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The Journal of Biomedical Research 2021年第1期35卷 36-46,I0014-I0016页

作者： Ming Xing Na Wang Hanyi Zeng Jun Zhang State Key Laboratory of Reproductive Medicine Department of Histology and EmbryologyNanjing Medical UniversityNanjingJiangsu 211166China

There is growing evidence that cellular metabolism can directly participate in epigenetic dynamics and consequently modulate gene ***,the role of metabolites in activating the key gene regulatory network for specialization of germ cell lineage remains largely ***,we identified some cellular metabolites with significant changes by untargeted metabolomics between mouse epiblast-like cells(EpiLCs)and primordial germ cell-like cells(PGCLCs).More importantly,we found that inhibition of glutaminolysis by bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide(BPTES)impeded PGCLC specialization,but the impediment could be rescued by addition ofα-ketoglutarate(αKG),the intermediate metabolite of oxidative phosphorylation and ***,adding aKG alone to the PGCLC medium accelerated the PGCLC specialization through promoting H3 K27 me3 ***,our study reveals the importance of metabolite aKG in the germ cell fate determination and highlights the essential role of cellular metabolism in shaping the cell identities through epigenetic events.

关键词： cellular metabolism α-ketoglutarate primordial germ cells epigenome

Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages throughα-ketoglutarate and mTORC1 signaling

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Cellular & Molecular Immunology 2024年第5期21卷 448-465页

作者： Zhengnan Cai Wan Li Sonja Hager Jayne Louise Wilson Leila Afjehi-Sadat Elke HHeiss Thomas Weichhart Petra Heffeter Wolfram Weckwerth Molecular Systems Biology(MOSYS) Department of Functional and Evolutionary EcologyUniversity of ViennaViennaAustria. Vienna Doctoral School of Ecology and Evolution University of ViennaViennaAustria. Center for Cancer Research and Comprehensive Cancer Center Medical University of ViennaViennaAustria. Department of Food Chemistry and Toxicology Faculty of ChemistryUniversity of ViennaViennaAustria. Center for Pathobiochemistry and Genetics Institute of Medical GeneticsMedical University of ViennaViennaAustria. Research Support Facility Mass Spectrometry UnitFaculty of Life ScienceUniversity of ViennaViennaAustria. Department of Pharmaceutical Sciences University of ViennaViennaAustria. Vienna Metabolomics Center(VIME) University of ViennaViennaAustria.

Phosphoglycerate dehydrogenase(PHGDH)has emerged as a crucial factor in macromolecule synthesis,neutralizing oxidative stress,and regulating methylation reactions in cancer cells,lymphocytes,and endothelial ***,the role of PHGDH in tumor-associated macrophages(TAMs)is poorly ***,we found that the T helper 2(Th2)cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and *** of PHGDH disrupts cellular metabolism and mitochondrial respiration,which are essential for immunosuppressive ***,PHGDH-mediated serine biosynthesis promotesα-ketoglutarate production,which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor *** ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth,reduced TAM infiltration,a phenotypic shift of M2-like TAMs toward an M1-like phenotype,downregulated PD-L1 expression and enhanced antitumor T-cell *** study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.

关键词： PHGDH de novo serine synthesis α-ketoglutarate mTORC1 protumorigenic tumor-associated macrophages,metabolomics

Effect of Pre-treatment of α-ketoglutarate on Cyanide-induced Toxicity and Alterations in Various Physiological Variables in Rodents

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Biomedical and Environmental Sciences 2007年第1期20卷 56-63页

作者： RAJKUMAR TULSAWANI DEO KUMAR R.BHATTACHARYA Division of Pharmacology and Toxicology Defence Research and Development Establishment Jhansi Road Gwalior 474 002 M.P. India

Objective To investigate the effects of pre-treatment of α-ketoglutarate （α-KG） on cyanide-induced lethality and changes in various physiological parameters in rodents. Methods The LD50 of potassium cyanide （KCN） given orally （po）, intraperitoneally （ip）, subcutaneously （sc） or intravenously （iv） was determined in male mice, in the presence or absence α-KG given po, ip or iv. α-KG was administered 10, 20 or 40 min prior to KCN at 0.50, 1.0 or 2.0 g/kg by po or ip route, and at 0.10, 0.20 or 0.40 g/kg by iv route. Protection index （PI） was calculated as the ratio of LD50 of KCN in the presence of α-KG （protected animals） and LD50 of KCN in the absence of α-KG （unprotected animals）. In a separate experiment, several physiological variables viz. mean arterial pressure （MAP）, heart rate （HR）, respiratory rate （RR）, neuromuscular transmission （NMT） and rectal temperature （RT） were measured in anesthetized female rats pre-treated （-10 rain） with po （2.0 g/kg） or iv （0.125 g/kg） α-KG and then administered sub-lethal （0.75 LD50） or lethal （2.0, 4.0 or 8.0 LD50） doses of KCN （po）. Results PI of 4.52, 6.40 and 7.60 at -10 min, 3.20, 5.40 and 6.40 at -20 min, and 1.40, 3.20 and 5.40 at -40 min of po administration with α-KG was observed for 0.50, 1.0 and 2.0 g/kg doses, respectively, against KCN given by po route. When KCN was given ip, a PI of 3.38, 4.79 and 5.70 was observed for 0.50, 1.0 and 2.0 g/kg α-KG given ip （-10 min）, respectively. A lower PI of 3.37, 2.83 and 2.38 was observed when KCN given sc was challenged by 2.0 g/kg α-KG given ip at -10, -20 or -40 min, respectively. Similarly, a PI of 3.37, 2.83 and 2.0 was noted when KCN given sc was antagonized by 2.0 g/kg α-KG given po at -10, -20 or -40 rain, respectively. No appreciable protection was observed when lower doses of α-KG （ip or po） challenged KCN given by sc route. Pre-treatment of iv or po administration of α-KG did not afford any protection against KCN given po or iv route. Oral treatment of 0.75 LD50 KCN

