. )._ Scientific Reports, 2022. DOI: 10.1038/s41598-022-18660-4. PMID: 36002532.\n- **Mohammadi 2025.** _Repurposing FDA-approved drugs to find a novel inhibitor of alpha-ketoglutarate-dependent dioxygenase FTO to treat esophageal cancer._ Research in Pharmaceutical Sciences, 2025. DOI: 10.4103/RPS.RPS_9_25. PMID: 40687281.\n- **Stuart 2014.** _A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process._ Cancer & Metabolism, 2014. DOI: 10.1186/2049-3002-2-4. PMID: 24612826.\n- **Mizerska-Kowalska 2022.** _Alpha Ketoglutarate Downregulates the Neutral Endopeptidase and Enhances the Growth Inhibitory Activity of Thiorphan in Highly Aggressive Osteosarcoma Cells._ Molecules, 2022. DOI: 10.3390/molecules28010097. PMID: 36615293.\n- **Lin 2015.** _D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2._ Nature Communications, 2015. DOI: 10.1038/ncomms8768. PMID: 26178471.\n- **Vishnoi 2013.** _Comparative Study of Various Delivery Methods for the Supply of Alpha-Ketoglutarate to the Neural Cells for Tissue Engineering._ BioMed Research International, 2013. DOI: 10.1155/2013/294679. PMID: 23878803.\n- **Hasegawa 2026.** _Alpha-Ketoglutarate Drives an Osteogenic and Extracellular Matrix Gene Program in Periodontal Ligament Fibroblasts via Selective Reduction of H3K27me3._ Biology, 2026. DOI: 10.3390/biology15050372. PMID: 41823800.\n- **Wu 2016.** _Alpha-Ketoglutarate: Physiological Functions and Applications._ Biomolecules & Therapeutics, 2016. DOI: 10.4062/biomolther.2015.078. PMID: 26759695.\n- **Zhang 2020.** _Alpha-ketoglutarate utilization in Saccharomyces cerevisiae : transport, compartmentation and catabolism._ Scientific Reports, 2020. DOI: 10.1038/s41598-020-69178-6. PMID: 32733060.\n- **Doroftei 2024.** _A scoping review regarding reproductive capacity modulation based on alpha-ketoglutarate supplementation._ Reproduction (Cambridge, England), 2024. DOI: 10.1530/REP-24-0137. PMID: 39189990.\n- **Fiehn 2016.** _Registered report: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate._ eLife, 2016. DOI: 10.7554/eLife.12626. PMID: 26943899.\n\n### Background References\n\n*Canonical reference values and methodological references cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).*\n\n- **Studenski 2011.** _Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA. 2011;305(1):50-58._ DOI: 10.1001/jama.2010.1923. PMID: 21205966.\n- **Perera 2006.** _Perera S, Mody SH, Woodman RC, Studenski SA. Meaningful change and responsiveness in common physical performance measures in older adults. J Am Geriatr Soc. 2006;54(5):743-749._ DOI: 10.1111/j.1532-5415.2006.00701.x. PMID: 16696738.\n- **ADA 2024.** _American Diabetes Association. Standards of Care in Diabetes. Diabetes Care. 2024;47(Suppl 1)._ DOI: 10.2337/dc24-S006.\n- **WHO 2000.** _World Health Organization. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series 894. 2000._ PMID: 11234459.\n- **Cruz-Jentoft 2019.** _Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(1):16-31._ DOI: 10.1093/ageing/afy169. PMID: 30312372.\n- **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ (methodological reference) DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.\n","metadata":{"abstract":"Evidence-honesty note: 46/53 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on Alpha-ketoglutarate across 53 accepted source papers and 2847 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 45 adjacent clinical sources, and 8 mechanistic or model-system sources, with 1 cross-study disagreement across the evidence base. Positive study-level signals are summarized in the safety and comorbidity outcome class, null signals in the contextual adjacent evidence, cardiometabolic and mechanism outcome classes, and negative signals in no dominant outcome class.","article_type":"rapid_evidence_synthesis","counts":{"retrieved_count":53,"selected_count":53,"review_like_count":2,"primary_like_count":51,"year_start":2013,"year_end":2026},"gates":[{"name":"leakage_blocker","passed":true,"reason":"final body must not contain reviewer or pipeline leakage"},{"name":"count_reconciliation","passed":true,"reason":"selected count must equal review-like + primary-like counts"},{"name":"core_claims_resolved","passed":true,"reason":"title/abstract/conclusion claims must not remain unresolved"}],"author_agent_id":"agent-v3-full-paper-live","integrity":{"recommendation":"pass","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null},"public_visibility":"listed","source_submission_id":"5e389f1a-19f8-469e-b6ec-4f1e60c38dc4","submission_identity_key":"sha256:797e93f438fab4c29953ca5b9f8ed3ebc1d7cd1f1a34f32540663c8b5c0d2332","submission_payload_hash":"sha256:20e26353a028662846684153cfe4a87effc387d29ddc3e1be52db546d06c0918","content_hash":"sha256:259fc5c5201345c13b9fef14f0b856e34339657122e85c238bac7b91bb4b1d3d","source_citation_hash":"sha256:f76b65a03929fd37f440cb8707fd127098e608bc360694e24c1f252900b66024","author_signature":"sha256:259fc5c5201345c13b9fef14f0b856e34339657122e85c238bac7b91bb4b1d3d","run_id":"synthesis-alpha_ketoglutarate_akg-v06-DAILY-2026-06-20T04-00-35Z","topic":"alpha_ketoglutarate_akg","domain_slug":"longevity","category":"longevity","identity_source":"api_key","authenticated_agent_id":"agent-v3-full-paper-live","doi":"10.17605/OSF.IO/84YSJ","doi_status":"minted","osf_status":"minted","osf_project_id":"p8nk6","osf_guid":"84ysj","osf_url":"https://osf.io/84ysj/","osf":{"enabled":true,"status":"minted","project_id":"p8nk6","guid":"84ysj","url":"https://osf.io/84ysj/","doi":"10.17605/OSF.IO/84YSJ"},"prompt_version":"editor-v1-clean-runtime","provider":"reviewer-panel","model":"MiniMax-M3|google/gemma-4-31b-it|mistralai/mistral-small-2603","tokens_in":0,"tokens_out":0,"cost_usd":0.0,"osf_auth_source":"oauth_agent_token","dw_artifact_id":"claim_dfb61cdfc5da412e","dw_chain_url":"https://provenance.researka.org/artifacts/claim_dfb61cdfc5da412e/chain","dw_api_chain_url":"https://provenance.researka.org/api/artifacts/claim_dfb61cdfc5da412e/chain","dw_source_artifact_id":"source_46b4509576424530","dw_input_artifact_ids":["source_7984f85215bb4c85","source_8c24d557c6f64dc5","source_eb0ead3c41db4ae1","source_d0ec4f4243c84546","source_1197d7e17eb642a1","source_5d1698b7319a4397"],"dw_step_id":"step_ce7d2c0c6d8f4fd7","dw_step_hash":"3b6491f86f3f3743eb00b75f7203462ab82a6c2ec3f24f6b88c1aafc28102f8e","dw_status":"registered","sha256":"sha256:37328d5aaed91b76091d8226a3bde183f040e369d69d14c5e30c4b8ec94e1bb5"},"created_at":"2026-06-20T10:19:25.455198+04:00"},"sidecars":[{"name":"citation_traces.json","media_type":"application/json","content":{"publication_id":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","traces":[{"claim_id":"claim_1","claim":"Evidence-honesty note: 46/53 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on Alpha-ketoglutarate across 53 accepted source papers and 2847 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 45 adjacent clinical sources, and 8 mechanistic or model-system sources, with 1 cross-study disagreement across the evidence base. Positive study-level signals are summarized in the safety and comorbidity outcome class, null signals in the contextual adjacent evidence, cardiometabolic and mechanism outcome classes, and negative signals in no dominant outcome class.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"Evidence-honesty note: 46/53 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"This paper synthesizes evidence on Alpha-ketoglutarate across 53 accepted source papers and 2847 high-confidence extracted claims.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 45 adjacent clinical sources, and 8 mechanistic or model-system sources, with 1 cross-study disagreement across the evidence base.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"Positive study-level signals are summarized in the safety and comorbidity outcome class, null signals in the contextual adjacent evidence, cardiometabolic and mechanism outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"The conclusion is that Alpha-ketoglutarate remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","claim":"This manuscript is reported as a Evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-alpha_ketoglutarate_akg-v06-DAILY-2026-06-20T04-00-35Z`.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","claim":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","claim":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses).","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_10","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, immune and inflammation, immune and inflammation, mechanism, mortality and survival, muscle function, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","claim":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"| Contextual Adjacent Evidence | n=33; claims=1572 | no extracted directional signal in 31/33 sources | 30 indirect; 1 protocol; 2 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","claim":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","claim":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"33 included sources were assigned to this outcome class. Directional coding: null=31, unclear=2. Directness coding: indirect=30, protocol=1, review=2.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"4 included sources were assigned to this outcome class. Directional coding: mixed=1, null=3. Directness coding: mechanistic=4.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=1, mechanistic=2.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","claim":"3 included sources were assigned to this outcome class. Directional coding: null=1, unclear=2. Directness coding: indirect=3.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_20","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_21","claim":"Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","claim":"3 included sources were assigned to this outcome class. Directional coding: null=2, unclear=1. Directness coding: indirect=3.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_23","claim":"2 included sources were assigned to this outcome class. Directional coding: null=1, positive=1. Directness coding: mechanistic=2.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_24","claim":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_25","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_26","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_27","claim":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_28","claim":"Additional corpus sources included animal/preclinical evidence; the most consequential scope gap is the near-absence of long-term, hard-outcome randomized evidence in non-diabetic, community-dwelling adults. Consequently, every human claim in this synthesis that is anchored to a clinical event — whether survival in flap surgery (Huang 2025), aneurysm progression (Liu 2022), or diabetic cardiomyopathy (Dhat 2023) — is supported only by indirect, indirect-directness sources, and the headline conclusions cannot be transported to general adult populations without a dedicated long-term mortality RCT, of which the corpus contains none.","citation_support":[{"source_id":"source_13","study":"Epigenetic modifier alpha-ketoglutarate modulates aberrant gene body methylation and hydroxymethylation marks in diabetic heart","doi":"10.1186/s13072-023-00489-4","url":"https://doi.org/10.1186/s13072-023-00489-4","support_kind":"cited_as_match","cited_as":"Dhat 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetic patients. Hyperglycemic myocardial microenvironment significantly alters chromatin architecture and the transcriptome, resulting in aberrant activation of signaling pathways in a diabetic heart. Epigenetic marks play vital roles in transcriptional reprogramming during the development of DCM. The current study is aimed to profile genome-wide DNA (hydroxy)methylation patterns in the hearts of control and streptozotocin (STZ)-induced diabetic rats and decipher the effect of modulation of DNA methylation by alpha-ketoglutarate (AKG), a TET enzyme cofactor, on the progression of DCM. METHODS: Diabetes was induced in male adult Wistar rats with an intraperitoneal injection of STZ. Diabetic and vehicle control animals were randomly divided into groups with/without AKG treatment. Cardiac function was monitored by performing cardiac catheterization. Global methylation (5mC) and hydroxymethylation (5hmC) patterns were mapped in the Left ventricular tissue of control and diabetic rats with the help of an enrichment-based (h)MEDIP-sequencing technique by using antibodies specific for 5mC and 5hmC."}],"candidate_sources":[]},{"claim_id":"claim_29","claim":"Finally, the corpus contains a mechanism-to-clinic gap for the most clinically relevant claim, namely that αKG influences cardiovascular, skeletal, and longevity outcomes in humans. Mechanistic plausibility is densely documented: PI3K/Akt/HIF-1α angiogenesis in skin flaps (Huang 2025), PHD1-dependent NF-κB suppression in osteoclastogenesis (Tian 2023b), epigenetic H3K27me3 reduction in periodontal regeneration (Hasegawa 2026), histone methylation rescue in age-related osteoporosis (Wang 2020), and Tnfrsf12a/Fn14 histone-modification protection against cancer cachexia (Ruiz 2023). However, each of these sources is either preclinical (An 2021, Iwaniak 2022, Bayliak 2017, Kalawaj 2020), mechanistic-only (Iniguez 2022, Cai 2016, Qiu 2025, Sekita 2021, Wu 2018, Burdyliuk 2017, Showalter 2017, Fiehn 2016), or review/protocol-level (Sandalova 2023, Lamichhane 2023, Doroftei 2024, Wu 2016). The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. Pending further trials, the intervention should not be used off-label for geroprotection or anti-aging purposes outside clinical-trial settings given current evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","citation_support":[{"source_id":"source_3","study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","support_kind":"cited_as_match","cited_as":"Qiu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice."},{"source_id":"source_12","study":"Alpha Ketoglutarate Exerts In Vitro Anti-Osteosarcoma Effects through Inhibition of Cell Proliferation, Induction of Apoptosis via the JNK and Caspase 9-Dependent Mechanism, and Suppression of TGF-β and VEGF Production and Metastatic Potential of Cells","doi":"10.3390/ijms21249406","url":"https://doi.org/10.3390/ijms21249406","support_kind":"cited_as_match","cited_as":"Kalawaj 2020","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Osteosarcoma (OS) is the most common type of primary bone tumor. Currently, there are limited treatment options for metastatic OS. Alpha-ketoglutarate (AKG), i.e., a multifunctional intermediate of the Krebs cycle, is one of the central metabolic regulators of tumor fate and plays an important role in cancerogenesis and tumor progression. There is growing evidence suggesting that AKG may represent a novel adjuvant therapeutic opportunity in anti-cancer therapy. The present study was intended to check whether supplementation of Saos-2 and HOS osteosarcoma cell lines (harboring a TP53 mutation) with exogenous AKG exerted an anti-cancer effect. The results revealed that AKG inhibited the proliferation of both OS cell lines in a concentration-dependent manner. As evidenced by flow cytometry, AKG blocked cell cycle progression at the G 1 stage in both cell lines, which was accompanied by a decreased level of cyclin D1 in HOS and increased expression of p21 Waf1/Cip1 protein in Saos-2 cells (evaluated with the ELISA method). Moreover, AKG induced apoptotic cell death and caspase-3 activation in both OS cell lines (determined by cytometric analysis)."