The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress

Redox Biology, Год журнала: 2023, Номер 62, С. 102663 - 102663

Опубликована: Март 10, 2023

Osteoarthritis (OA) is an age-related metabolic disease. Low-grade inflammation and oxidative stress are the last common pathway of OA. α-ketoglutarate (α-KG) essential physiological metabolite from mitochondrial tricarboxylic acid (TCA) cycle, with multiple functions, including anti-inflammation antioxidation, exhibits decreased serum levels age. Herein, we aimed to investigate effect mechanism α-KG on We first quantified in human cartilage tissue osteoarthritic chondrocytes induced by IL-1β. Besides, IL-1β-induced were treated different concentrations α-KG. Chondrocyte proliferation apoptosis, synthesis degradation extracellular matrix, mediators analyzed. RNA sequencing was used explore α-KG, mitophagy further detected. These results verified anterior cruciate ligament transection (ACLT) OA rat model. found that content 31.32% damaged medial than normal lateral 36.85% compared control. supplementation reversed chondrocyte inhibition increased transcriptomic proteinic expression ACAN COL2A1 vivo vitro, but inhibited MMP13, ADAMTS5, IL-6, TNF-α. In mechanism, promoted ROS generation, these effects could be prevented Mdivi-1 (a inhibitor). Overall, chondrocytes. Moreover, alleviate phenotype regulating stress, suggesting its potential as a therapeutic target ameliorate

Язык: Английский

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Lachnospiraceae -derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus

Science Advances, Год журнала: 2023, Номер 9(44)

Опубликована: Ноя. 3, 2023

Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain unclear. Here, we report association placental inflammation (tumor necrosis factor–α) abnormal maternal glucose metabolism in patients with GDM, high fermentable dietary fiber (HFDF; konjac ) could reduce GDM development through gut flora–short-chain fatty acid–placental axis mouse model. Mechanistically, HFDF increases abundances Lachnospiraceae butyrate, reduces placental-derived by enhancing barrier inhibiting transfer bacterial-derived lipopolysaccharide, ultimately resists high-fat diet–induced resistance. butyrate have similar anti-GDM anti–placental effects, they can ameliorate function pregnancy outcome effects probably dampening immune dysfunction. These findings demonstrate involvement important inflammation–related progression great potential HFDFs to susceptibility gut-flora-placenta axis.

Язык: Английский

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Blood‐Glucose‐Powered Metabolic Fuel Cell for Self‐Sufficient Bioelectronics

Advanced Materials, Год журнала: 2023, Номер 35(21)

Опубликована: Март 9, 2023

Abstract Currently available bioelectronic devices consume too much power to be continuously operated on rechargeable batteries, and are often powered wirelessly, with attendant issues regarding reliability, convenience, mobility. Thus, the availability of a robust, self‐sufficient, implantable electrical generator that works under physiological conditions would transformative for many applications, from driving implants prostheses programing cellular behavior patients’ metabolism. Here, capitalizing new copper‐containing, conductively tuned 3D carbon nanotube composite, an blood‐glucose‐powered metabolic fuel cell is designed monitors blood‐glucose levels, converts excess glucose into during hyperglycemia, produces sufficient energy (0.7 mW cm −2 , 0.9 V, 50 m glucose) drive opto‐ electro‐genetic regulation vesicular insulin release engineered beta cells. It shown this integration monitoring elimination excessive blood by combined electro‐metabolic conversion insulin‐release‐mediated consumption enables restore homeostasis in automatic, closed‐loop manner experimental model type‐1 diabetes.

Язык: Английский

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α-Ketoglutarate prevents hyperlipidemia-induced fatty liver mitochondrial dysfunction and oxidative stress by activating the AMPK-pgc-1α/Nrf2 pathway

Redox Biology, Год журнала: 2024, Номер 74, С. 103230 - 103230

Опубликована: Июнь 13, 2024

α-Ketoglutarate (AKG), a crucial intermediate in the tricarboxylic acid cycle, has been demonstrated to mitigate hyperlipidemia-induced dyslipidemia and endothelial damage. While hyperlipidemia stands as major trigger for non-alcoholic fatty liver disease, protection of AKG on hepatic metabolic disorders remains underexplored. This study aims investigate potential protective effects mechanisms against lipid caused by acute hyperlipidemia. Our observations indicate that effectively alleviates accumulation, mitochondrial dysfunction, loss redox homeostasis P407-induced mice, well palmitate-injured HepG2 cells primary hepatocytes. Mechanistic insights reveal preventive are mediated activating AMPK-PGC-1α/Nrf2 pathway. In conclusion, our findings shed light role mechanism ameliorating abnormal liver, suggesting AKG, an endogenous nutrient, holds promising addressing conditions.

