|
|
|
题名
|
作者
|
年代
|
出处
|
被引量
|
| 1 | Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma显示文摘Hepatocellular carcinoma(HCC)is an aggressive human cancer with increasing incidence worldwide.Multiple efforts have been made to explore pharmaceutical therapies to treat HCC,such as targeted tyrosine kinase inhibitors,immune based therapies and combination of chemotherapy.However,limitations exist in current strategies including chemoresistance for instance.Tumor initiation and progression is driven by reprogramming of metabolism,in particular during HCC development.Recently,metabolic associated fatty liver disease(MAFLD),a reappraisal of new nomenclature for nonalcoholic fatty liver disease(NAFLD),indicates growing appreciation of metabolism in the pathogenesis of liver disease,including HCC,thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment.In this review,we introduce directions by highlighting the metabolic targets in glucose,fatty acid,amino acid and glutamine metabolism,which are suitable for HCC pharmaceutical intervention.We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment.Furthermore,opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed. | Danyu Du Chan Liu Mengyao Qin Xiao Zhang Tao Xi Shengtao Yuan Haiping Hao Jing Xiong | 2022 | Acta Pharmaceutica Sinica B2022，12，2： | 27 |
| 2 | The role of the HIF-1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer显示文摘Background:As a rate-limiting enzyme of glycolysis,pyruvate kinase muscle isozyme M2(PKM2)participates in tumor metabolism and growth.The regulatory network of PKM2 in cancer is complex and has not been fully studied in bladder cancer.The 5-methylcytidine(m5C)modification in PKM2 mRNA might participate in the pathogenesis of bladder cancer and need to be further clarified.This study aimed to investigate the biological function and regulatory mechanism of PKM2 in bladder cancer.Methods:The expression of PKM2 and Aly/REF export factor(ALYREF)was measured by Western blotting,qRT-PCR,and immunohistochemistry.The bioprocesses of bladder cancer cells were demonstrated by a series of experiments in vitro and in vivo.RNA immunoprecipitation,RNA-sequencing,and dualluciferase reporter assays were conducted to explore the potential regulatory mechanisms of PKM2 in bladder cancer.Results:In bladder cancer,we first demonstrated that ALYREF stabilized PKM2 mRNA and bound to its m5C sites in 3′-untranslated regions.Overexpression of ALYREF promoted bladder cancer cell proliferation by PKM2-mediated glycolysis.Furthermore,high expression of PKM2 and ALYREF predicted poor survival in bladder cancer patients.Finally,we found that hypoxia-inducible factor-1alpha(HIF-1α)indirectly up-regulated the expression of PKM2 by activating ALYREF in addition to activating its transcription directly.Conclusions:The m5C modification in PKM2 mRNA in the HIF-1α/ALYREF/PKM2 axis may promote the glucose metabolism of bladder cancer,providing a new promising therapeutic target for bladder cancer. | Jing-Zi Wang Wei Zhu Jie Han Xiao Yang Rui Zhou Hong-Cheng Lu Hao Yu Wen-Bo Yuan Peng-Chao Li Jun Tao Qiang Lu Ji-Fu Wei Haiwei Yang | 2021 | Cancer Communications2021，41，7： | 17 |
| 3 | PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation显示文摘A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch between aerobic glycolysis and OXPHOS are unclear. Here we show that the M2 isoform of pyruvate kinase (PKM2), one of the rate-limiting enzymes in glycolysis, interacts with mitofusin 2 (MFN2), a key regulator of mitochondrial fusion, to promote mitochondrial fusion and OXPHOS, and attenuate glycolysis. mTOR increases the PKM2:MFN2 interaction by phosphorylating MFN2 and thereby modulates the effect of PKM2: MFN2 on glycolysis, mitochondrial fusion and OXPHOS. Thus, an mTOR-MFN2-PKM2 signaling axis couples glycolysis and OXPHOS to modulate cancer cell growth. | Tong Li Jinbo Han Liangjie Jia Xiao Hu Liqun Chen Yiguo Wang | 2019 | Protein & Cell2019，10，8： | 10 |