},{"source_id":"source_16","study":"Alpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway","doi":"10.1186/s13619-025-00264-8","url":"https://doi.org/10.1186/s13619-025-00264-8","support_kind":"cited_as_match","cited_as":"Huang 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Random-pattern skin flaps are widely employed in tissue reconstruction, however, their survival is frequently hindered by ischemia, leading to necrosis. Metabolic alterations have been implicated in playing critical roles in angiogenesis during tissue repair. Using RNA sequencing analysis in a mouse model, we identified significant disruptions in glutamine metabolism, which substantially impaired angiogenesis within random-pattern skin flaps. Although local glutamine repletion failed to alleviate ischemia, administering α-ketoglutarate (α-KG) markedly promoted angiogenesis, as evidenced at both gene and protein levels. In human umbilical vein endothelial cells,α-KG enhanced the stability of hypoxia-inducible factor (HIF-1) alpha through activation of the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. Notably, α-KG treatment improved flap viability by augmenting blood perfusion, an effect correlated with upregulation of vascular endothelial growth factor expression."},{"source_id":"source_17","study":"Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations","doi":"10.1038/s41467-020-19360-1","url":"https://doi.org/10.1038/s41467-020-19360-1","support_kind":"cited_as_match","cited_as":"Wang 2020","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Age-related osteoporosis is characterized by the deterioration in bone volume and strength, partly due to the dysfunction of bone marrow mesenchymal stromal/stem cells (MSCs) during aging. Alpha-ketoglutarate (αKG) is an essential intermediate in the tricarboxylic acid (TCA) cycle. Studies have revealed that αKG extends the lifespan of worms and maintains the pluripotency of embryonic stem cells (ESCs). Here, we show that the administration of αKG increases the bone mass of aged mice, attenuates age-related bone loss, and accelerates bone regeneration of aged rodents. αKG ameliorates the senescence-associated (SA) phenotypes of bone marrow MSCs derived from aged mice, as well as promoting their proliferation, colony formation, migration, and osteogenic potential. Mechanistically, αKG decreases the accumulations of H3K9me3 and H3K27me3, and subsequently upregulates BMP signaling and Nanog expression. Collectively, our findings illuminate the role of αKG in rejuvenating MSCs and ameliorating age-related osteoporosis, with a promising therapeutic potential in age-related diseases."},{"source_id":"source_19","study":"Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)—intervention study protocol","doi":"10.1007/s11357-023-00813-6","url":"https://doi.org/10.1007/s11357-023-00813-6","support_kind":"cited_as_match","cited_as":"Sandalova 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Targeting molecular processes of aging will enable people to live healthier and longer lives by preventing age-related diseases. Geroprotectors are compounds with the potential to increase healthspan and lifespan. Even though many of them have been tested in animal models, the translation to humans is limited. Alpha-Ketoglutarate (AKG) has been studied widely in model animals, but there are few studies testing its geroprotective properties in humans. ABLE is a double blinded placebo-controlled randomized trial (RCT) of 1 g sustained release Ca-AKG versus placebo for 6 months of intervention and 3 months follow up including 120 40-60-year-old healthy individuals with a higher DNA methylation age compared to their chronological age. The primary outcome is the decrease in DNA methylation age from baseline to the end of the intervention. A total of 120 participants will be randomized to receive either sustained release Ca-AKG or placebo. Secondary outcomes include changes in the inflammatory and metabolic parameters in blood, handgrip strength and leg extension strength, arterial stiffness, skin autofluorescence, and aerobic capacity from baseline to 3 months, 6 months, and 9 months."},{"source_id":"source_20","study":"Elevation of Intracellular Alpha-Ketoglutarate Levels Inhibits Osteoclastogenesis by Suppressing the NF-κB Signaling Pathway in a PHD1-Dependent Manner","doi":"10.3390/nu15030701","url":"https://doi.org/10.3390/nu15030701","support_kind":"cited_as_match","cited_as":"Tian 2023b","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Age-related osteoporosis, a high-prevalence disease in the aged population, is generally attributed to the excessive activity of osteoclasts. Most approved drugs treat osteoporosis by inhibition of osteoclasts. Although in vivo studies have shown that alpha-ketoglutarate (AKG), an intermediate in the TCA cycle, can ameliorate age-related osteoporosis, the effects of AKG on osteoclastogenesis and the underlying mechanism of its action have not been studied yet. Here, we showed that the elevation of intracellular AKG levels by supplementing dimethyl AKG (DM-AKG, a cell-permeable derivative of AKG) inhibits the receptor activator of NF-κB ligand (RANKL)-induced osteoclasts differentiation from primary bone marrow-derived macrophages (BMMs) and RAW264.7 cells in vitro. We further found that DM-AKG treatment suppresses NF-κB signaling and oxidative phosphorylation (OXPHOS) during RANKL-induced osteoclastogenesis in RAW264.7 cells. Interestingly, dimethyl oxalylglycine (DMOG), an AKG competitive inhibitor of AKG-dependent prolyl hydroxylases (PHDs), antagonizes the suppression of the RANKL-activated NF-κB signaling pathway caused by DM-AKG treatment."},{"source_id":"source_24","study":"Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia","doi":"10.3390/genes14091818","url":"https://doi.org/10.3390/genes14091818","support_kind":"cited_as_match","cited_as":"Ruiz 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Previous studies have shown that inhibition of TNF family member FN14 (gene: TNFRSF12A ) in colon tumors decreases inflammatory cytokine expression and mitigates cancer-induced cachexia. However, the molecular mechanisms underlying the regulation of FN14 expression remain unclear. Tumor microenvironments are often devoid of nutrients and oxygen, yet how the cachexic response relates to the tumor microenvironment and, importantly, nutrient stress is unknown. Here, we looked at the connections between metabolic stress and FN14 expression. We found that TNFRSF12A expression was transcriptionally induced during glutamine deprivation in cancer cell lines. We also show that the downstream glutaminolysis metabolite, alpha-ketoglutarate (aKG), is sufficient to rescue glutamine-deprivation-promoted TNFRSF12A induction. As aKG is a co-factor for histone de-methylase, we looked at histone methylation and found that histone H3K4me3 at the Tnfrsf12a promoter is increased under glutamine-deprived conditions and rescued via DM-aKG supplementation. Finally, expression of Tnfrsf12a and cachexia-induced weight loss can be inhibited in vivo by DM-aKG in a mouse cancer cachexia model."},{"source_id":"source_36","study":"Alpha-Ketoglutarate Drives an Osteogenic and Extracellular Matrix Gene Program in Periodontal Ligament Fibroblasts via Selective Reduction of H3K27me3","doi":"10.3390/biology15050372","url":"https://doi.org/10.3390/biology15050372","support_kind":"cited_as_match","cited_as":"Hasegawa 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Periodontal disease is a chronic inflammatory condition that destroys tooth-supporting tissues, particularly the alveolar bone and the periodontal ligament, and effective regenerative therapies remain limited. While the role of metabolic-epigenomic crosstalk in determining cell fate is well established, the specific mechanism by which a tricarboxylic acid (TCA) cycle metabolite can modulate chromatin regulation to promote periodontal regeneration remains to be elucidated. The impact of one TCA cycle metabolite, alpha-ketoglutarate (α-KG), was examined in human periodontal ligament fibroblasts cultured under osteogenic induction and profiled by ALP assays, RT-qPCR, analyses of multiple histone modifications, ATAC-seq, and RNA-seq. α-KG increased ALP activity and upregulated genes associated with osteogenesis and the extracellular matrix (ECM). ATAC-seq revealed minimal genome-wide accessibility changes, whereas histone analyses showed reduced H3K27me3, consistent with an epigenetic mechanism that does not require extensive chromatin opening."},{"source_id":"source_42","study":"Glutaminase 1 regulates the release of extracellular vesicles during neuroinflammation through key metabolic intermediate alpha-ketoglutarate","doi":"10.1186/s12974-018-1120-x","url":"https://doi.org/10.1186/s12974-018-1120-x","support_kind":"cited_as_match","cited_as":"Wu 2018","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Extracellular vesicles (EVs) are important in the intercellular communication of the central nervous system, and their release is increased during neuroinflammation. Our previous data demonstrated an increased release of EVs during HIV-1 infection and immune activation in glial cells. However, the molecular mechanism by which infection and inflammation increase EV release remains unknown. In the current study, we investigated the role of glutaminase 1 (GLS1)-mediated glutaminolysis and the production of a key metabolic intermediate α-ketoglutarate on EV release. METHODS: Human monocyte-derived macrophage primary cultures and a BV2 microglia cell line were used to represent the innate immune cells in the CNS. Transmission electron microscopy, nanoparticle tracking analysis, and Western blots were used to determine the EV regulation. GLS1 overexpression was performed using an adenovirus vector in vitro and transgenic mouse models in vivo. Data were evaluated statistically by ANOVA, followed by the Bonferroni post-test for paired observations. RESULTS: Our data revealed an increased release of EVs in GLS1-overexpressing HeLa cells."},{"source_id":"source_43","study":"Replication Study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate","doi":"10.7554/eLife.26030","url":"https://doi.org/10.7554/eLife.26030","support_kind":"cited_as_match","cited_as":"Showalter 2017","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"In 2016, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fiehn et al., 2016), that described how we intended to replicate selected experiments from the paper \"The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate\" (Ward et al., 2010). Here, we report the results of those experiments. We found that cells expressing R172K mutant IDH2 did not display isocitrate-dependent NADPH production above vector control levels, in contrast to the increased production observed with wild-type IDH2. Conversely, expression of R172K mutant IDH2 resulted in increased alpha-ketoglutarate-dependent consumption of NADPH compared to wild-type IDH2 or vector control. These results are similar to those reported in the original study (Figure 2; Ward et al., 2010). Further, expression of R172K mutant IDH2 resulted in increased 2HG levels within cells compared to the background levels observed in wild-type IDH2 and vector control, similar to the original study (Figure 3D; Ward et al., 2010)."},{"source_id":"source_47","study":"Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways","doi":"10.1038/srep26802","url":"https://doi.org/10.1038/srep26802","support_kind":"cited_as_match","cited_as":"Cai 2016","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Skeletal muscle weight loss is accompanied by small fiber size and low protein content. Alpha-ketoglutarate (AKG) participates in protein and nitrogen metabolism. The effect of AKG on skeletal muscle hypertrophy has not yet been tested, and its underlying mechanism is yet to be determined. In this study, we demonstrated that AKG (2%) increased the gastrocnemius muscle weight and fiber diameter in mice. Our in vitro study also confirmed that AKG dose increased protein synthesis in C2C12 myotubes, which could be effectively blocked by the antagonists of Akt and mTOR. The effects of AKG on skeletal muscle protein synthesis were independent of glutamate, its metabolite. We tested the expression of GPR91 and GPR99. The result demonstrated that C2C12 cells expressed GPR91, which could be upregulated by AKG. GPR91 knockdown abolished the effect of AKG on protein synthesis but failed to inhibit protein degradation. These findings demonstrated that AKG promoted skeletal muscle hypertrophy via Akt/mTOR signaling pathway. In addition, GPR91 might be partially attributed to AKG-induced skeletal muscle protein synthesis."},{"source_id":"source_52","study":"Alpha-Ketoglutarate: Physiological Functions and Applications","doi":"10.4062/biomolther.2015.078","url":"https://doi.org/10.4062/biomolther.2015.078","support_kind":"cited_as_match","cited_as":"Wu 2016","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Alpha-ketoglutarate (AKG) is a key molecule in the Krebs cycle determining the overall rate of the citric acid cycle of the organism. It is a nitrogen scavenger and a source of glutamate and glutamine that stimulates protein synthesis and inhibits protein degradation in muscles. AKG as a precursor of glutamate and glutamine is a central metabolic fuel for cells of the gastrointestinal tract as well. AKG can decrease protein catabolism and increase protein synthesis to enhance bone tissue formation in the skeletal muscles and can be used in clinical applications. In addition to these health benefits, a recent study has shown that AKG can extend the lifespan of adult Caenorhabditis elegans by inhibiting ATP synthase and TOR. AKG not only extends lifespan, but also delays age-related disease. In this review, we will summarize the advances in AKG research field, in the content of its physiological functions and applications."}],"candidate_sources":[]},{"claim_id":"claim_30","claim":"This synthesis maps 53 included sources on Alpha Ketoglutarate Akg across 10 outcome classes and 1 cross-study disagreement. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.","citation_support":[],"candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0.","source_id":"source_5","support_kind":"candidate_source_row"}]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","content_hash":"sha256:259fc5c5201345c13b9fef14f0b856e34339657122e85c238bac7b91bb4b1d3d","nodes":[{"id":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","type":"publication","title":"Research Synthesis: Alpha-ketoglutarate — full paper"},{"id":"claim_1","type":"claim","text":"Evidence-honesty note: 46/53 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on Alpha-ketoglutarate across 53 accepted source papers and 2847 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 45 adjacent clinical sources, and 8 mechanistic or model-system sources, with 1 cross-study disagreement across the evidence base. Positive study-level signals are summarized in the safety and comorbidity outcome class, null signals in the contextual adjacent evidence, cardiometabolic and mechanism outcome classes, and negative signals in no dominant outcome class."},{"id":"claim_2","type":"claim","text":"Evidence-honesty note: 46/53 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims."},{"id":"claim_3","type":"claim","text":"This paper synthesizes evidence on Alpha-ketoglutarate across 53 accepted source papers and 2847 high-confidence extracted claims."},{"id":"claim_4","type":"claim","text":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 45 adjacent clinical sources, and 8 mechanistic or model-system sources, with 1 cross-study disagreement across the evidence base."},{"id":"claim_5","type":"claim","text":"Positive study-level signals are summarized in the safety and comorbidity outcome class, null signals in the contextual adjacent evidence, cardiometabolic and mechanism outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_6","type":"claim","text":"The conclusion is that Alpha-ketoglutarate remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_7","type":"claim","text":"This manuscript is reported as a Evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-alpha_ketoglutarate_akg-v06-DAILY-2026-06-20T04-00-35Z`."},{"id":"claim_8","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text."