Язык: Английский

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Increased hepatic gluconeogenesis and type 2 diabetes mellitus

Trends in Endocrinology and Metabolism, Год журнала: 2024, Номер 35(12), С. 1062 - 1077

Опубликована: Май 29, 2024

Язык: Английский

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Influence of glutamine metabolism on diabetes Development:A scientometric review

Heliyon, Год журнала: 2024, Номер 10(4), С. e25258 - e25258

Опубликована: Фев. 1, 2024

Objective"Metabolism affects function" is the consensus of researchers at present. It has potential clinical application value to study effects regulating glutamine (Gln) metabolism on diabetes physiology or pathology. Our research aimed summarize latest progress, frontier hot topics and future development trends in this field from perspective scientometrics.MethodsRelevant literatures reviews were obtained Web Science (WoS) between January 1, 2001 May 31, 2022. An online analysis platform bibliometrics, CiteSpace, VOS viewer software used generate visual knowledge network graphs, including publication countries, institutions authors partnership analysis, co-occurrence co-citation as well citations keywords burst detection acquire hotspots.ResultsOur results showed that a total 945 publications WoS database met requirements, with articles being main type. The overall characteristics an increasing trend number citations. United States was leading way hub for aggregating collaborations across countries. Vanderbilt University delivered high-quality impact most published articles. DeBerardinis, RJ representative author his contents Gln mitochondrial glutaminolysis. Significantly, there relative lack collaboration authors. In addition, "type 2 diabetes", "glutamine", "metabolism", "gene expression" "metabolomics" categories high frequency references cluster keywords. Analysis popular "branched chain", "oxidative phosphorylation", "kinase", "insulin sensitivity", "tca cycle", "magnetic resonance spectroscopy" "flux analysis" new directions emerging methods explore link diabetes. Overall, exploring gradual upward diabetes.ConclusionThis comprehensive scientometric identified general outlook provided valuable guidance ongoing research. Strategies regulate hold promise novel target treat diabetes, integration intersection multidisciplinary provides cooperation strategies technical guarantees field.

Язык: Английский

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A multiomics approach reveals evidence for phenylbutyrate as a potential treatment for combined D,L-2- hydroxyglutaric aciduria

Molecular Genetics and Metabolism, Год журнала: 2024, Номер 142(3), С. 108495 - 108495

Опубликована: Май 15, 2024

To identify therapies for combined D, L-2-hydroxyglutaric aciduria (C-2HGA), a rare genetic disorder caused by recessive variants in the SLC25A1 gene. Patients C-2HGA were identified and diagnosed whole exome sequencing biochemical genetics testing. Patient derived fibroblasts then treated with phenylbutyrate functional effects assessed metabolomics RNA-sequencing. In this study, we demonstrated that patient exhibited impaired cellular bioenergetics. Moreover, Fibroblasts form one worsened bioenergetics when supplemented citrate. We hypothesized treating cells (PB), an FDA approved pharmaceutical drug conjugates glutamine renal excretion, would reduce mitochondrial 2-ketoglutarate, thereby leading to improved Metabolomic RNA-seq analyses of PB-treated significant decrease intracellular 2-hydroxyglutarate, levels mRNA coding citrate synthase isocitrate dehydrogenase. Consistent known action PB, increased level phenylacetylglutamine was consistent acting as 2-ketoglutarate sink. Our pre-clinical studies suggest supplementation has possibility exacerbating energy metabolism condition. However, improvement suggests might have interventional utility disease.