| 4 | Progress in the biological function of alpha-enolase显示文摘Alpha-enolase(ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. It is a multifunctional glycolytic enzyme involved in cellular stress, bacterial and fungal infections, autoantigen activities, the occurrence and metastasis of cancer, parasitic infections, and the growth, development and reproduction of organisms. This article mainly reviews the basic characteristics and biological functions of ENO1. | Hong Ji Jianfa Wang Jingru Guo Yue Li Shuai Lian Wenjin Guo Huanmin Yang Fanzhi Kong Li Zhen Li Guo Yanzhi Liu | 2016 | Animal Nutrition2016，，1： | 9 |
| 5 | Excessive Cu and Zn affecting on distribution of the metals and activities of glycolytic and nitrogen incorporating key enzymes in mycelia of ectomycorrhizal fungi Suillus bovinus显示文摘Concentration of copper and zinc in isolated Suillus bovinus mycelia, used nutrient solution and 0.5 mol/L EDTA mycelia washing solution were measured to investigate the distribution of heavy metals in mycelia growth in excess copper or zinc nutrient solution. Treated with zinc, most of added zinc maintained in used solution, and 9.8%/14.6% was in/on mycelia in treatment, and in treatment 2 was 3.9%/8.0% in/on mycelia. In the copper applications, copper stimulated in more than on mycelia, i.e., 25.9%/4.5% in/on mycelia in treatment, and 7%/18.8% in/on mycelia while most of copper retained in used nutrient solution. Certain amount of copper or zinc uptake by mycelia led to pronounced influence on glycolysis and nitrogen incorporating process of Suillus bovinus, while the tested enzymes kept constant in treatment. In crude extracts of copper treatment 2 mycelia, activities of HK, PFK and GS were inhibited and decrease to 63%, 48% and 38% and GlDH increased by 68% of the control, respectively. The behaviors of these tested enzymes toward zinc corresponded in general with that towards copper. The potential protection of Suillus bovinus for its host plant under excess copper or zinc threaten was discussed. | HUANG Yi, TAO Shu(Department of Urban and Environmental Sciences, Peking University, Beijing 100871, China. | 2001 | Journal of Environmental Sciences2001，13，3： | 9 |
| 6 | Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication显示文摘Aerobic glycolysis, i.e., the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e., the 'reverse Warburg effect'. Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors. | Minjong Lee Jung-Hwan Yoon | 2015 | World Journal of Biological Chemistry2015，6，3： | 9 |
| 7 | Thermogenic protein UCP1 and UCP3 expression in non- small cell lung cancer: relation with glycolysis and anaerobic metabolism显示文摘Uncoupling protein 1(UCP1)is a proton transporter/channel residing on the inner mitochondrial membrane and is involved in cellular heat production.Using immunohistochemistry,we investigated the expression of UCP1 and UCP3 in a series of 98 patients with non-small cell lung cancer(NSCLC)treated with surgery.Expression patterns were correlated with histopathological variables,prognosis,and the expression of enzymes/proteins related to cell metabolism.Bronchial epithelium did not express UCP1 or UCP3,while alveolar cells strongly expressed UCP1.In tumors,strong expression of UCP1 and UCP3 was recorded in43/98(43.8%)and 27/98(27.6%)cases,respectively.UCP1 was significantly associated with squamous cell histology(P=0.05),whilst UCP3 was more frequently overexpressed in large cell carcinomas(P=0.08),and was inversely related to necrosis(P=0.009).In linear regression analysis,UCP1 was directly related to markers of glycolysis[hexokinase(HXKII)and phosphofructokinase(PFK1)]and anaerobic glucose metabolism[pyruvate dehydrogenase kinase(PDK1)and lactate dehydrogenase(LDH5)].UCP3 was directly linked with a glucose transporter(GLUT2),monocarboxylate transporter(MCT2),glycolysis markers(PFK1 and aldolase),and with the phosphorylation of pyruvate dehydrogenase(p PDH).Kaplan-Meier survival analysis showed that UCP3 was significantly related to poor prognosis in squamous cell carcinomas(P=0.04).UCP1 and UCP3 are overexpressed in a large subgroup of non-small cell lung tumors and their expression coincides with increased glucose absorption,intensified glycolysis,and anaerobic glucose usage.Whether UCPs are targets for therapeutic interventions in lung cancer is a hypothesis that demands further investigation. | Alexandra Giatromanolaki Konstantina Balaska Dimitra Kalamida Christos Kakouratos Efthimios Sivridis Michael I. Koukourakis | 2017 | Cancer Biology & Medicine2017，14，4： | 8 |