},{"id":"claim_9","type":"claim","text":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses)."},{"id":"claim_10","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, immune and inflammation, immune and inflammation, mechanism, mortality and survival, muscle function, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_11","type":"claim","text":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified."},{"id":"claim_12","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_13","type":"claim","text":"| Contextual Adjacent Evidence | n=33; claims=1572 | no extracted directional signal in 31/33 sources | 30 indirect; 1 protocol; 2 review | limited corpus depth in this outcome class |"},{"id":"claim_14","type":"claim","text":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim."},{"id":"claim_15","type":"claim","text":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate."},{"id":"claim_16","type":"claim","text":"33 included sources were assigned to this outcome class. Directional coding: null=31, unclear=2. Directness coding: indirect=30, protocol=1, review=2."},{"id":"claim_17","type":"claim","text":"4 included sources were assigned to this outcome class. Directional coding: mixed=1, null=3. Directness coding: mechanistic=4."},{"id":"claim_18","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=1, mechanistic=2."},{"id":"claim_19","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=1, unclear=2. Directness coding: indirect=3."},{"id":"claim_20","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_21","type":"claim","text":"Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim."},{"id":"claim_22","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=2, unclear=1. Directness coding: indirect=3."},{"id":"claim_23","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=1, positive=1. Directness coding: mechanistic=2."},{"id":"claim_24","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2."},{"id":"claim_25","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_26","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_27","type":"claim","text":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim."},{"id":"claim_28","type":"claim","text":"Additional corpus sources included animal/preclinical evidence; the most consequential scope gap is the near-absence of long-term, hard-outcome randomized evidence in non-diabetic, community-dwelling adults. Consequently, every human claim in this synthesis that is anchored to a clinical event — whether survival in flap surgery (Huang 2025), aneurysm progression (Liu 2022), or diabetic cardiomyopathy (Dhat 2023) — is supported only by indirect, indirect-directness sources, and the headline conclusions cannot be transported to general adult populations without a dedicated long-term mortality RCT, of which the corpus contains none."},{"id":"claim_29","type":"claim","text":"Finally, the corpus contains a mechanism-to-clinic gap for the most clinically relevant claim, namely that αKG influences cardiovascular, skeletal, and longevity outcomes in humans. Mechanistic plausibility is densely documented: PI3K/Akt/HIF-1α angiogenesis in skin flaps (Huang 2025), PHD1-dependent NF-κB suppression in osteoclastogenesis (Tian 2023b), epigenetic H3K27me3 reduction in periodontal regeneration (Hasegawa 2026), histone methylation rescue in age-related osteoporosis (Wang 2020), and Tnfrsf12a/Fn14 histone-modification protection against cancer cachexia (Ruiz 2023). However, each of these sources is either preclinical (An 2021, Iwaniak 2022, Bayliak 2017, Kalawaj 2020), mechanistic-only (Iniguez 2022, Cai 2016, Qiu 2025, Sekita 2021, Wu 2018, Burdyliuk 2017, Showalter 2017, Fiehn 2016), or review/protocol-level (Sandalova 2023, Lamichhane 2023, Doroftei 2024, Wu 2016). The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. Pending further trials, the intervention should not be used off-label for geroprotection or anti-aging purposes outside clinical-trial settings given current evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging."},{"id":"claim_30","type":"claim","text":"This synthesis maps 53 included sources on Alpha Ketoglutarate Akg across 10 outcome classes and 1 cross-study disagreement. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit."},{"id":"source_1","type":"source","study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2023","excerpt":"BACKGROUND: Carbonylated proteins (CPs) serve as specific indicators of increased reactive oxygen and nitrogen species (RONS) production in cancer cells, attributed to the dysregulated mitochondrial energy metabolism known as the Warburg effect. The aim of this study was to investigate the potential of alpha-ketoglutarate (aKG), 5-hydroxymethylfurfural (5-HMF), and their combination as mitochondrial-targeting antioxidants in MTC-SK or NCI-H23 cancer cells. METHODS: MTC-SK and NCI-H23 cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of aKG, 5-HMF, and the combined aKG + 5-HMF solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of MTC-SK and NCI-H23 cells. RESULTS: The mitochondrial activity of MTC-SK cells exhibited a concentration- and time-dependent reduction upon treatment with aKG, 5-HMF, or the combined aKG + 5-HMF. The half-maximal inhibitory concentration (IC50%) for mitochondrial activity was achieved at 500 µg/mL aKG, 200 µg/mL 5-HMF, and 200 µg/mL aKG + 66.7 µg/mL 5-HMF after 72 h."},{"id":"source_2","type":"source","study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2022","excerpt":"BACKGROUND: We recently showed that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) has a solid antitumoral effect on the Jurkat cell line due to the fact of its antioxidative, caspase-3 and apoptosis activities, but no negative effect on human fibroblasts was obtained. The question arises how the single compounds, aKG and 5-HMF, affect peroxynitrite (ONOO - ) and nitration of tyrosine residues, Jurkat cell proliferation and caspase-activated apoptosis. METHODS: The ONOO - luminol-induced chemiluminescence reaction was used to measure the ONOO - scavenging function of aKG or 5-HMF, and their protection against nitration of tyrosine residues on bovine serum albumin was estimated with the ELISA technique. The Jurkat cell line was cultivated in the absence or presence of aKG or 5-HMF solutions between 0 and 3.5 µM aKG or 0 and 4 µM 5-HMF. Jurkat cells were tested for cell proliferation, mitochondrial activity and caspase-activated apoptosis. RESULTS: aKG showed a concentration-dependent reduction in ONOO - , resulting in a 90% elimination of ONOO - using 200 mM aKG."},{"id":"source_3","type":"source","study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Qiu 2025","excerpt":"It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cells (EPCs) dysfunction plays a critical role in the development of diabetic vascular complications. In the present study, we evaluated whether alpha-ketoglutarate (AKG) could improve the impaired function of EPCs, rescue EPC-mediated angiogenesis, and prevent cerebral ischemic injury in diabetic mice ( Mus musculus ). Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg -1 ·d -1 , i. p.). The diabetic mice were randomly divided into two groups, half of the mice were treated daily by oral gavage with AKG (4 g·kg -1 ·d -1 ), and the other half were treated daily with the same amount of vehicle (saline solution) via gavage for 4 consecutive weeks. We found that administration of AKG significantly reduced the cerebral ischemic injury, promoted angiogenesis and improved EPCs function in diabetic mice."},{"id":"source_4","type":"source","study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021","excerpt":"We have recently shown that a combined solution containing alpha-ketoglutarate (aKG) and 5-hydroxymethyl-furfural (5-HMF) might have anti-tumoral potential due to its antioxidative activities. The question arises if these substances have caspase-3- and apoptosis-activating effects on the cell proliferation in Jurkat and HF-SAR cells. Antioxidative capacity of several combined aKG + 5-HMF solution was estimated by cigarette smoke radical oxidized proteins of fetal calf serum (FCS) using the estimation of carbonylated proteins. The usage of 500 µg/mL aKG + 166.7 µg/mL 5-HMF showed the best antioxidative capacity to inhibit protein modification of more than 50% compared to control measurement. A Jurkat cell line and human fibroblasts (HF-SAR) were cultivated in the absence or presence of combined AKG + 5-HMF solutions between 0 µg/mL aKG + 0 µg/mL 5-HMF and different concentrations of 500 µg/mL aKG + 166.7 µg/mL 5-HMF. Aliquots of Jurkat cells were tested for cell proliferation, mitochondrial activity, caspase activity, apoptotic cells and of the carbonylated protein content as marker of oxidized proteins in cell lysates after 24, 48, and 72 h of incubation."},{"id":"source_5","type":"source","study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2022","excerpt":"To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp ( Cyprinus carpio ), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3 , claudin-7 , ZO-1 , and MLCK were significantly up-regulated in the LP+0."},{"id":"source_6","type":"source","study":"Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice","year":2021,"doi":"10.1016/j.redox.2021.102088","url":"https://doi.org/10.1016/j.redox.2021.102088","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"An 2021","excerpt":"Increasing evidence indicates the involvement of myocardial oxidative injury and mitochondrial dysfunction in the pathophysiology of heart failure (HF). Alpha-ketoglutarate (AKG) is an intermediate metabolite of the tricarboxylic acid (TCA) cycle that participates in different cellular metabolic and regulatory pathways. The circulating concentration of AKG was found to decrease with ageing and is elevated after acute exercise and resistance exercise and in HF. Recent studies in experimental models have shown that dietary AKG reduces reactive oxygen species (ROS) production and systemic inflammatory cytokine levels, regulates metabolism, extends lifespan and delays the occurrence of age-related decline. However, the effects of AKG on HF remain unclear. In the present study, we explored the effects of AKG on left ventricular (LV) systolic function, the myocardial ROS content and mitophagy in mice with transverse aortic constriction (TAC)."},{"id":"source_7","type":"source","study":"Alpha-Ketoglutarate: An Effective Feed Supplement in Improving Bone Metabolism and Muscle Quality of Laying Hens: A Preliminary Study","year":2020,"doi":"10.3390/ani10122420","url":"https://doi.org/10.3390/ani10122420","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Tomaszewska 2020","excerpt":"The aim of the experiment was to assess the effect of dietary alpha-ketoglutarate (AKG) supplementation on performance, serum hormonal indices, duodenum and jejunum histomorphometry, meat quality characteristics, bone quality traits and cartilage degradation in laying hens with a mature skeletal system. Forty-eight 30 week-old Bovans Brown laying hens were randomly assigned to a control group or the group fed the basal diet plus 1.0% AKG. The experimental trial lasted 30 weeks. The supplementation of AKG increases blood serum content of leptin, ghrelin, bone alkaline phosphatate and receptor activator of nuclear factor kappa-Β ligand, while osteoprotegerin and osteocalcin decrease. While dietary AKG was given to laying hens negatively influenced villus length, crypt depth, villus/crypt ratio and absorptive surface area in duodenum and jejunum, these changes have no effect on feed intake, weight gain, nor laying performance. In breast muscles, no significant changes in skeletal muscle fatty acid composition were observed, however, a higher shear force and decreased cholesterol content following AKG supplementation were noted, showing the improvement of muscle quality."},{"id":"source_8","type":"source","study":"Evaluation of Alpha-Ketoglutarate Supplementation on the Improvement of Intestinal Antioxidant Capacity and Immune Response in Songpu Mirror Carp ( Cyprinus carpio ) After Infection With Aeromonas hydrophila","year":2021,"doi":"10.3389/fimmu.2021.690234","url":"https://doi.org/10.3389/fimmu.2021.690234","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2021","excerpt":"As an intermediate substance of the tricarboxylic acid cycle and a precursor substance of glutamic acid synthesis, the effect of alpha-ketoglutarate on growth and protein synthesis has been extensively studied. However, its prevention and treatment of pathogenic bacteria and its mechanism have not yet been noticed. To evaluate the effects of alpha-ketoglutarate on intestinal antioxidant capacity and immune response of Songpu mirror carp, a total of 360 fish with an average initial weight of 6.54 ± 0.08 g were fed diets containing alpha-ketoglutarate with 1% for 8 weeks. At the end of the feeding trial, the fish were challenged with Aeromonas hydrophila for 2 weeks. The results indicated that alpha-ketoglutarate supplementation significantly increased the survival rate of carp after infection with Aeromonas hydrophila ( P < 0.05), and the contents of immune digestion enzymes including lysozyme, alkaline phosphatase and the concentration of complement C4 were markedly enhanced after alpha-ketoglutarate supplementation ( P < 0.05)."},{"id":"source_9","type":"source","study":"Dietary Alpha-Ketoglutarate Partially Abolishes Adverse Changes in the Small Intestine after Gastric Bypass Surgery in a Rat Model","year":2022,"doi":"10.3390/nu14102062","url":"https://doi.org/10.3390/nu14102062","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Iwaniak 2022","excerpt":"Alpha-ketoglutarate (AKG) is one of the key metabolites that play a crucial role in cellular energy metabolism. Bariatric surgery is a life-saving procedure, but it carries many gastrointestinal side effects. The present study investigated the beneficial effects of dietary AKG on the structure, integrity, and absorption surface of the small intestine after bariatric surgery. Male 7-week-old Sprague Dowley rats underwent gastric bypass surgery, after which they received AKG, 0.2 g/kg body weight/day, administered in drinking water for 6 weeks. Changes in small intestinal morphology, including histomorphometric parameters of enteric plexuses, immunolocalization of claudin 3, MarvelD3, occludin and zonula ocludens 1 in the intestinal mucosa, and selected hormones, were evaluated. Proliferation, mucosal and submucosal thickness, number of intestinal villi and Paneth cells, and depth of crypts were increased; however, crypt activity, the absorption surface, the expression of claudin 3, MarvelD3, occludin and zonula ocludens 1 in the intestinal epithelium were decreased after gastric bypass surgery."},{"id":"source_10","type":"source","study":"Alpha-ketoglutarate supplementation improves hyperglycemia and attenuates the decrease in GLUT4 and PGC-1α proteins in adipose tissue of streptozotocin-high-fat diet-induced diabetic mice","year":2025,"doi":"10.1017/jns.2025.10059","url":"https://doi.org/10.1017/jns.2025.10059","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Takemura 2025","excerpt":"Alpha-ketoglutarate (AKG) is a well-known intermediate of the tricarboxylic acid cycle and plays an important role in the catabolism of branched-chain amino acids (BCAAs: leucine, isoleucine, and valine). While previous study suggested that AKG enhances glucose metabolism, its effect on the adaptation of muscles and adipocytes has not been well studied in diabetic condition. This study aimed to determine whether AKG improves glucose metabolism in the skeletal muscles and adipose tissues in diabetic mice. Male institute of cancer research mice were divided into control, diabetic, and diabetic + AKG groups. Diabetes (DM) was induced by a high fat diet consumption and streptozotocin (STZ) injection. Mice in the DM + AKG group were administered 1% AKG in drinking water for 6 weeks. The non-fasting plasma glucose level was significantly higher in the diabetic group than that in the control and DM + AKG groups ( P < 0.05). No significant difference was observed in glucose transporter 4 (GLUT4) protein levels in the muscles between the DM and DM + AKG groups."