关键词： Cyanide Toxicity Physiological variables Protection α-ketoglutarate

IDH1 mutation inhibits differentiation of astrocytes and glioma cells with low oxoglutarate dehydrogenase expression by disturbingα-ketoglutarate-related metabolism and epigenetic modification

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Life Metabolism 2024年第2期3卷 24-37页

作者： Yuanlin Zhao Ying Yang Risheng Yang Chao Sun Xing Gao Xiwen Gu Yuan Yuan Yating Nie Shenhui Xu Ruili Han Lijun Zhang Jing Li Peizhen Hu Yingmei Wang Huangtao Chen Xiangmei Cao Jing Wu Zhe Wang Yu Gu Jing Ye State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Department of PathologyXijing Hospital and School of Basic MedicineFourth Military Medical UniversityXi’anShaanxi 710032China Department of Pathology Air Force Hospital of Southern Theater CommandGuangzhouGuangdong 510000China Department of Neurology Tangdu HospitalFourth Military Medical UniversityXi’anShaanxi 710038China Department of Clinical Diagnosis Tangdu HospitalFourth Military Medical UniversityXi’anShaanxi 710038China Department of Neurosurgery the Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxi 710004China Department of Pathology School of Basic Medical SciencesNingxia Medical UniversityYinchuanNingxia 750004China Institute of Analytical Chemistry and Instrument for Life Science The Key Laboratory of Biomedical Information Engineering of Ministry of EducationSchool of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxi 710049China

Isocitrate dehydrogenase(IDH)mutations frequently occur in lower-grade gliomas and secondary *** IDHs exhibit a gain-of-function activity,leading to the production of D-2-hydroxyglutarate(D-2HG)by reducing α-ketoglutarate(α-KG),a central player in metabolism and epigenetic ***,the role ofα-KG homeostasis in IDH-mutated gliomagenesis remains *** this study,we found that low expression of oxoglutarate dehydrogenase(OGDH)was a common feature in IDH-mutated gliomas,as well as *** low expression of OGDH resultedin the accumulation of α-KG and promoted astrocyte ***,IDH1 mutation significantly reducedα-KG levels and increased glutaminolysis and DNA/histone methylation in *** metabolic and epigenetic alterations inhibited astrocyte maturation and led to cortical dysplasia in ***,our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells,while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation ofα-KG and increasing ***,we found that l-glutamine increasedα-KG levels and augmented the differentiation-promoting effects of AGI5198,an IDH1-mutant inhibitor,in IDH1-mutant glioma ***,this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas,providing a potential strategy for the treatment of IDH-mutant gliomas by targetingα-KG homeostasis.

关键词： α-ketoglutarate IDH1 mutation OGDH l-glutamine gliomas

Mitochondrial malic enzyme 2 promotes breast cancer metastasis via stabilizing HIF-1α under hypoxia

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Chinese Journal of Cancer Research 2021年第3期33卷 308-322页

作者： Duo You Danfeng Du Xueke Zhao Xinmin Li Minfeng Ying Xun Hu Cancer Institute(Key Laboratory for Cancer Intervention and Prevention China National Ministry of EducationZhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences)The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310000China State Key Laboratory of Esophageal Cancer Prevention&Treatment and Henan Key Laboratory of Esophageal Cancer Research of the First Affiliated Hospital Zhengzhou UniversityZhengzhou 450000China Department of Pathology Women and Infants Hospital of ZhengzhouZhengzhou 450000China

Objective: α-ketoglutarate(α-KG) is the substrate to hydroxylate collagen and hypoxia-inducible factor-1α(HIF-1α), which are important for cancer metastasis. Previous studies have shown that the upregulation of collagen prolyl 4-hydroxylase in breast cancer cells stabilizes the expression of HIF-1α by depleting α-KG levels. We hypothesized that mitochondrial malic enzyme 2(ME2) might also affect HIF-1α expression via modulating α-KG levels in breast cancer ***: We evaluated ME2 protein expression in 100 breast cancer patients using immunohistochemistry and correlated with clinicopathological indicators. The effect of ME2 knockout on cancer metastasis was evaluated using an orthotopic breast cancer model. The effect of ME2 knockout or knockdown on the levels of α-KG and HIF-1α proteins in breast cancer cell lines was determined both in vitro and in ***: ME2 was found to be upregulated in the human breast cancerous tissues compared with the matched precancerous tissues(P<0.001). The elevated expression of ME2 was associated with a poor prognosis(P=0.019).ME2 upregulation was also related to lymph node metastasis(P=0.016), pathological staging(P=0.033), and vascular cancer embolus(P=0.014). Also, ME2 knockout significantly inhibited lung metastasis in vivo. In the tumors formed by ME2 knockout cells, the levels of α-KG were significantly increased and collagen hydroxylation level did not change significantly but HIF-1α protein expression was significantly decreased, compared to the control samples. In cell culture, cells with ME2 knockout or knockdown demonstrated significantly higher α-KG levels but significantly lower HIF-1α protein expression than control cells under hypoxia. Exogenous malate and α-KG exerted similar effect on HIF-1α in breast cancer cells to ME2 knockout or knockdown. Additionally,treatment with malate significantly decreased 4 T1 breast cancer lung metastasis. ME2 expression was associated with HIF-1α levels in human breast canc

关键词： Malic enzyme 2 breast cancer metastasis malate α-ketoglutarate hypoxia-inducible factor-1α