| 8 | The tortuous path of lactate shuttle discovery:From cinders and boards to the lab and ICU显示文摘Once thought to be a waste product of oxygen limited(anaerobic)metabolism,lactate is now known to form continuously under fully oxygenated(aerobic)conditions.Lactate shuttling between producer(driver)and consumer cells fulfills at least 3 purposes;lactate is:(1)a major energy source,(2)the major gluconeogenic precursor,and(3)a signaling molecule.The Lactate Shuttle theory is applicable to diverse fields such as sports nutrition and hydration,resuscitation from acidosis and Dengue,treatment of traumatic brain injury,maintenance of glycemia,reduction of inflammation,cardiac support in heart failure and following a myocardial infarction,and to improve cognition.Yet,dysregulated lactate shuttling disrupts metabolic flexibility,and worse,supports oncogenesis.Lactate production in cancer(the Warburg effect)is involved in all main sequela for carcinogenesis:angiogenesis,immune escape,cell migration,metastasis,and self-sufficient metabolism.The history of the tortuous path of discovery in lactate metabolism and shuttling was discussed in the 2019 American College of Sports Medicine Joseph B.Wolffe Lecture in Orlando,FL. | George A.Brooks | 2020 | Journal of Sport and Health Science2020，9，5： | 7 |
| 9 | Wortmannin influences hypoxia-inducible factor-1 alpha expression and glycolysis in esophageal carcinoma cells显示文摘AIM: To investigate the influence of phosphatidylinositol-3-kinase protein kinase B(PI3K/AKT)-HIF-1α signaling pathway on glycolysis in esophageal carcinoma cells under hypoxia. METHODS: Esophageal carcinoma cell lines Eca109 and TE13 were cultured under hypoxia environment, and the protein, m RNA and activity levels of hypoxia inducible factor-1 alpha(HIF-1α), glucose transporter 1, hexokinase-Ⅱ, phosphofructokinase 2 and lactate dehydrogenase-A were determined. Supernatant lactic acid concentrations were also detected. The PI3K/AKT signaling pathway was then inhibited with wortmannin, and the effects of hypoxia on the expression or activities of HIF-1α, associated glycolytic enzymes and lactic acid concentrations were observed. Esophageal carcinoma cells were then transfected with interference plasmid with HIF-1α-targeting si RNA to assess impact of the high expression of HIF-1α on glycolysis.RESULTS: HIF-1α is highly expressed in the esophageal carcinoma cell lines tested, and with decreasing levels of oxygen, the expression of HIF-1α and the associated glycolytic enzymes and the extracellular lactic acid concentration were enhanced in the esophageal carcinoma cell lines Eca109 and TE13. In both normoxia and hypoxic conditions, the level of glycolytic enzymesand the secretion of lactic acid were both reduced by wortmannin. The expression and activities of glycolytic enzymes and the lactic acid concentration in cells were reduced by inhibiting HIF-1α, especially the decreasing level of glycolysis was significant under hypoxic conditions.CONCLUSION: The PI3K/AKT pathway and HIF-1α are both involved in the process of glycolysis in esophageal cancer cells. | Ling Zeng Hai-Yun Zhou Na-Na Tang Wei-Feng Zhang Gui-Jun He Bo Hao Ya-Dong Feng Hong Zhu | 2016 | World Journal of Gastroenterology2016，22，20： | 7 |