},{"id":"source_11","type":"source","study":"Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia","year":2025,"doi":"10.1038/s41467-025-64360-8","url":"https://doi.org/10.1038/s41467-025-64360-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Sun 2025","excerpt":"The maintenance of metabolic homeostasis relies on the ability to flexibly transit between catabolic and anabolic states in response to insulin signaling. Here we show insulin-activated ATM is a critical mediator of this process, facilitating the swift transition between catabolic-and-anabolic fates of glucose by regulating the functional status of PKM2 and HIF1α. In Ataxia-Telangiectasia (A-T), these mechanisms are disrupted, resulting in intrinsic insulin resistance and glucose intolerance. Consequently, cells exhibit a compensatory dependence on glutamine as an alternative metabolite for energy metabolism. Cerebellar degeneration, a hallmark of A-T, is characterized by the pronounced vulnerability of Purkinje cells, attributed to their unexpected sensitivity to insulin. Supplementation with α-ketoglutarate, the α-keto acid backbone of glutamine, has demonstrated potentials in alleviating glutamine dependence and attenuating Purkinje cell degeneration."},{"id":"source_12","type":"source","study":"Alpha Ketoglutarate Exerts In Vitro Anti-Osteosarcoma Effects through Inhibition of Cell Proliferation, Induction of Apoptosis via the JNK and Caspase 9-Dependent Mechanism, and Suppression of TGF-β and VEGF Production and Metastatic Potential of Cells","year":2020,"doi":"10.3390/ijms21249406","url":"https://doi.org/10.3390/ijms21249406","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Kalawaj 2020","excerpt":"Osteosarcoma (OS) is the most common type of primary bone tumor. Currently, there are limited treatment options for metastatic OS. Alpha-ketoglutarate (AKG), i.e., a multifunctional intermediate of the Krebs cycle, is one of the central metabolic regulators of tumor fate and plays an important role in cancerogenesis and tumor progression. There is growing evidence suggesting that AKG may represent a novel adjuvant therapeutic opportunity in anti-cancer therapy. The present study was intended to check whether supplementation of Saos-2 and HOS osteosarcoma cell lines (harboring a TP53 mutation) with exogenous AKG exerted an anti-cancer effect. The results revealed that AKG inhibited the proliferation of both OS cell lines in a concentration-dependent manner. As evidenced by flow cytometry, AKG blocked cell cycle progression at the G 1 stage in both cell lines, which was accompanied by a decreased level of cyclin D1 in HOS and increased expression of p21 Waf1/Cip1 protein in Saos-2 cells (evaluated with the ELISA method). Moreover, AKG induced apoptotic cell death and caspase-3 activation in both OS cell lines (determined by cytometric analysis)."},{"id":"source_13","type":"source","study":"Epigenetic modifier alpha-ketoglutarate modulates aberrant gene body methylation and hydroxymethylation marks in diabetic heart","year":2023,"doi":"10.1186/s13072-023-00489-4","url":"https://doi.org/10.1186/s13072-023-00489-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Dhat 2023","excerpt":"BACKGROUND: Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetic patients. Hyperglycemic myocardial microenvironment significantly alters chromatin architecture and the transcriptome, resulting in aberrant activation of signaling pathways in a diabetic heart. Epigenetic marks play vital roles in transcriptional reprogramming during the development of DCM. The current study is aimed to profile genome-wide DNA (hydroxy)methylation patterns in the hearts of control and streptozotocin (STZ)-induced diabetic rats and decipher the effect of modulation of DNA methylation by alpha-ketoglutarate (AKG), a TET enzyme cofactor, on the progression of DCM. METHODS: Diabetes was induced in male adult Wistar rats with an intraperitoneal injection of STZ. Diabetic and vehicle control animals were randomly divided into groups with/without AKG treatment. Cardiac function was monitored by performing cardiac catheterization. Global methylation (5mC) and hydroxymethylation (5hmC) patterns were mapped in the Left ventricular tissue of control and diabetic rats with the help of an enrichment-based (h)MEDIP-sequencing technique by using antibodies specific for 5mC and 5hmC."},{"id":"source_14","type":"source","study":"Dietary Alpha-Ketoglutarate Supplementation Improves Bone Growth, Phosphorus Digestion, and Growth Performance in Piglets","year":2023,"doi":"10.3390/ani13040569","url":"https://doi.org/10.3390/ani13040569","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Tian 2023","excerpt":"Phosphorus (P) pollution from modern swine production is a major environmental problem. Dietary interventions to promote bone growth can improve the utilization of dietary P, and thereby reduce its emission. Recent in vitro studies have shown that alpha-ketoglutarate (AKG) exerts a pro-osteogenic effect on osteoblast cells. This study aimed to evaluate the effects of AKG supplementation on bone growth, P and Ca digestion, and the gut microbial profile in piglets. Thirty-two piglets were randomly assigned into two dietary groups. The piglets were fed a basic diet containing 10 g/kg AKG or 10 g/kg maize starch (control) for 28 days. On days 21-28, titanium dioxide was used as an indicator to determine the apparent digestibility of P. AKG supplementation improved the bone mineral density, length, weight, and geometrical and strength properties of the femur and tibia. Furthermore, AKG supplementation increased apparent ileal and total tract digestibility of P. Colonic microbiota analysis results showed that AKG supplementation increased α-diversity and beneficial bacteria, including Lactobacillus and Clostridium butyricum , and decreased nitrogen fixation and chemoheterotrophy."},{"id":"source_15","type":"source","study":"Effects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation","year":2026,"doi":"10.3390/cells15030281","url":"https://doi.org/10.3390/cells15030281","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Khamineh 2026","excerpt":"Ovarian cancer remains one of the leading causes of cancer-related mortality among women, underscoring the need for novel combination strategies that effectively inhibit tumor cell growth while limiting adverse effects. N-acetylcysteine (NAC) and alpha-ketoglutarate (AKG) are biologically active compounds with reported anticancer properties; however, their combined effects in ovarian cancer are not well characterized. In this study, we applied an integrative approach combining network pharmacology analysis with in vitro experiments to investigate the effects of NAC and AKG on OVCAR3 ovarian cancer cells. Common molecular targets of NAC and AKG were identified by intersecting predicted compound targets with ovarian cancer-associated genes, followed by protein-protein interaction network construction and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Experimental validation assessed the effects of NAC and AKG, alone and in combination, on cell viability, apoptosis, migration, and clonogenic capacity. Network analysis identified 70 shared target genes enriched in pathways related to apoptosis, cellular stress responses, and cell migration."},{"id":"source_16","type":"source","study":"Alpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway","year":2025,"doi":"10.1186/s13619-025-00264-8","url":"https://doi.org/10.1186/s13619-025-00264-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Huang 2025","excerpt":"Random-pattern skin flaps are widely employed in tissue reconstruction, however, their survival is frequently hindered by ischemia, leading to necrosis. Metabolic alterations have been implicated in playing critical roles in angiogenesis during tissue repair. Using RNA sequencing analysis in a mouse model, we identified significant disruptions in glutamine metabolism, which substantially impaired angiogenesis within random-pattern skin flaps. Although local glutamine repletion failed to alleviate ischemia, administering α-ketoglutarate (α-KG) markedly promoted angiogenesis, as evidenced at both gene and protein levels. In human umbilical vein endothelial cells,α-KG enhanced the stability of hypoxia-inducible factor (HIF-1) alpha through activation of the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. Notably, α-KG treatment improved flap viability by augmenting blood perfusion, an effect correlated with upregulation of vascular endothelial growth factor expression."},{"id":"source_17","type":"source","study":"Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations","year":2020,"doi":"10.1038/s41467-020-19360-1","url":"https://doi.org/10.1038/s41467-020-19360-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wang 2020","excerpt":"Age-related osteoporosis is characterized by the deterioration in bone volume and strength, partly due to the dysfunction of bone marrow mesenchymal stromal/stem cells (MSCs) during aging. Alpha-ketoglutarate (αKG) is an essential intermediate in the tricarboxylic acid (TCA) cycle. Studies have revealed that αKG extends the lifespan of worms and maintains the pluripotency of embryonic stem cells (ESCs). Here, we show that the administration of αKG increases the bone mass of aged mice, attenuates age-related bone loss, and accelerates bone regeneration of aged rodents. αKG ameliorates the senescence-associated (SA) phenotypes of bone marrow MSCs derived from aged mice, as well as promoting their proliferation, colony formation, migration, and osteogenic potential. Mechanistically, αKG decreases the accumulations of H3K9me3 and H3K27me3, and subsequently upregulates BMP signaling and Nanog expression. Collectively, our findings illuminate the role of αKG in rejuvenating MSCs and ameliorating age-related osteoporosis, with a promising therapeutic potential in age-related diseases."},{"id":"source_18","type":"source","study":"Alpha-ketoglutarate ameliorates abdominal aortic aneurysm via inhibiting PXDN/HOCL/ERK signaling pathways","year":2022,"doi":"10.1186/s12967-022-03659-2","url":"https://doi.org/10.1186/s12967-022-03659-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Liu 2022","excerpt":"Abdominal aortic aneurysm (AAA) represents the serious vascular degenerative disorder, which causes high incidence and mortality. Alpha-ketoglutarate (AKG), a crucial metabolite in the tricarboxylic acid (TCA) cycle, has been reported to exert significant actions on the oxidative stress and inflammation. However, its role in AAA still remains elusive. Herein, we examined the effects of AKG on the formation of AAA. The study established an elastase-induced mouse abdominal aortic aneurysms model as well as a TNF-α-mediated vascular smooth muscle cells (VSMCs) model, respectively. We displayed that AKG pre-treatment remarkably prevented aneurysmal dilation assessed by diameter and volume and reduced aortic rupture. In addition, it was also observed that AKG treatment suppressed the development of AAA by attenuating the macrophage infiltration, elastin degradation and collagen fibers remodeling. In vitro, AKG potently decreased TNF-α-induced inflammatory cytokines overproduction, more apoptotic cells and excessive superoxide. Mechanistically, we discovered that upregulation of vpo1 in AAA was significantly suppressed by AKG treatment."},{"id":"source_19","type":"source","study":"Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)—intervention study protocol","year":2023,"doi":"10.1007/s11357-023-00813-6","url":"https://doi.org/10.1007/s11357-023-00813-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Sandalova 2023","excerpt":"Targeting molecular processes of aging will enable people to live healthier and longer lives by preventing age-related diseases. Geroprotectors are compounds with the potential to increase healthspan and lifespan. Even though many of them have been tested in animal models, the translation to humans is limited. Alpha-Ketoglutarate (AKG) has been studied widely in model animals, but there are few studies testing its geroprotective properties in humans. ABLE is a double blinded placebo-controlled randomized trial (RCT) of 1 g sustained release Ca-AKG versus placebo for 6 months of intervention and 3 months follow up including 120 40-60-year-old healthy individuals with a higher DNA methylation age compared to their chronological age. The primary outcome is the decrease in DNA methylation age from baseline to the end of the intervention. A total of 120 participants will be randomized to receive either sustained release Ca-AKG or placebo. Secondary outcomes include changes in the inflammatory and metabolic parameters in blood, handgrip strength and leg extension strength, arterial stiffness, skin autofluorescence, and aerobic capacity from baseline to 3 months, 6 months, and 9 months."},{"id":"source_20","type":"source","study":"Elevation of Intracellular Alpha-Ketoglutarate Levels Inhibits Osteoclastogenesis by Suppressing the NF-κB Signaling Pathway in a PHD1-Dependent Manner","year":2023,"doi":"10.3390/nu15030701","url":"https://doi.org/10.3390/nu15030701","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Tian 2023b","excerpt":"Age-related osteoporosis, a high-prevalence disease in the aged population, is generally attributed to the excessive activity of osteoclasts. Most approved drugs treat osteoporosis by inhibition of osteoclasts. Although in vivo studies have shown that alpha-ketoglutarate (AKG), an intermediate in the TCA cycle, can ameliorate age-related osteoporosis, the effects of AKG on osteoclastogenesis and the underlying mechanism of its action have not been studied yet. Here, we showed that the elevation of intracellular AKG levels by supplementing dimethyl AKG (DM-AKG, a cell-permeable derivative of AKG) inhibits the receptor activator of NF-κB ligand (RANKL)-induced osteoclasts differentiation from primary bone marrow-derived macrophages (BMMs) and RAW264.7 cells in vitro. We further found that DM-AKG treatment suppresses NF-κB signaling and oxidative phosphorylation (OXPHOS) during RANKL-induced osteoclastogenesis in RAW264.7 cells. Interestingly, dimethyl oxalylglycine (DMOG), an AKG competitive inhibitor of AKG-dependent prolyl hydroxylases (PHDs), antagonizes the suppression of the RANKL-activated NF-κB signaling pathway caused by DM-AKG treatment."},{"id":"source_21","type":"source","study":"Alpha-ketoglutarate enhances adipose-derived stem cells survival in wound healing by hypoxia-inducible factor 1-alpha-mediated redox homeostasis and glycogen-dependent bioenergetics","year":2026,"doi":"10.4252/wjsc.v18.i2.113694","url":"https://doi.org/10.4252/wjsc.v18.i2.113694","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Dilimulati 2026","excerpt":"BACKGROUND: Adipose-derived stem cells (ADSCs) hold significant therapeutic potential for regenerative medicine, particularly in wound healing, owing to their multipotency, paracrine activity, and relative abundance. However, the clinical application of ADSC-based therapies is substantially limited by the harsh microenvironment of acute wounds, characterized by hypoxia, nutrient deprivation, and oxidative stress, which leads to massive apoptotic cell death post-transplantation. Preconditioning strategies to enhance cellular resilience have thus gained considerable interest. Recent insights from cancer biology highlight the crucial role of metabolic reprogramming, orchestrated by hypoxia-inducible factor-1α (HIF-1α), in promoting survival under stress. Our previous work demonstrated that preconditioning with α-ketoglutarate (α-KG) enhances ADSC survival and accelerates wound healing, purportedly through HIF-1α upregulation. Nevertheless, the precise metabolic mechanisms by which α-KG preconditioning confers cytoprotection remain incompletely elucidated."