Язык: Английский

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Alpha-ketoglutarate promotes anxiety, activates autophagy, and suppresses antioxidant enzymes in the cerebral cortex of female mice on cafeteria diet

Brain Research Bulletin, Год журнала: 2025, Номер 222, С. 111255 - 111255

Опубликована: Фев. 12, 2025

Alpha-ketoglutarate (AKG), an intermediate of the tricarboxylic acid cycle, has been found to mitigate oxidative stress and inflammation. In turn, a cafeteria diet (CD), obesogenic diet, is often associated with This study aimed determine whether AKG can level effects CD on animal behavior, markers, glycolytic flow, autophagy in mouse cerebral cortex. Female C57BL/6J mice were divided into two groups fed either standard or for eight weeks. For next four weeks, each group continued be previous diet; however, half individuals within received drinking water 1% AKG. Using open field test, we that combination promoted development anxiety signs. Both decreased exploratory behavior mice, significant additive effect combined diet. On diets supplemented AKG, animals produced fewer fecal boli, measure emotionality. all experimental diets, had lower activities antioxidant related enzymes, no differences enzymes. The AKG-supplemented induced transcription autophagy-related genes targets forkhead box O factor, involved regulation carbohydrate metabolism. Transcriptional changes by partly abrogated CD. These findings suggest particularly when CD, may modulate behavioral responses intensity brain altering key metabolic autophagic pathways.

Язык: Английский

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Non-targeted metabolomic study in plasma in rats with post-traumatic osteoarthritis model

PLoS ONE, Год журнала: 2025, Номер 20(3), С. e0315708 - e0315708

Опубликована: Март 12, 2025

Purpose This study aimed to examine the differential expression profiles of plasma metabolites in rat models post-traumatic osteoarthritis (PTOA) and elucidate roles their pathways progression PTOA using bioinformatics analysis. Method Plasma samples were collected from 24 SD female rats model PTOA, metabolomic assays conducted. The divided into three groups: surgically induced mild group (Group A: 3 weeks postoperative modified Hulth model; age 2 months), severe B: 5 normal control C: healthy aged months). Metabolites structurally identified by comparing retention times, molecular masses, secondary fragmentation spectra, collision energies, other metabolite data with a database (provided Shanghai Applied Protein Technology Co., Ltd.). Target prediction pathway analysis subsequently performed Results experiment revealed that group, levels Alpha-ketoglutarate, Isocitric acid, Dichloroacetate, increased significantly compared whereas Linolenic Lactose, others decreased significantly. These findings suggest these can serve as biomarkers for diagnosis early PTOA. In Diosgenin, Indoleacrylic elevated may also be used diagnosis. Adrenosterone, (+)-chlorpheniramine, Phenanthridine higher while Menadione, Adenosine 5’-monophosphate, Arg-Gly-Asp lower. Conclusions Taurocholate, indoleacrylic alpha-ketoglutarate, isocitric acid joint injury rats. adenosine exhibited between groups rats, potentially reflecting injury’s severity. Further investigation molecules human tissues is warranted ascertain utility humans.

Язык: Английский

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Proline hydroxylase 2 (PHD2) promotes brown adipose thermogenesis by enhancing the hydroxylation of UCP1

Molecular Metabolism, Год журнала: 2023, Номер 73, С. 101747 - 101747

Опубликована: Июнь 4, 2023

Brown adipose tissue (BAT) plays a crucial role in regulating non-shivering thermogenesis under cold exposure. Proline hydroxylases (PHDs) were found to be involved adipocyte differentiation and lipid deposition. However, the effects of PHDs on regulatory mechanisms BAT are not fully understood. We detected expression different tissues by using immunoblotting real-time PCR. Further, immunoblotting, PCR, immunostaining performed determine correlation between proline hydroxylase 2 (PHD2) UCP1 expression. Inhibitor PHD2-sgRNA viruses used construct PHD2-deficiency model vivo vitro investigate impacts PHD2 thermogenesis. Afterward, interaction hydroxylation modification level verified Co-IP assays immunoblotting. Finally, effect specific expression/activity was further confirmed site-directed mutation mass spectrometry analysis. PHD2, but PHD1 PHD3, highly enriched BAT, colocalized, positively correlated with UCP1. Inhibition or knockdown significantly suppressed exposure aggravated obesity mice fed HFD. Mechanistically, mitochondrial bound regulated UCP1, which enhanced thermogenic activation attenuated knockdown. Furthermore, PHD2-dependent promoted stability protein. Mutation prolines (Pro-33, 133, 232) mitigated PHD2-elevated reversed PHD2-increased stability. This study suggested an important for regulation enhancing

Язык: Английский

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