| 10 | Endothelial cell metabolism in sepsis显示文摘BACKGROUND:Endothelial dysfunction in sepsis is a pathophysiological feature of septic organ failure.Endothelial cells(ECs)exhibit specific metabolic traits and release metabolites to adapt to the septic state in the blood to maintain vascular homeostasis.METHODS:Web of Science and PubMed were searched from inception to October 1,2022.The search was limited to the English language only.Two reviewers independently identified studies related to EC metabolism in sepsis.The exclusion criteria were duplicate articles according to multiple search criteria.RESULTS:Sixty articles were included,and most of them were cell and animal studies.These studies reported the role of glycolysis,oxidative phosphorylation,fatty acid metabolism,and amino acid metabolism in EC homeostasis.including glycolysis,oxidative phosphorylation,fatty acid metabolism and amino acid metabolism.However,dysregulation of EC metabolism can contribute to sepsis progression.CONCLUSION:There are few clinical studies on EC metabolism in sepsis.Related research mainly focuses on basic research,but some scientific problems have also been clarified.Therefore,this review may provide an overall comprehension and novel aspects of EC metabolism in sepsis. | Jue-xian Wei Hui-lin Jiang Xiao-hui Chen | 2023 | World Journal of Emergency Medicine2023，14，1： | 5 |
| 11 | Insulin gene enhancer protein 1 mediates glycolysis and tumorigenesis of gastric cancer through regulating glucose transporter 4显示文摘Background:Insulin gene enhancer protein 1,(ISL1),a LIM-homeodomain transcription factor,is involved in multiple tumors and is associated with insulin secretion and metabolic phenotypes.However,the role of ISL1 in stimulating glycolysis to promote tumorigenesis in gastric cancer(GC)is unclear.In this study,we aimed to characterize the expression pattern of ISL1 in GC patients and explore its molecular biological mechanism in glycolysis and tumorigenesis.Methods:We analyzed the expression and clinical significance of ISL1 in GC using immunohistochemistry and real-time polymerase chain reaction(PCR).Flow cytometry and IncuCyte assays were used to measure cell proliferation after ISL1 knockdown.RNA-sequencing was performed to identify differentially expressed genes,followed by Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis and Gene Set Enrichment Analysis(GSEA)to reveal key signaling pathways likely regulated by ISL1 in GC.Alteration of the glycolytic ability of GC cells with ISL1 knockdown was validated by measuring the extracellular acidification rate(ECAR)and oxygen consumption rate(OCR)and by detecting glucose consumption and lactate production.The expression of glucose transporter 4(GLUT4)and ISL1 was assessed by Western blotting,immunohistochemistry,and immunofluorescent microscopy.The luciferase reporter activity and chromatin immunoprecipitation assays were performed to determine the transcriptional regulation of ISL1 on GLUT4.Results:High levels of ISL1 and GLUT4 expression was associated with short survival of GC patients.ISL1 knockdown inhibited cell proliferation both in vitro and in vivo.KEGG analysis and GSEA for RNA-sequencing data indicated impairment of the glycolysis pathway in GC cells with ISL1 knockdown,which was validated by reduced glucose uptake and lactate production,decreased ECAR,and increased OCR.Mechanistic investigation indicated that ISL1 transcriptionally regulated GLUT4 through binding to its promoter.Conclusion:ISL1 facilitates glycolysis and tumorigenesis in GC via the transcriptional regulation of GLUT4. | Ting Guo Yan-Hua Bai Xiao-Jing Cheng Hai-Bo Han Hong Du Ying Hu Shu-Qin Jia Xiao-Fang Xing Jia-Fu Ji | 2021 | Cancer Communications2021，41，3： | 5 |
| 12 | External use of Ruyanneixiao cream efficiently blocks precancerous mammary lesions by interfering with glycolysis induced by inhibition of hypoxia inducible factor-1α, hexokinase 2, phosphofructokinase, and pyruvate kinase M2 expression显示文摘OBJECTIVE:To investigate the effect of Ruyanneixiao cream(RYNX) on the expression of hypoxia inducible factor-1α(HIF-1α), hexokinase 2(HK2),phosphofructokinase(PFK), and pyruvate kinase M2(PKM2) mRNA and protein in MCF-10 AT cells and in an animal model of precancerous mammary lesions.METHODS:Following treatment of MCF-10 AT cells with RYNX, tamoxifen(TAM) and YC-1 for 48 h,HIF-1α, HK2, PFK, PKM2 