},{"id":"source_22","type":"source","study":"Development and First-in-Human Translation of Hyperpolarized [1- 13 C]Alpha-Ketoglutarate MR Spectroscopy in the Brain","year":2026,"doi":"10.3390/s26092753","url":"https://doi.org/10.3390/s26092753","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Kim 2026","excerpt":"Alpha-ketoglutarate (aKG) is a central intermediate of cerebral energy metabolism and a precursor for glutamate synthesis in the brain. Alterations in aKG metabolism occur in pathological contexts, including isocitrate dehydrogenase (IDH) mutant astrocytomas and oligodendrogliomas, in which mutant IDH converts aKG to the oncometabolite 2-hydroxyglutarate. Given its central role in brain metabolism, non-invasive interrogation of aKG-dependent metabolic flux is needed. Hyperpolarized (HP) 13 C MR enables real-time visualization of metabolic conversion by transiently enhancing signal intensity by several orders of magnitude. Leveraging this approach, we report the first-in-human feasibility and safety study of HP [1- 13 C]aKG MR spectroscopy in the healthy brain (n = 3). A standard operating procedure (SOP) was developed for sterile [1- 13 C]aKG dose production, achieving reproducible polarization levels averaging 30.5 ± 2.2%."},{"id":"source_23","type":"source","study":"Effects of Alpha-Ketoglutarate Supplementation on Growth Performance, Diarrhea Incidence, Plasma Amino Acid, and Nutrient Digestibility in Weaned Piglets","year":2025,"doi":"10.3390/ani15121723","url":"https://doi.org/10.3390/ani15121723","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Sun 2025b","excerpt":"Alpha-ketoglutaric acid (AKG) is a key intermediate in the tricarboxylic acid cycle and plays a crucial role in energy production and amino acid metabolism. This study aimed to evaluate the effects of AKG on growth performance, nutrient digestibility, plasma biochemical parameters, and plasma amino acid profiles in weaned piglets. A total of 72 weaned piglets with an average weight of 7.33 kg (±0.50 kg) and an average age of 28 (±2 days) were randomly assigned to 3 dietary treatments with 6 replicates per group in a 42-day trial. The treatments included a basal diet (CT), a basal diet with 500 g/t AKG (AKG1), and a basal diet with 1000 g/t AKG (AKG2). Blood samples were collected on days 14 and 42, and fecal samples were collected on day 42. The results showed that diets including 500 g/t and 1000 g/t AKG significantly reduced diarrhea incidence in piglets compared to the CT group ( p < 0.01). Moreover, diets including 1000 g/t AKG enhanced fecal dry matter digestibility, plasma albumin (ALB), and glucose (GLU) concentrations on day 42 compared to the AKG1 group ( p < 0.05)."},{"id":"source_24","type":"source","study":"Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia","year":2023,"doi":"10.3390/genes14091818","url":"https://doi.org/10.3390/genes14091818","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Ruiz 2023","excerpt":"Previous studies have shown that inhibition of TNF family member FN14 (gene: TNFRSF12A ) in colon tumors decreases inflammatory cytokine expression and mitigates cancer-induced cachexia. However, the molecular mechanisms underlying the regulation of FN14 expression remain unclear. Tumor microenvironments are often devoid of nutrients and oxygen, yet how the cachexic response relates to the tumor microenvironment and, importantly, nutrient stress is unknown. Here, we looked at the connections between metabolic stress and FN14 expression. We found that TNFRSF12A expression was transcriptionally induced during glutamine deprivation in cancer cell lines. We also show that the downstream glutaminolysis metabolite, alpha-ketoglutarate (aKG), is sufficient to rescue glutamine-deprivation-promoted TNFRSF12A induction. As aKG is a co-factor for histone de-methylase, we looked at histone methylation and found that histone H3K4me3 at the Tnfrsf12a promoter is increased under glutamine-deprived conditions and rescued via DM-aKG supplementation. Finally, expression of Tnfrsf12a and cachexia-induced weight loss can be inhibited in vivo by DM-aKG in a mouse cancer cachexia model."},{"id":"source_25","type":"source","study":"Cholesterol Content, Fatty Acid Profile and Health Lipid Indices in the Egg Yolk of Eggs from Hens at the End of the Laying Cycle, Following Alpha-Ketoglutarate Supplementation","year":2021,"doi":"10.3390/foods10030596","url":"https://doi.org/10.3390/foods10030596","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Tomaszewska 2021","excerpt":"The current study aimed to assess the effects of dietary alpha-ketoglutarate (AKG) supplementation to laying hens on the fatty acid (FA) profile and cholesterol levels of the egg yolk at the end of production cycle. The experiment was performed on forty-eight Bovans Brown laying hens randomly assigned to either a control group (CONT) or a group supplemented with AKG. The CONT group was fed the basal diet, and the AKG group was fed the basal diet plus 1.0% AKG from the 31st until the 60th week of age, when FA profile, fat and cholesterol content of the egg yolks were determined. No significant changes in the cholesterol and total fat content of the egg yolks were observed. However, there were positive (the decrease in n-6 FA and the increase in MUFA), and negative (decrease in PUFA and n-3 FA, increase in TI and n-6/n-3 ratio) changes in FA profile following AKG supplementation. In conclusion, it was shown that dietary AKG after a 30-week long supplementation influence FA profile in egg yolk and its nutritional value."},{"id":"source_26","type":"source","study":"Effects of Dietary Alpha-Ketoglutarate Supplementation on Diarrhea Incidence and Nutrient Digestibility in Weaned Piglets Fed Low-Protein Diets","year":2025,"doi":"10.3390/vetsci12121163","url":"https://doi.org/10.3390/vetsci12121163","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Sun 2025c","excerpt":"Alpha-ketoglutarate (AKG) supplementation has been explored as a nutritional strategy to mitigate the negative effects of protein restriction. This study aims to evaluate the effects of supplementing a low-protein diet with AKG on growth performance, diarrhea incidence, and fecal nutrient digestibility in weaned piglets. A total of 60 weaned piglets (initial body weight: 7.53 kg; age: 28 days old) were randomly distributed into three dietary treatments with five replicates per group, for a 42-day experimental period. The treatments consisted of a control diet (CT), a low-protein diet (LP), and a low-protein diet supplemented with 1000 g/t AKG (AKG). Fecal samples were collected on days 40-42 to determine the apparent digestibility of nutrients. The results showed that the feed conversion rate (FCR) in LP-group piglets were significantly higher than that of the CT group ( p = 0.028), while the crude protein (CP) digestibility was significantly lower in the LP group compared with the CT group ( p = 0.038). However, supplementing the low-protein diet with 1000 g/t AKG effectively mitigated these negative effects."},{"id":"source_27","type":"source","study":"Alpha-Ketoglutarate Promotes Goblet Cell Differentiation and Alters Urea Cycle Metabolites in DSS-Induced Colitis Mice","year":2022,"doi":"10.3390/nu14061148","url":"https://doi.org/10.3390/nu14061148","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Iniguez 2022","excerpt":"The metabolite, alpha-ketoglutarate (aKG), shows promise as an approach for ameliorating colitis, but much remains unknown about the full extent of its effects on the metabolome and mucosal barrier. To further elucidate this matter, C57BL/6 male mice received drinking water with or without 1% aKG for three weeks, then were subjected to 2.5% dextran sulfate sodium (DSS) induction for 7 days followed by 7 days of recovery. Cecal content and intestinal tissue samples were analyzed for changes in metabolite profile and signaling pathways. Gas chromatography-mass spectrometry (GC-MS) metabolomics revealed a separation between the metabolome of mice treated with or without aKG; putrescine and glycine were significantly increased; and ornithine and amide products, oleamide and urea were significantly decreased. Based on a pathway analysis, aKG treatment induced metabolite changes and enriched glutathione metabolism and the urea cycle. Additionally, signaling pathways committing epithelial cells to the secretory lineage were elevated in aKG-treated mice."},{"id":"source_28","type":"source","study":"Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test","year":2021,"doi":"10.18632/aging.203736","url":"https://doi.org/10.18632/aging.203736","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Demidenko 2021","excerpt":"The search continues for possible interventions that delay and/or reverse biological aging, resulting in extended healthspan and lifespan. Interventions delaying aging in animal models are well established; however, most lack validation in humans. The length of human lifespan makes it impractical to perform survival analysis. Instead, aging biomarkers, such as DNA methylation (DNAm) clocks, have been developed to monitor biological age. Herein we report a retrospective analysis of DNA methylation age in 42 individuals taking Rejuvant®, an alpha-ketoglutarate based formulation, for an average period of 7 months. DNAm testing was performed at baseline and by the end of treatment with Rejuvant® supplementation. Remarkably, individuals showed an average decrease in biological aging of 8 years (p-value=6.538x10 -12 ). Furthermore, the supplementation with Rejuvant® is robust to individual differences, as indicated by the fact that a large majority of participants decreased their biological age. Moreover, we found that Rejuvant® is of additional benefit to chronologically and biologically older individuals."},{"id":"source_29","type":"source","study":"Alpha-Ketoglutarate: A Potential Inner Mitochondrial and Cytosolic Protector against Peroxynitrite and Peroxynitrite-Induced Nitration?","year":2021,"doi":"10.3390/antiox10091501","url":"https://doi.org/10.3390/antiox10091501","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Greilberger 2021b","excerpt":"The generation of peroxynitrite (ONOO - ) is associated with several diseases, including atherosclerosis, hypertension, neurodegeneration, cancer, inflammation, and sepsis. Alpha-ketoglutarate (αKG) is a known potential highly antioxidative agent for radical oxidative species such as peroxides. The question arises as to whether αKG is also a potential scavenger of ONOO - and a potential protector against ONOO - -mediated nitration of proteins. NMR studies of 1 mM αKG in 100 mM phosphate-buffered saline at pH 7.4 and pH 6.0 were carried out in the presence or absence of a final concentration of 2 mM ONOO - . An ONOO - -luminol-induced chemiluminescence reaction was used to measure the scavenging function of several concentrations of αKG; quantification of αKG was performed via spectrophotometric enzymatic assay of αKG in the absence or presence of 0, 1, or 2 mM ONOO - . The nitration of tyrosine residues on proteins was measured on ONOO - -treated bovine serum albumin (BSA) in the presence or absence of 0-24 mM αKG by an ELISA technique using a specific anti-IgG against nitro-tyrosine. The addition of ONOO - to αKG led to the formation of succinic acid and nitrite at pH 7."},{"id":"source_30","type":"source","study":"Lack of association of the alpha-ketoglutarate-dependent dioxygenase (FTO) gene polymorphisms with pulmonary tuberculosis risk: a systematic review and meta-analysis","year":2023,"doi":"10.1097/MS9.0000000000001188","url":"https://doi.org/10.1097/MS9.0000000000001188","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Lamichhane 2023","excerpt":"OBJECTIVE: Our meta-analysis aims to explore the association of two single nucleotide variants; rs9939609 and rs8050136, within the FTO gene with risk of pulmonary tuberculosis (PTB). METHODS: The association of two single nucleotide variants with PTB in three genetic models was evaluated using pooled odds ratios (ORs) with 95% CIs. RESULTS: No significant association was observed between the rs9939609 polymorphism and PTB when assuming an allelic model (OR: 1.10; 95% CI: 0.85-1.41; P =0.47; I 2 = 64.98%), a recessive model (OR: 2.04; 95% CI: 0.87-4.77; P =0.10; I 2 = 67.18%), or a dominant model (OR: 0.96; 95% CI: 0.83-1.11; P =0.56; I 2 = 27.45%). Likewise, no association was observed between rs8050136 polymorphism and PTB when assuming allelic model (OR: 1.17; 95% CI: 0.87-1.58; P =0.31; I 2 = 64.20%) or recessive model (OR: 1.04; 95% CI: 0.32-3.38; P =0.95; I 2 = 68.82%) or dominant model (OR: 1.22; 95% CI: 0.87-1.71; P =0.26; I 2 = 58.69%). CONCLUSION: There might be no association between the rs9939609 and rs8050136 variants in the FTO gene, and the risk of PTB."},{"id":"source_31","type":"source","study":"AKT signaling is associated with epigenetic reprogramming via the upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation","year":2021,"doi":"10.1186/s13287-021-02578-1","url":"https://doi.org/10.1186/s13287-021-02578-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Sekita 2021","excerpt":"BACKGROUND: Phosphoinositide-3 kinase (PI3K)/AKT signaling participates in cellular proliferation, survival and tumorigenesis. The activation of AKT signaling promotes the cellular reprogramming including generation of induced pluripotent stem cells (iPSCs) and dedifferentiation of primordial germ cells (PGCs). Previous studies suggested that AKT promotes reprogramming by activating proliferation and glycolysis. Here we report a line of evidence that supports the notion that AKT signaling is involved in TET-mediated DNA demethylation during iPSC induction. METHODS: AKT signaling was activated in mouse embryonic fibroblasts (MEFs) that were transduced with OCT4, SOX2 and KLF4. Multiomics analyses were conducted in this system to examine the effects of AKT activation on cells undergoing reprogramming. RESULTS: We revealed that cells undergoing reprogramming with artificially activated AKT exhibit enhanced anabolic glucose metabolism and accordingly increased level of cytosolic α-ketoglutarate (αKG), which is an essential cofactor for the enzymatic activity of the 5-methylcytosine (5mC) dioxygenase TET. Additionally, the level of TET is upregulated."},{"id":"source_32","type":"source","study":"The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease","year":2021,"doi":"10.3390/life11040321","url":"https://doi.org/10.3390/life11040321","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Csaban 2021","excerpt":"There is increasing evidence that several mitochondrial abnormalities are present in the brains of patients with Alzheimer's disease (AD). Decreased alpha-ketoglutarate dehydrogenase complex (αKGDHc) activity was identified in some patients with AD. The αKGDHc is a key enzyme in the Krebs cycle. This enzyme is very sensitive to the harmful effect of reactive oxygen species, which gives them a critical role in the Alzheimer and mitochondrial disease research area. Previously, several genetic risk factors were described in association with AD. Our aim was to analyze the associations of rare damaging variants in the genes encoding αKGDHc subunits and AD. The three genes ( OGDH , DLST , DLD ) encoding αKGDHc subunits were sequenced from different brain regions of 11 patients with histologically confirmed AD and the blood of further 35 AD patients. As a control group, we screened 134 persons with whole-exome sequencing. In all subunits, a one-one rare variant was identified with unknown significance based on American College of Medical Genetics and Genomics (ACMG) classification."},{"id":"source_33","type":"source","study":"Foliar application of alpha-ketoglutarate plus nitrogen improves drought resistance in soybean ( Glycine max L. Merr. )","year":2022,"doi":"10.1038/s41598-022-18660-4","url":"https://doi.org/10.1038/s41598-022-18660-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Gai 2022","excerpt":"The aim of the present research was to understand the impacts of foliar nitrogen and α-oxoglutarate on proline accumulation, photosynthesis, and ammonium assimilation of soybean seedlings subjected to drought stress. The data in the present study demonstrated that foliar α-oxoglutarate and nitrogen significantly enhanced leaf glutamine synthetase (GS) activity, glutamate dehydrogenase (GDH) activity, glutamate content, proline content, relative water content (RWC) and photosynthesis of soybean seedlings exposed to drought stress at each stage. Accordingly, the ammonium content was significantly reduced by foliar α-oxoglutarate and nitrogen. These results suggested that a combination of foliar nitrogen plus α-oxoglutarate had an advantage over either foliar nitrogen or foliar α-oxoglutarate in increasing the proline accumulation under drought stress and a combination of foliar nitrogen plus α-oxoglutarate could better mitigate the adverse impacts of drought stress."},{"id":"source_34","type":"source","study":"Repurposing FDA-approved drugs to find a novel inhibitor of alpha-ketoglutarate-dependent dioxygenase FTO to treat esophageal cancer","year":2025,"doi":"10.4103/RPS.RPS_9_25","url":"https://doi.org/10.4103/RPS.RPS_9_25","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Mohammadi 2025","excerpt":"BACKGROUND AND PURPOSE: The Fat mass and obesity-associated protein (FTO) plays a significant role in esophageal cancer by regulating N6-methyladenosine (m6A) modification. FTO inhibition has shown potential in cancer therapies but remains underexplored. This study aimed to identify a safer, FDA-approved compound for FTO inhibition that can be used in combination with chemotherapy drugs. EXPERIMENTAL APPROACH: FDA-approved drugs were screened from the Zinc 15 database using AutoDock Vina against the 3D structure of FTO (PDB ID: 3LFM). Discovery Studio software was used to determine binding interactions. The GROMACS package was used for molecular dynamics simulations. A non-toxic concentration was determined through an MTT assay on KYSE-30 esophageal cancer cells. The ELISA assay was used to measure the m6A levels in RNA. FINDINGS/RESULTS: Four compounds, ergotamine, midazolam, digoxin, and loratadine, were identified. Loratadine (ΔG: -8.9) formed stable interactions with FTO, specifically with residues Ser229, Tyr109, Leu109, Val229, and His231. Molecular dynamic simulations of the FTO-loratadine complex revealed higher RMSD fluctuations (0.4-0."},{"id":"source_35","type":"source","study":"Alpha Ketoglutarate Downregulates the Neutral Endopeptidase and Enhances the Growth Inhibitory Activity of Thiorphan in Highly Aggressive Osteosarcoma Cells","year":2022,"doi":"10.3390/molecules28010097","url":"https://doi.org/10.3390/molecules28010097","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Mizerska-Kowalska 2022","excerpt":"Since natural substances are widely explored as epigenetic modulators of gene expression and epigenetic abnormalities are important causes of cancerogenesis, factors with pro-tumor activities subjected to epigenetic control, e.g., neutral endopeptidase (NEP, neprilysin), are promising anticancer targets for potential therapies acting via epigenetic regulation of gene expression. Alpha-ketoglutarate (AKG) is a naturally occurring co-substrate for enzymes involved in histone and DNA demethylation with suggested anti-cancer activity. Hence, we investigated a potential effect of AKG on the NEP expression in cells derived from various cancers (cervical, colon, osteosarcoma) and normal epithelial cells and osteoblasts. Moreover, the overall methylation status of histone H3 was explored to establish the molecular target of AKG activity. Additionally, it was investigated whether AKG in combination with thiorphan (NEP specific inhibitor) exhibited enhanced anticancer activity."},{"id":"source_36","type":"source","study":"Alpha-Ketoglutarate Drives an Osteogenic and Extracellular Matrix Gene Program in Periodontal Ligament Fibroblasts via Selective Reduction of H3K27me3","year":2026,"doi":"10.3390/biology15050372","url":"https://doi.org/10.3390/biology15050372","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Hasegawa 2026","excerpt":"Periodontal disease is a chronic inflammatory condition that destroys tooth-supporting tissues, particularly the alveolar bone and the periodontal ligament, and effective regenerative therapies remain limited. While the role of metabolic-epigenomic crosstalk in determining cell fate is well established, the specific mechanism by which a tricarboxylic acid (TCA) cycle metabolite can modulate chromatin regulation to promote periodontal regeneration remains to be elucidated. The impact of one TCA cycle metabolite, alpha-ketoglutarate (α-KG), was examined in human periodontal ligament fibroblasts cultured under osteogenic induction and profiled by ALP assays, RT-qPCR, analyses of multiple histone modifications, ATAC-seq, and RNA-seq. α-KG increased ALP activity and upregulated genes associated with osteogenesis and the extracellular matrix (ECM). ATAC-seq revealed minimal genome-wide accessibility changes, whereas histone analyses showed reduced H3K27me3, consistent with an epigenetic mechanism that does not require extensive chromatin opening."},{"id":"source_37","type":"source","study":"Alpha-ketoglutarate utilization in Saccharomyces cerevisiae : transport, compartmentation and catabolism","year":2020,"doi":"10.1038/s41598-020-69178-6","url":"https://doi.org/10.1038/s41598-020-69178-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Zhang 2020","excerpt":"α-Ketoglutarate (αKG) is a metabolite of the tricarboxylic acid cycle, important for biomass synthesis and a precursor for biotechnological products like 1,4-butanediol. In the eukaryote Saccharomyces cerevisiae αKG is present in different compartments. Compartmentation and (intra-)cellular transport could interfere with heterologous product pathways, generate futile cycles and reduce product yields. Batch and chemostat cultivations at low pH (≤ 5) showed that αKG can be transported, catabolized and used for biomass synthesis. The uptake mechanism of αKG was further investigated under αKG limited chemostat conditions at different pH (3, 4, 5, and 6). At very low pH (3, 4) there is a fraction of undissociated αKG that could diffuse over the periplasmic membrane. At pH 5 this fraction is very low, and the observed growth and residual concentration requires a permease/facilitated uptake mechanism of the mono-dissociated form of αKG. Consumption of αKG under mixed substrate conditions was only observed for low glucose concentrations in chemostat cultivations, suggesting that the putative αKG transporter is repressed by glucose."},{"id":"source_38","type":"source","study":"A scoping review regarding reproductive capacity modulation based on alpha-ketoglutarate supplementation","year":2024,"doi":"10.1530/REP-24-0137","url":"https://doi.org/10.1530/REP-24-0137","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Doroftei 2024","excerpt":"IN BRIEF: Alpha-ketoglutarate is a common metabolite in the tricarboxylic acid cycle and is central in modulating the reproductive potential in animal models. The present scoping review systematically covers the spectrum of a wide range of evidence from different viewpoints, focusing on the underlying processes and mechanisms of the developmental framework, aiming to fill the gaps within the existing literature. ABSTRACT: Alpha-ketoglutarate is an important intermediate molecule in the tricarboxylic acid cycle with a prominent role in distinct biological processes such as cellular energy metabolism, epigenetic regulation, and signaling pathways. We conducted a registered scoping review (OSF: osf.io/b8nyt) to explore the impact of exogenous supplementation on reproductive capabilities. Our strategy included evaluating the main research literature from different databases like PubMed-MEDLINE, Web of ScienceTM, Scopus, and Excerpta Medica dataBASE using a specific systematic layout to encompass all investigations based on experimental models and critically compare the results."},{"id":"source_39","type":"source","study":"Alpha-Ketoglutarate in Low-Protein Diets for Growing Pigs: Effects on Cecal Microbial Communities and Parameters of Microbial Metabolism","year":2018,"doi":"10.3389/fmicb.2018.01057","url":"https://doi.org/10.3389/fmicb.2018.01057","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2018","excerpt":"Alpha-ketoglutarate (AKG), a critical molecule in the tricarboxylic acid cycle, is beneficial to intestinal functions. However, its influence on intestinal microbiota and metabolism is not fully understood. We investigated the effects of a low-protein (LP) diet supplemented with AKG on cecal microbial communities and the parameters of microbial metabolism in growing pigs. Twenty-seven young pigs (Large White × Landrace) with an average initial body weight of 11.96 ± 0.18 kg were randomly allotted into three groups ( n = 9): a normal protein (NP) diet containing 20% crude protein (CP); LP diet formulated with 17% CP (LP diet); or LP diet supplemented with 10 g kg -1 of AKG (ALP diet). After a 35-day trial period, the digesta of the cecum were collected to analyze the concentrations of ammonia and short-chain fatty acids (SCFAs). We also performed a microbial analysis. Although no significant differences were found in performance among the diet groups, pigs fed the ALP diet had greater average daily gain (ADG) when compared with those in the LP group."},{"id":"source_40","type":"source","study":"Effects of Dietary Supplementation of Alpha-Ketoglutarate in a Low-Protein Diet on Fatty Acid Composition and Lipid Metabolism Related Gene Expression in Muscles of Growing Pigs","year":2019,"doi":"10.3390/ani9100838","url":"https://doi.org/10.3390/ani9100838","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2019","excerpt":"The aim of the current study was to investigate whether dietary supplementation with alpha-ketoglutarate (AKG) in a reduced crude protein (CP) diet would affect fatty acid composition and lipid metabolism related gene expression in the muscles of growing pigs. A total of 27 Large White × Landrace growing pigs at 44 ± 1 d of age (11.96 ± 0.18 kg) were randomly allocated to three treatments ( n = 9). Dietary treatments included: (1) normal protein diet with 20% crude protein (CP) (NP); (2) a low crude protein diet formulated to contain approximately 17% CP (LP); and (3) a low crude protein diet with 17% CP supplemented with 1% AKG at the expense of regular corn components (ALP). The experimental trial lasted 35 d. The results showed that compared with the NP and LP diets, supplementation with AKG in a low-protein diet increased the intramuscular fat (IMF), oleic acid (C18:1n-9), and monounsaturated fatty acid (MUFA) contents ( p < 0.05), and tended to increase the percentage of palmitoleic acid (C16:1) and stearic acid (C18:0) ( p < 0.10) in the biceps femoris and longissimus dorsi muscles of growing pigs."},{"id":"source_41","type":"source","study":"Effects of Long-Term Cultivation on Medium with Alpha-Ketoglutarate Supplementation on Metabolic Processes of Saccharomyces cerevisiae","year":2017,"doi":"10.1155/2017/8754879","url":"https://doi.org/10.1155/2017/8754879","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Burdyliuk 2017","excerpt":"During last years, alpha-ketoglutarate (AKG), an important intermediate in the Krebs cycle, has been intensively studied as a dietary supplement with stress-protective and potential antiaging effects. Here, we examined the effects of exogenous AKG on metabolic processes and survival of yeast Saccharomyces cerevisiae during long-term cultivation. Growth on AKG had no effect on the total cell number but increased the number of reproductively active cells at the late days of cultivation (from day 7 to day 15). A gradual increase in levels of total protein, glycogen, and trehalose was found over 7-day cultivation with more pronounced effects in AKG-grown cells. In control cells, metabolic activity and the activities of superoxide dismutase and catalase decreased, whereas levels of carbonyl proteins and low-molecular-mass thiols increased during 7-day cultivation. This suggests development of oxidative stress in stationary phase cells. Meanwhile, stationary phase cells cultured on AKG possessed higher levels of low-molecular-mass thiols and lower levels of carbonyl proteins and α -dicarbonyl compounds when compared to control ones."},{"id":"source_42","type":"source","study":"Glutaminase 1 regulates the release of extracellular vesicles during neuroinflammation through key metabolic intermediate alpha-ketoglutarate","year":2018,"doi":"10.1186/s12974-018-1120-x","url":"https://doi.org/10.1186/s12974-018-1120-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2018","excerpt":"BACKGROUND: Extracellular vesicles (EVs) are important in the intercellular communication of the central nervous system, and their release is increased during neuroinflammation. Our previous data demonstrated an increased release of EVs during HIV-1 infection and immune activation in glial cells. However, the molecular mechanism by which infection and inflammation increase EV release remains unknown. In the current study, we investigated the role of glutaminase 1 (GLS1)-mediated glutaminolysis and the production of a key metabolic intermediate α-ketoglutarate on EV release. METHODS: Human monocyte-derived macrophage primary cultures and a BV2 microglia cell line were used to represent the innate immune cells in the CNS. Transmission electron microscopy, nanoparticle tracking analysis, and Western blots were used to determine the EV regulation. GLS1 overexpression was performed using an adenovirus vector in vitro and transgenic mouse models in vivo. Data were evaluated statistically by ANOVA, followed by the Bonferroni post-test for paired observations. RESULTS: Our data revealed an increased release of EVs in GLS1-overexpressing HeLa cells."},{"id":"source_43","type":"source","study":"Replication Study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate","year":2017,"doi":"10.7554/eLife.26030","url":"https://doi.org/10.7554/eLife.26030","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Showalter 2017","excerpt":"In 2016, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fiehn et al., 2016), that described how we intended to replicate selected experiments from the paper \"The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate\" (Ward et al., 2010). Here, we report the results of those experiments. We found that cells expressing R172K mutant IDH2 did not display isocitrate-dependent NADPH production above vector control levels, in contrast to the increased production observed with wild-type IDH2. Conversely, expression of R172K mutant IDH2 resulted in increased alpha-ketoglutarate-dependent consumption of NADPH compared to wild-type IDH2 or vector control. These results are similar to those reported in the original study (Figure 2; Ward et al., 2010). Further, expression of R172K mutant IDH2 resulted in increased 2HG levels within cells compared to the background levels observed in wild-type IDH2 and vector control, similar to the original study (Figure 3D; Ward et al., 2010)."