mRNA and protein expression was analyzed.Fifty female SD rats were randomly divided into control, model, TAM, and highand low-dose RYNX groups, with 10 rats in each group.A precancerous mammary lesion model was established for all groups except the control group.High-and low-dose RYNX cream containing TAM was coated on the breasts of animals in the corresponding groups.The rat mammary tissue was removed in the 10 th week and HIF-1α, HK2, PFK,PKM2 mRNA and protein was analyzed.RESULTS:In vitro analyses demonstrated that, compared with the matrix group, HIF-1α, HK2, PFK,PKM2 mRNA and protein expression was significantly decreased in the RYNX group(P < 0.05).Compared with the YC-1 + RYNX group, HK2, PFK,and PKM2 protein expression was significantly reduced in the RYNX group.HIF-1α, HK2, PFK, and PKM2 protein expression was increased significantly in the model group(P < 0.05) compared with the control group, while HIF-1α, HK2, PFK, and PKM2 mRNA and protein expression was significantly decreased in both the high-and low-dose RYNX groups(P < 0.05), with the effect being greater in the high-dose group.CONCLUSION:RYNX can block precancerous breast lesions by decreasing the expression of HK2,PFK, and PKM2 mRNA and protein via inhibition of HIF-1α mRNA and protein overexpression in a dose-dependent manner. | Li Xiaobo Ma Min Zhang Guijuan Ma Yi Liao Rui Chen Ruixue Yan Xianxin Bie Fengjie Huang Maojie Liang Shijie | 2017 | Journal of Traditional Chinese Medicine2017，37，2： | 5 |
| 13 | Ouabain impairs cancer metabolism and activates AMPK-Src signaling pathway in human cancer cell lines显示文摘In addition to the well-known cardiotonic effects,cardiac glycosides(CGs)produce potent anticancer effects with various molecular mechanisms.We previously show that ouabain induces autophagic cell death in human lung cancer cells by regulating AMPK-mediated mTOR and Src-mediated ERK1/2 signaling pathways.However,whether and how AMPK and Src signaling interacts in ouabain-treated cancer cells remains unclear.Given the pivotal role of AMPK in metabolism,whether ouabain affects cancer cell metabolism remains elusive.In this study we showed that treatment with ouabain(25 nM)caused simultaneous activation of AMPK and Src signaling pathways in human lung cancer A549 cells and human breast cancer MCF7 cells.Cotreatment with AMPK inhibitor compound C or siRNA greatly abrogates ouabain-induced Src activation,whereas cotreatment with Src inhibitor PP2 has little effect on ouabain-induced AMPK activity,suggesting that AMPK served as an upstream regulator of the Src signaling pathway.On the other hand,ouabain treatment greatly depletes ATP production in A549 and MCF7 cells,and supplement of ATP(100μM)blocked ouabain-induced AMPK activation.We further demonstrated that ouabain greatly inhibited the mitochondrial oxidative phosphorylation(OXPHOS)in the cancer cells,and exerted differential metabolic effects on glycolysis depending on cancer cell type.Taken together,this study reveals that the altered cancer cell metabolism caused by ouabain may contribute to AMPK activation,as well as its cytotoxicity towards cancer cells. | Jia-jia Shen Yue-chen Zhan Hui-ying Li Zhen Wang | 2020 | Acta Pharmacologica Sinica2020，41，1： | 5 |
| 14 | Embryonic liver fordin is involved in glucose glycolysis of hepatic stellate cell by regulating PI3K/Akt signaling显示文摘AIM To investigate the role of embryonic liver fordin(ELF) in liver fibrosis by regulating hepatic stellate cells(HSCs) glucose glycolysis.METHODS The expression of ELF and the glucose glycolysisrelated proteins were evaluated in activated HSCs. si RNA was used to silence ELF expression in activated HSCs in vitro and the subsequent changes in PI3K/Akt signaling and glucose glycolysis-related proteins were observed.RESULTS The expression of ELF increased remarkably in HSCs of the fibrosis mouse model and HSCs that were cultured for 3 wk in vitro. Glucose glycolysis-related proteins showed an obvious increase in the activated HSCs, such as phosphofructokinase, platelet