},{"id":"source_44","type":"source","study":"Alpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway","year":2017,"doi":"10.18632/oncotarget.16875","url":"https://doi.org/10.18632/oncotarget.16875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"He 2017","excerpt":"Alpha-ketoglutarate (AKG) is a critical nutritional factor in the maintenance of intestinal homeostasis. However, the relative mechanism of AKG has not been well understood. It was recently shown that the interaction between nuclear factor kappa B (NF-κB)-mediated inflammatory pathway and pregnane X receptor (PXR)-regulated detoxification pathway is a check and balance mechanism for keeping the homeostatic state of the intestine, preventing the onset of intestinal inflammation which may lead to cancer. In the current study we used lipopolysaccharide (LPS)-challenged piglet and intestinal porcine epithelial cells-J2 models to investigate the effects of dietary AKG supplementation on the intestinal immune system and PXR regulated target expression. We found that LPS induced significant activation of the NF-κB-mediated inflammatory pathway with concomitant impairment of intestinal nutrient absorption. AKG administration increased intracellular AKG and its metabolite concentrations and enhanced the mRNA expression of alpha-ketoglutarate dehydrogenase in vivo and in vitro . Thus dietary AKG supplementation reversed the adverse effects induced by LPS."},{"id":"source_45","type":"source","study":"Administration of alpha-ketoglutarate improves epithelial restitution under stress injury in early-weaning piglets","year":2017,"doi":"10.18632/oncotarget.20555","url":"https://doi.org/10.18632/oncotarget.20555","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"He 2017b","excerpt":"Alpha-ketoglutarate (AKG) is an important cellular metabolite that participates in energy production and amino acid metabolism. However, the protective effects and mechanism of AKG on mucosal lesions have not been well understood. This study was conducted to investigate the effects of dietary AKG supplementation on epithelial restitution in early-weaning piglets under Escherichia coli lipopolysaccharide (LPS) induction. A total of 32 weaned piglets were used in a 2 × 2 factorial design; the major factors were dietary treatment (basal diet or AKG diet) and inflammatory challenge (LPS or saline). The results showed that AKG supplementation improved the growth performance and intestinal morphology in the LPS-induced early-weaning piglets. Compared with the basal diet, the AKG diet remarkably decreased the concentration and mRNA expression of intestinal inflammatory cytokines (IL-1β, IL-6, and IL-12) in the LPS-induced piglets."},{"id":"source_46","type":"source","study":"Growth on Alpha-Ketoglutarate Increases Oxidative Stress Resistance in the Yeast Saccharomyces cerevisiae","year":2017,"doi":"10.1155/2017/5792192","url":"https://doi.org/10.1155/2017/5792192","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Bayliak 2017","excerpt":"Alpha-ketoglutarate (AKG) is an important intermediate in cell metabolism, linking anabolic and catabolic processes. The effect of exogenous AKG on stress resistance in S. cerevisiae cells was studied. The growth on AKG increased resistance of yeast cells to stresses, but the effects depended on AKG concentration and type of stressor. Wild-type yeast cells grown on AKG were more resistant to hydrogen peroxide, menadione, and transition metal ions (Fe 2+ and Cu 2+ ) but not to ethanol and heat stress as compared with control ones. Deficiency in SODs or catalases abolished stress-protective effects of AKG. AKG-supplemented growth led to higher values of total metabolic activity, level of low-molecular mass thiols, and activities of catalase and glutathione reductase in wild-type cells compared with the control. The results suggest that exogenous AKG may enhance cell metabolism leading to induction of mild oxidative stress. It turn, it results in activation of antioxidant system that increases resistance of S. cerevisiae cells to H 2 O 2 and other stresses. The presence of genes encoding SODs or catalases is required for the expression of protective effects of AKG."},{"id":"source_47","type":"source","study":"Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways","year":2016,"doi":"10.1038/srep26802","url":"https://doi.org/10.1038/srep26802","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Cai 2016","excerpt":"Skeletal muscle weight loss is accompanied by small fiber size and low protein content. Alpha-ketoglutarate (AKG) participates in protein and nitrogen metabolism. The effect of AKG on skeletal muscle hypertrophy has not yet been tested, and its underlying mechanism is yet to be determined. In this study, we demonstrated that AKG (2%) increased the gastrocnemius muscle weight and fiber diameter in mice. Our in vitro study also confirmed that AKG dose increased protein synthesis in C2C12 myotubes, which could be effectively blocked by the antagonists of Akt and mTOR. The effects of AKG on skeletal muscle protein synthesis were independent of glutamate, its metabolite. We tested the expression of GPR91 and GPR99. The result demonstrated that C2C12 cells expressed GPR91, which could be upregulated by AKG. GPR91 knockdown abolished the effect of AKG on protein synthesis but failed to inhibit protein degradation. These findings demonstrated that AKG promoted skeletal muscle hypertrophy via Akt/mTOR signaling pathway. In addition, GPR91 might be partially attributed to AKG-induced skeletal muscle protein synthesis."},{"id":"source_48","type":"source","study":"Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase","year":2013,"doi":"10.1186/1750-1172-8-192","url":"https://doi.org/10.1186/1750-1172-8-192","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Soreze 2013","excerpt":"BACKGROUND: Synthesis and apoenzyme attachment of lipoic acid have emerged as a new complex metabolic pathway. Mutations in several genes involved in the lipoic acid de novo pathway have recently been described (i.e., LIAS, NFU1, BOLA3, IBA57), but no mutation was found so far in genes involved in the specific process of attachment of lipoic acid to apoenzymes pyruvate dehydrogenase (PDHc), α-ketoglutarate dehydrogenase (α-KGDHc) and branched chain α-keto acid dehydrogenase (BCKDHc) complexes. METHODS: Exome capture was performed in a boy who developed Leigh disease following a gastroenteritis and had combined PDH and α-KGDH deficiency with a unique amino acid profile that partly ressembled E3 subunit (dihydrolipoamide dehydrogenase / DLD) deficiency. Functional studies on patient fibroblasts were performed. Lipoic acid administration was tested on the LIPT1 ortholog lip3 deletion strain yeast and on patient fibroblasts. RESULTS: Exome sequencing identified two heterozygous mutations (c.875C > G and c.535A > G) in the LIPT1 gene that encodes a mitochondrial lipoyltransferase which is thought to catalyze the attachment of lipoic acid on PDHc, α-KGDHc, and BCKDHc."},{"id":"source_49","type":"source","study":"A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process","year":2014,"doi":"10.1186/2049-3002-2-4","url":"https://doi.org/10.1186/2049-3002-2-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Stuart 2014","excerpt":"BACKGROUND: Targeting cancer cell metabolism is recognized as a promising arena for development of cancer chemotherapeutics. Moreover, redox metabolism is also systematically altered in tumor cells. Indeed, there is growing reason to believe that tumor-specific alteration of redox control of metabolism will be central to understanding and attacking malignancy. We report here that lipoate analog CPI-613 attacks a gate-keeping, lipoate-using metabolic enzyme, alpha-ketoglutarate dehydrogenase (KGDH), by a redox mechanism selectively in tumors cells. RESULTS: CPI-613 inhibited KGDH function strongly and rapidly, selectively in tumor cells. Moreover, CPI-613 induced a correspondingly rapid, powerful redox signal in tumor cell mitochondria. This signal was associated with redox modification of KGDH (including extensive enzyme glutathionylation and redox blockage of enzyme lipoate sulfhydryls), correlating with KGDH inactivation. The source of this tumor-specific mitochondrial redox modulatory signal was not electron transport complexes (I or III), but was largely or entirely the E3 (dihydrolipoamide dehydrogenase) component of dehydrogenases, including KGDH."},{"id":"source_50","type":"source","study":"D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2","year":2015,"doi":"10.1038/ncomms8768","url":"https://doi.org/10.1038/ncomms8768","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Lin 2015","excerpt":"Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG). In cancer, mutant IDH1/2 reduces α-KG to D2-hydroxyglutarate (D2-HG) disrupting α-KG-dependent dioxygenases. However, the physiological relevance of controlling the interconversion of D2-HG into α-KG, mediated by D2-hydroxyglutarate dehydrogenase (D2HGDH), remains obscure. Here we show that wild-type D2HGDH elevates α-KG levels, influencing histone and DNA methylation, and HIF1α hydroxylation. Conversely, the D2HGDH mutants that we find in diffuse large B-cell lymphoma are enzymatically inert. D2-HG is a low-abundance metabolite, but we show that it can meaningfully elevate α-KG levels by positively modulating mitochondrial IDH activity and inducing IDH2 expression. Accordingly, genetic depletion of IDH2 abrogates D2HGDH effects, whereas ectopic IDH2 rescues D2HGDH-deficient cells. Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and α-KG-mediated epigenetic remodelling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases."},{"id":"source_51","type":"source","study":"Comparative Study of Various Delivery Methods for the Supply of Alpha-Ketoglutarate to the Neural Cells for Tissue Engineering","year":2013,"doi":"10.1155/2013/294679","url":"https://doi.org/10.1155/2013/294679","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Vishnoi 2013","excerpt":"Delivery of growth factors or bioactive molecules plays an important role in tissue engineering, as the duration to which these are supplied can modulate the cell fate. Thus, the delivery method plays an important role, and the same is presented in this work wherein the exogenous supply of alpha-ketoglutarate ( α -KG) gave better results for fast proliferating cells as compared to delivery by microspheres or microspheres incorporated scaffolds which can be used while culturing slow growing cells. All these studies were performed in two dimensional (2D) and three dimensional (3D) setups in which chitosan-gelatin-polypyrrole has been used as 3-D scaffolds. Chitosan and gelatin microspheres alone as well as incorporated in the cryogels were characterized. MTT assay done using neuro-2a cell line showed approximately 42% and 70% increment in cellular proliferation when gelatin and chitosan microspheres were added in a 3-D setup, respectively, as compared to the control. Biochemical analysis of ammonia showed 6-fold reductions in ammonia level in a 3-D setup compared to the control."},{"id":"source_52","type":"source","study":"Alpha-Ketoglutarate: Physiological Functions and Applications","year":2016,"doi":"10.4062/biomolther.2015.078","url":"https://doi.org/10.4062/biomolther.2015.078","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wu 2016","excerpt":"Alpha-ketoglutarate (AKG) is a key molecule in the Krebs cycle determining the overall rate of the citric acid cycle of the organism. It is a nitrogen scavenger and a source of glutamate and glutamine that stimulates protein synthesis and inhibits protein degradation in muscles. AKG as a precursor of glutamate and glutamine is a central metabolic fuel for cells of the gastrointestinal tract as well. AKG can decrease protein catabolism and increase protein synthesis to enhance bone tissue formation in the skeletal muscles and can be used in clinical applications. In addition to these health benefits, a recent study has shown that AKG can extend the lifespan of adult Caenorhabditis elegans by inhibiting ATP synthase and TOR. AKG not only extends lifespan, but also delays age-related disease. In this review, we will summarize the advances in AKG research field, in the content of its physiological functions and applications."},{"id":"source_53","type":"source","study":"Registered report: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate","year":2016,"doi":"10.7554/eLife.12626","url":"https://doi.org/10.7554/eLife.12626","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fiehn 2016","excerpt":"The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from \"The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate\" by Ward and colleagues, published in Cancer Cell in 2010 (Ward et al., 2010). The experiments that will be replicated are those reported in Figures 2, 3 and 5. Ward and colleagues demonstrate the mutations in isocitrate dehydrogenase 2 (IDH2), commonly found in acute myeloid leukemia (AML), abrogate the enzyme's wild-type activity and confer to the mutant neomorphic activity that produces the oncometabolite 2-hydroxyglutarate (2-HG) (Figures 2 and 3)."}],"edges":[{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_1","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_2","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_3","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_4","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_5","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_6","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_7","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_8","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_9","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_10","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_11","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_12","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_13","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_14","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_15","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_16","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_17","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_18","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_19","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_20","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_21","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_22","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_23","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_24","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_25","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_26","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_27","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_28","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_29","type":"contains_claim"},{"from":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","to":"claim_30","type":"contains_claim"}],"screening":{"identified":53,"screened":53,"excluded":0,"included":53,"included_or_retained":53,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"53 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]}}},{"name":"contradiction_map.json","media_type":"application/json","content":{"publication_id":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","screening":{"identified":53,"screened":53,"excluded":0,"included":53,"included_or_retained":53,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"53 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["The conclusion is that Alpha-ketoglutarate remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","4 included sources were assigned to this outcome class. Directional coding: mixed=1, null=3. Directness coding: mechanistic=4.","Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.","Finally, the corpus contains a mechanism-to-clinic gap for the most clinically relevant claim, namely that αKG influences cardiovascular, skeletal, and longevity outcomes in humans. Mechanistic plausibility is densely documented: PI3K/Akt/HIF-1α angiogenesis in skin flaps (Huang 2025), PHD1-dependent NF-κB suppression in osteoclastogenesis (Tian 2023b), epigenetic H3K27me3 reduction in periodontal regeneration (Hasegawa 2026), histone methylation rescue in age-related osteoporosis (Wang 2020), and Tnfrsf12a/Fn14 histone-modification protection against cancer cachexia (Ruiz 2023). However, each of these sources is either preclinical (An 2021, Iwaniak 2022, Bayliak 2017, Kalawaj 2020), mechanistic-only (Iniguez 2022, Cai 2016, Qiu 2025, Sekita 2021, Wu 2018, Burdyliuk 2017, Showalter 2017, Fiehn 2016), or review/protocol-level (Sandalova 2023, Lamichhane 2023, Doroftei 2024, Wu 2016). The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. Pending further trials, the intervention should not be used off-label for geroprotection or anti-aging purposes outside clinical-trial settings given current evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\nDifferent RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-Ketoglutarate: An Effective Feed Supplement in Improving Bone Metabolism and Muscle Quality of Laying Hens: A Preliminary Study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEvaluation of Alpha-Ketoglutarate Supplementation on the Improvement of Intestinal Antioxidant Capacity and Immune Response in Songpu Mirror Carp ( Cyprinus carpio ) After Infection With Aeromonas hydrophila,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nDietary Alpha-Ketoglutarate Partially Abolishes Adverse Changes in the Small Intestine after Gastric Bypass Surgery in a Rat Model,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-ketoglutarate supplementation improves hyperglycemia and attenuates the decrease in GLUT4 and PGC-1α proteins in adipose tissue of streptozotocin-high-fat diet-induced diabetic mice,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Alpha Ketoglutarate Exerts In Vitro Anti-Osteosarcoma Effects through Inhibition of Cell Proliferation, Induction of Apoptosis via the JNK and Caspase 9-Dependent Mechanism, and Suppression of TGF-β and VEGF Production and Metastatic Potential of Cells\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEpigenetic modifier alpha-ketoglutarate modulates aberrant gene body methylation and hydroxymethylation marks in diabetic heart,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Dietary Alpha-Ketoglutarate Supplementation Improves Bone Growth, Phosphorus Digestion, and Growth Performance in Piglets\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-ketoglutarate ameliorates abdominal aortic aneurysm via inhibiting PXDN/HOCL/ERK signaling pathways,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)—intervention study protocol,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nElevation of Intracellular Alpha-Ketoglutarate Levels Inhibits Osteoclastogenesis by Suppressing the NF-κB Signaling Pathway in a PHD1-Dependent Manner,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-ketoglutarate enhances adipose-derived stem cells survival in wound healing by hypoxia-inducible factor 1-alpha-mediated redox homeostasis and glycogen-dependent bioenergetics,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nDevelopment and First-in-Human Translation of Hyperpolarized [1- 13 C]Alpha-Ketoglutarate MR Spectroscopy in the Brain,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Effects of Alpha-Ketoglutarate Supplementation on Growth Performance, Diarrhea Incidence, Plasma Amino Acid, and Nutrient Digestibility in Weaned Piglets\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Cholesterol Content, Fatty Acid Profile and Health Lipid Indices in the Egg Yolk of Eggs from Hens at the End of the Laying Cycle, Following Alpha-Ketoglutarate Supplementation\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffects of Dietary Alpha-Ketoglutarate Supplementation on Diarrhea Incidence and Nutrient Digestibility in Weaned Piglets Fed Low-Protein Diets,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-Ketoglutarate Promotes Goblet Cell Differentiation and Alters Urea Cycle Metabolites in DSS-Induced Colitis Mice,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-Ketoglutarate: A Potential Inner Mitochondrial and Cytosolic Protector against Peroxynitrite and Peroxynitrite-Induced Nitration?,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nLack of association of the alpha-ketoglutarate-dependent dioxygenase (FTO) gene polymorphisms with pulmonary tuberculosis risk: a systematic review and meta-analysis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"AKT signaling is associated with epigenetic reprogramming via the upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nFoliar application of alpha-ketoglutarate plus nitrogen improves drought resistance in soybean ( Glycine max L. Merr. ),not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nRepurposing FDA-approved drugs to find a novel inhibitor of alpha-ketoglutarate-dependent dioxygenase FTO to treat esophageal cancer,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha Ketoglutarate Downregulates the Neutral Endopeptidase and Enhances the Growth Inhibitory Activity of Thiorphan in Highly Aggressive Osteosarcoma Cells,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-Ketoglutarate Drives an Osteogenic and Extracellular Matrix Gene Program in Periodontal Ligament Fibroblasts via Selective Reduction of H3K27me3,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Alpha-ketoglutarate utilization in Saccharomyces cerevisiae : transport, compartmentation and catabolism\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nA scoping review regarding reproductive capacity modulation based on alpha-ketoglutarate supplementation,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAlpha-Ketoglutarate in Low-Protein Diets for Growing Pigs: Effects on Cecal Microbial Communities and Parameters of Microbial Metabolism,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffects of Dietary Supplementation of Alpha-Ketoglutarate in a Low-Protein Diet on Fatty Acid Composition and Lipid Metabolism Related Gene Expression in Muscles of Growing Pigs,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffects of Long-Term Cultivation on Medium with Alpha-Ketoglutarate Supplementation on Metabolic Processes of Saccharomyces cerevisiae,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nGlutaminase 1 regulates the release of extracellular vesicles during neuroinflammation through key metabolic intermediate alpha-ketoglutarate,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nReplication Study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAdministration of alpha-ketoglutarate improves epithelial restitution under stress injury in early-weaning piglets,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nGrowth on Alpha-Ketoglutarate Increases Oxidative Stress Resistance in the Yeast Saccharomyces cerevisiae,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nA strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nD2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nComparative Study of Various Delivery Methods for the Supply of Alpha-Ketoglutarate to the Neural Cells for Tissue Engineering,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAlpha-Ketoglutarate: Physiological Functions and Applications,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nRegistered report: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n"},{"name":"risk_of_bias.json","media_type":"application/json","content":{"publication_id":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised in public sidecar.","sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice","doi":"10.1016/j.redox.2021.102088","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-Ketoglutarate: An Effective Feed Supplement in Improving Bone Metabolism and Muscle Quality of Laying Hens: A Preliminary Study","doi":"10.3390/ani10122420","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Evaluation of Alpha-Ketoglutarate Supplementation on the Improvement of Intestinal Antioxidant Capacity and Immune Response in Songpu Mirror Carp ( Cyprinus carpio ) After Infection With Aeromonas hydrophila","doi":"10.3389/fimmu.2021.690234","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Dietary Alpha-Ketoglutarate Partially Abolishes Adverse Changes in the Small Intestine after Gastric Bypass Surgery in a Rat Model","doi":"10.3390/nu14102062","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate supplementation improves hyperglycemia and attenuates the decrease in GLUT4 and PGC-1α proteins in adipose tissue of streptozotocin-high-fat diet-induced diabetic mice","doi":"10.1017/jns.2025.10059","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia","doi":"10.1038/s41467-025-64360-8","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha Ketoglutarate Exerts In Vitro Anti-Osteosarcoma Effects through Inhibition of Cell Proliferation, Induction of Apoptosis via the JNK and Caspase 9-Dependent Mechanism, and Suppression of TGF-β and VEGF Production and Metastatic Potential of Cells","doi":"10.3390/ijms21249406","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Epigenetic modifier alpha-ketoglutarate modulates aberrant gene body methylation and hydroxymethylation marks in diabetic heart","doi":"10.1186/s13072-023-00489-4","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Dietary Alpha-Ketoglutarate Supplementation Improves Bone Growth, Phosphorus Digestion, and Growth Performance in Piglets","doi":"10.3390/ani13040569","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Effects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation","doi":"10.3390/cells15030281","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway","doi":"10.1186/s13619-025-00264-8","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations","doi":"10.1038/s41467-020-19360-1","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate ameliorates abdominal aortic aneurysm via inhibiting PXDN/HOCL/ERK signaling pathways","doi":"10.1186/s12967-022-03659-2","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)—intervention study protocol","doi":"10.1007/s11357-023-00813-6","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Elevation of Intracellular Alpha-Ketoglutarate Levels Inhibits Osteoclastogenesis by Suppressing the NF-κB Signaling Pathway in a PHD1-Dependent Manner","doi":"10.3390/nu15030701","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate enhances adipose-derived stem cells survival in wound healing by hypoxia-inducible factor 1-alpha-mediated redox homeostasis and glycogen-dependent bioenergetics","doi":"10.4252/wjsc.v18.i2.113694","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Development and First-in-Human Translation of Hyperpolarized [1- 13 C]Alpha-Ketoglutarate MR Spectroscopy in the Brain","doi":"10.3390/s26092753","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Effects of Alpha-Ketoglutarate Supplementation on Growth Performance, Diarrhea Incidence, Plasma Amino Acid, and Nutrient Digestibility in Weaned Piglets","doi":"10.3390/ani15121723","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia","doi":"10.3390/genes14091818","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Cholesterol Content, Fatty Acid Profile and Health Lipid Indices in the Egg Yolk of Eggs from Hens at the End of the Laying Cycle, Following Alpha-Ketoglutarate Supplementation","doi":"10.3390/foods10030596","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Effects of Dietary Alpha-Ketoglutarate Supplementation on Diarrhea Incidence and Nutrient Digestibility in Weaned Piglets Fed Low-Protein Diets","doi":"10.3390/vetsci12121163","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-Ketoglutarate Promotes Goblet Cell Differentiation and Alters Urea Cycle Metabolites in DSS-Induced Colitis Mice","doi":"10.3390/nu14061148","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test","doi":"10.18632/aging.203736","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-Ketoglutarate: A Potential Inner Mitochondrial and Cytosolic Protector against Peroxynitrite and Peroxynitrite-Induced Nitration?","doi":"10.3390/antiox10091501","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Lack of association of the alpha-ketoglutarate-dependent dioxygenase (FTO) gene polymorphisms with pulmonary tuberculosis risk: a systematic review and meta-analysis","doi":"10.1097/MS9.0000000000001188","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"AKT signaling is associated with epigenetic reprogramming via the upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation","doi":"10.1186/s13287-021-02578-1","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease","doi":"10.3390/life11040321","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Foliar application of alpha-ketoglutarate plus nitrogen improves drought resistance in soybean ( Glycine max L. Merr. )","doi":"10.1038/s41598-022-18660-4","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Repurposing FDA-approved drugs to find a novel inhibitor of alpha-ketoglutarate-dependent dioxygenase FTO to treat esophageal cancer","doi":"10.4103/RPS.RPS_9_25","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha Ketoglutarate Downregulates the Neutral Endopeptidase and Enhances the Growth Inhibitory Activity of Thiorphan in Highly Aggressive Osteosarcoma Cells","doi":"10.3390/molecules28010097","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-Ketoglutarate Drives an Osteogenic and Extracellular Matrix Gene Program in Periodontal Ligament Fibroblasts via Selective Reduction of H3K27me3","doi":"10.3390/biology15050372","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate utilization in Saccharomyces cerevisiae : transport, compartmentation and catabolism","doi":"10.1038/s41598-020-69178-6","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"A scoping review regarding reproductive capacity modulation based on alpha-ketoglutarate supplementation","doi":"10.1530/REP-24-0137","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Alpha-Ketoglutarate in Low-Protein Diets for Growing Pigs: Effects on Cecal Microbial Communities and Parameters of Microbial Metabolism","doi":"10.3389/fmicb.2018.01057","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Effects of Dietary Supplementation of Alpha-Ketoglutarate in a Low-Protein Diet on Fatty Acid Composition and Lipid Metabolism Related Gene Expression in Muscles of Growing Pigs","doi":"10.3390/ani9100838","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Effects of Long-Term Cultivation on Medium with Alpha-Ketoglutarate Supplementation on Metabolic Processes of Saccharomyces cerevisiae","doi":"10.1155/2017/8754879","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Glutaminase 1 regulates the release of extracellular vesicles during neuroinflammation through key metabolic intermediate alpha-ketoglutarate","doi":"10.1186/s12974-018-1120-x","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Replication Study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate","doi":"10.7554/eLife.26030","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway","doi":"10.18632/oncotarget.16875","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Administration of alpha-ketoglutarate improves epithelial restitution under stress injury in early-weaning piglets","doi":"10.18632/oncotarget.20555","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Growth on Alpha-Ketoglutarate Increases Oxidative Stress Resistance in the Yeast Saccharomyces cerevisiae","doi":"10.1155/2017/5792192","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways","doi":"10.1038/srep26802","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase","doi":"10.1186/1750-1172-8-192","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process","doi":"10.1186/2049-3002-2-4","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2","doi":"10.1038/ncomms8768","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Comparative Study of Various Delivery Methods for the Supply of Alpha-Ketoglutarate to the Neural Cells for Tissue Engineering","doi":"10.1155/2013/294679","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Alpha-Ketoglutarate: Physiological Functions and Applications","doi":"10.4062/biomolther.2015.078","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Registered report: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate","doi":"10.7554/eLife.12626","risk_of_bias":"not appraised in public sidecar","directness":"primary"}]}}]}