and glucose transporter 1. ELF-si RNA, which perfectly silenced the expression of ELF in activated HSCs, led to the induction of glucose glycolysis-related proteins and extracellular matrix(ECM) components. Moreover, p Akt, which is an important downstream factor in PI3K/Akt signaling, showed a significant change in response to the ELF silencing. The expression of glucose glycolysisrelated proteins and ECM components decreased remarkably when the PI3K/Akt signaling was blocked by Ly294002 in the activated HSCs. CONCLUSION ELF is involved in HSC glucose glycolysis by regulating PI3K/Akt signaling. | Wei Tu Jin Ye Zhi-Jun Wang | 2016 | World Journal of Gastroenterology2016，22，38： | 5 |
| 15 | Modules for in vitro metabolic engineering:Pathway assembly for biobased production of value-added chemicals显示文摘Bio-based chemical production has drawn attention regarding the realization of a sustainable society.In vitro metabolic engineering is one of the methods used for the bio-based production of value-added chemicals.This method involves the reconstitution of natural or artificial metabolic pathways by assembling purified/semi-purified enzymes in vitro.Enzymes from distinct sources can be combined to construct desired reaction cascades with fewer biological constraints in one vessel,enabling easier pathway design with high modularity.Multiple modules have been designed,built,tested,and improved by different groups for different purpose.In this review,we focus on these in vitro metabolic engineering modules,especially focusing on the carbon metabolism,and present an overview of input modules,output modules,and other modules related to cofactor management. | Hironori Taniguchi Kenji Okano Kohsuke Honda | 2017 | Synthetic and Systems Biotechnology2017，2，2： | 5 |
| 16 | Glucocorticoid receptor promotes the function of myeloid-derived suppressor cells by suppressing HIF1α-dependent glycolysis显示文摘Immunomodulatory signaling imposes tight regulations on metabolic programs within immune cells and consequentially determines immune response outcomes.Although the glucocorticoid receptor(GR)has been recently implicated in regulating the function of myeloid-derived suppressor cells(MDSCs),whether the dysregulation of GR in MDSCs is involved in immune-mediated hepatic diseases and how GR regulates the function of MDSCs in such a context remains unknown.Here,we revealed the dysregulation of GR expression in MDSCs during innate immunological hepatic injury(IMH)and found that GR regulates the function of MDSCs through modulating HIF1α-dependent glycolysis.Pharmacological modulation of GR by its agonist(dexamethasone,Dex)protects IMH mice against inflammatory injury.Mechanistically,GR signaling suppresses HIF1αand HIF1α-dependent glycolysis in MDSCs and thus promotes the immune suppressive activity of MDSCs.Our studies reveal a role of GR-HIF1αin regulating the metabolism and function of MDSCs and further implicate MDSC GR signaling as a potential therapeutic target in hepatic diseases that are driven by innate immune cell-mediated systemic inflammation. | Yun Lu Huanrong Liu Yujing Bi Hui Yang Yan Li Jian Wang Zhengguo Zhang Yu Wang Chunxiao Li Anna Jia Linian Han Ying Hu Yong Zhao Ruoning Wang Guangwei Liu | 2018 | Cellular & Molecular Immunology2018，15，6： | 4 |
| 17 | Mitochondria: A critical hub for hepatic stellate cells activation during chronic liver diseases显示文摘Background: Upon liver injury, quiescent hepatic stellate cells(q HSCs), reside in the perisinusoidal space, phenotypically transdifferentiate into myofibroblast-like cells(MFBs). The q HSCs in the normal liver are less fibrogenic, migratory, and also have less proliferative potential. However, activated HSCs(a HSCs) are more fibrogenic and have a high migratory and proliferative MFBs phenotype. HSCs activation is a highly energetic process that needs abundant intracellular energy in the form of adenosine triphosphate(ATP) for the synthesis of extracellular matrix(ECM) in the injured liver to substantiate the injury. Data sources: The articles were collected through Pub Med and EMBASE using search terms 'mitochondria and hepatic stellate cells', 'mitochondria and HSCs', 'mitochondria and hepatic fibrosis', 'mitochondria and liver diseases', and 'mitochondria and chronic liver disease', and relevant publications published before September 31, 2020 were included in this review. Results: Mitochondria homeostasis is affected during HSCs activation. Mitochondria in a HSCs are highly energetic and are in a high metabolically active state exhibiting increased activity such as glycolysis and respiration. a HSCs have high glycolytic enzymes expression and glycolytic activity induced by Hedgehog(Hh) signaling from injured hepatocytes. Increased glycolysis and aerobic glycolysis(Warburg effect) endproducts in a HSCs consequently activate the ECM-related gene expressions. Increased Hh signaling from injured hepatocytes downregulates peroxisome proliferator-activated receptor-γ expression and decreases lipogenesis in a HSCs. Glutaminolysis and tricarboxylic acid cycle liberate ATPs that fuel HSCs to proliferate and produce ECM during their activation. Conclusions: Available studies suggest that mitochondria functions can increase in parallel with HSCs activation. Therefore, mitochondrial modulators should be tested in an elaborate manner to control or prevent the HSCs activation during liver injury to subsequently regress hepatic fibrosis. | Devaraj Ezhilarasan | 2021 | Hepatobiliary & Pancreatic Diseases International2021，20，4： | 4 |
| 18 | Targeting PFKL with penfluridol inhibits glycolysis and suppresses esophageal cancer tumorigenesis in an AMPK/FOXO3a/BIM-dependent manner显示文摘As one of the hallmarks of cancer,metabolic reprogramming leads to cancer progression,and targeting glycolytic enzymes could be useful strategies for cancer therapy.By screening a small molecule library consisting of 1320 FDA-approved drugs,we found that penfluridol,an antipsychotic drug used to treat schizophrenia,could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma(ESCC).Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol.By using drug affinity responsive target stability(DARTS)technology and proteomics,we identified phosphofructokinase,liver type(PFKL),a key enzyme in glycolysis,as a direct target of penfluridol.Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells,illustrating that PFKL is essential for the bioactivity of penfluridol.High PFKL expression is correlated with advanced stages and poor survival of ESCC patients,and silencing of PFKL significantly suppressed tumor growth.Mechanistically,direct binding of penfluridol and PFKL inhibits glucose consumption,lactate and ATP production,leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner.Taken together,PFKL is a potential prognostic biomarker and therapeutic target in ESCC,and penfluridol may be a new therapeutic option for management of this lethal disease. | Cancan Zheng Xiaomei Yu Yiyao Liang Yidong Zhu Yan He Long Liao Dingkang Wang Yanming Yang Xingfeng Yin Ang Li Qingyu He Bin Li | 2022 | Acta Pharmaceutica Sinica B2022，12，3： | 4 |
| 19 | A glycolysis-based ten-gene signature correlates with the clinical outcome, molecular subtype and IDH1 mutation in glioblastoma显示文摘Reprogrammed metabolism is a hallmark of cancer. Glioblastoma(GBM) tumor cells predominantly utilize aerobic glycolysis for the biogenesis of energy and intermediate nutrients. However, in GBM, the clinical significance of glycolysis and its underlying relations with the molecular features such as IDH1 mutation and subtype have not been elucidated yet. Herein, based on glioma datasets including TCGA(The Cancer Genome Atlas), REMBRANDT(Repository for Molecular Brain Neoplasia Data) and GSE16011 we established a glycolytic gene expression signature score(GGESS) by incorporating ten glycolytic genes. Then we performed survival analyses and investigated the correlations between GGESS and IDH1 mutation as well as the molecular subtypes in GBMs. The results showed that GGESS independently predicted unfavorable prognosis and poor response to chemotherapy of GBM patients. Notably, GGESS was high in GBMs of mesenchymal subtype but low in IDH1-mutant GBMs. Furthermore, we found that the promoter regions of tumor-promoting glycolytic genes were hypermethylated in IDH1-mutant GBMs.Finally, we found that high GGESS also predicted poor prognosis and poor response to chemotherapy when investigating IDH1-wild type GBM patients only. Collectively, glycolysis represented by GGESS predicts unfavorable clinical outcome of GBM patients and is closely associated with mesenchymal subtype and IDH1 mutation in GBMs. | Cong Chen Yu Shi Yong Li Zhi-Cheng He Kai Zhou Xiao-Ning Zhang Kai-Di Yang Jin-Rong Wu Hsiang-Fu Kung Yi-Fang Ping Xiu-Wu Bian | 2017 | Journal of Genetics and Genomics2017，44，11： | 4 |
| 20 | Transforming growth factor beta-1 upregulates glucose transporter 1 and glycolysis through canonical and noncanonical pathways in hepatic stellate cells显示文摘BACKGROUND Hepatic stellate cells(HSCs)are the key effector cells mediating the occurrence and development of liver fibrosis,while aerobic glycolysis is an important metabolic characteristic of HSC activation.Transforming growth factor-β1(TGF-β1)induces aerobic glycolysis and is a driving factor for metabolic reprogramming.The occurrence of glycolysis depends on a high glucose uptake level.Glucose transporter 1(GLUT1)is the most widely distributed glucose transporter in the body and mainly participates in the regulation of carbohydrate metabolism,thus affecting cell proliferation and growth.However,little is known about the relationship between TGF-β1 and GLUT1 in the process of liver fibrosis and the molecular mechanism underlying the promotion of aerobic glycolysis in HSCs.AIM To investigate the mechanisms of action of GLUT1,TGF-β1 and aerobic glycolysis in the process of HSC activation during liver fibrosis.METHODS Immunohistochemical staining and immunofluorescence assays were used to examine GLUT1 expression in fibrotic liver tissue.A Seahorse extracellular flux(XF)analyzer was used to examine changes in aerobic glycolytic flux,lactate production levels and glucose consumption levels in HSCs upon TGF-β1 stimulation.The mechanism by which TGF-β1 induces GLUT1 protein expression in HSCs was further explored by inhibiting/promoting the TGF-β1/mothersagainst-decapentaplegic-homolog 2/3(Smad2/3)signaling pathway and inhibiting the p38 and phosphoinositide 3-kinase(PI3K)/AKT signaling pathways.In addition,GLUT1 expression was silenced to observe changes in the growth and proliferation of HSCs.Finally,a GLUT1 inhibitor was used to verify the in vivo effects of GLUT1 on a mouse model of liver fibrosis.RESULTS GLUT1 protein expression was increased in both mouse and human fibrotic liver tissues.In addition,immunofluorescence staining revealed colocalization of GLUT1 and alpha-smooth muscle actin proteins,indicating that GLUT1 expression was related to the development of liver fibrosis.TGF-β1 caused an increase in aerobic glycolysis in HSCs and induced GLUT1 expression in HSCs by activating the Smad,p38 MAPK and P13K/AKT signaling pathways.The p38 MAPK and Smad pathways synergistically affected the induction of GLUT1 expression.GLUT1 inhibition eliminated the effect of TGF-β1 on HSC proliferation and migration.A GLUT1 inhibitor was administered in a mouse model of liver fibrosis,and GLUT1 inhibition reduced the degree of liver inflammation and liver fibrosis.CONCLUSION TGF-β1 induces GLUT1 expression in HSCs,a process related to liver fibrosis progression.In vitro experiments revealed that TGF-β1-induced GLUT1 expression might be one of the mechanisms mediating the metabolic reprogramming of HSCs.In addition,in vivo experiments also indicated that the GLUT1 protein promotes the occurrence and development of liver fibrosis. | Ming-Yu Zhou Ming-Liang Cheng Tao Huang Rui-Han Hu Gao-Liang Zou Hong Li Bao-Fang Zhang Juan-Juan Zhu Yong-Mei Liu Yang Liu Xue-Ke Zhao | 2021 | World Journal of Gastroenterology2021，27，40： | 4 |
您所在的机构暂未开通此部分的功能，请联系管理员