Alzheimer's disease (AD) is an irreversible neurodegenerative disease with a variety of pathogenic factors and complex pathogenesis, so that the disease has a high prevalence and mortality in the world. Although t...Alzheimer's disease (AD) is an irreversible neurodegenerative disease with a variety of pathogenic factors and complex pathogenesis, so that the disease has a high prevalence and mortality in the world. Although the current diagnosis and treatment equipment and drug research and development keep pace with the times, the current medical technology still can not completely cure the disease, so it is of great significance to explore the pathogenesis and treatment target of AD. The disorder of energy metabolism is one of the characteristic changes in the pathological process of AD. Aerobic glycolysis (AEG) is a special metabolic pathway in the brain, which can rapidly consume glucose to produce energy and substrate for neurons, improve synaptic plasticity, neuroinflammation and oxidative damage, and contribute to the recovery of memory and cognitive function. In recent years, many literatures have reported the mechanism of AEG in AD and the intervention of Tradit Chin Med on this mechanism. The purpose of this paper is to summarize the role of AEG in AD and the related research on the regulation and control of AEG in the treatment of AD by Tradit Chin Med, in order to provide reference and ideas for the prevention and treatment of AD with Tradit Chin Med in the future.展开更多
BACKGROUND Gastric precancerous lesions(GPL)precede the development of gastric cancer(GC).They are characterized by gastric mucosal intestinal metaplasia and dysplasia caused by various factors such as inflammation,ba...BACKGROUND Gastric precancerous lesions(GPL)precede the development of gastric cancer(GC).They are characterized by gastric mucosal intestinal metaplasia and dysplasia caused by various factors such as inflammation,bacterial infection,and injury.Abnormalities in autophagy and glycolysis affect GPL progression,and their effective regulation can aid in GPL treatment and GC prevention.Xiaojianzhong decoction(XJZ)is a classic compound for the treatment of digestive system diseases in ancient China which can inhibit the progression of GPL.However,its specific mechanism of action is still unclear.AIM To investigate the therapeutic effects of XJZ decoction on a rat GPL model and the mechanisms underlying its effects on autophagy and glycolysis regulation in GPLs.METHODS Wistar rats were randomly divided into six groups of five rats each and all groups except the control group were subjected to GPL model construction for 18 wk.The rats’body weight was monitored every 2 wk starting from the beginning of modeling.Gastric histopathology was examined using hematoxylin-eosin staining and Alcian blue-periodic acid-Schiff staining.Autophagy was observed using transmission electron microscopy.The expressions of autophagy,hypoxia,and glycolysis related proteins in gastric mucosa were detected using immunohistochemistry and immunofluorescence.The expressions of the following proteins in gastric tissues:B cell lymphoma/Leukemia-2 and adenovirus E1B19000 interacting protein 3(Bnip-3),microtubule associated protein 1 light chain 3(LC-3),moesin-like BCL2-interacting protein 1(Beclin-1),phosphatidylinositol 3-kimase(PI3K),protein kinase B(AKT),mammalian target of rapamycin(mTOR),p53,AMP-activated protein kinase(AMPK),and Unc-51 like kinase 1(ULK1)were detected using western blot.The relative expressions of autophagy,hypoxia,and glycolysis related mRNA in gastric tissues was detected using reverse transcription-polymerase chain reaction.RESULTS Treatment with XJZ increased the rats’body weight and improved GPL-related histopathological manifestations.It also decreased autophagosome and autolysosome formation in gastric tissues and reduced Bnip-3,Beclin-1,and LC-3II expressions,resulting in inhibition of autophagy.Moreover,XJZ down-regulated glycolysis-related monocarboxylate transporter(MCT1),MCT4,and CD147 expressions.XJZ prevented the increase of autophagy level by decreasing gastric mucosal hypoxia,activating the PI3K/AKT/mTOR pathway,inhibiting the p53/AMPK pathway activation and ULK1 Ser-317 and Ser-555 phosphorylation.In addition,XJZ improved abnormal gastric mucosal glucose metabolism by ameliorating gastric mucosal hypoxia and inhibiting ULK1 expression.CONCLUSION This study demonstrates that XJZ may inhibit autophagy and glycolysis in GPL gastric mucosal cells by improving gastric mucosal hypoxia and regulating PI3K/AKT/mTOR and p53/AMPK/ULK1 signaling pathways,providing a feasible strategy for the GPL treatment.展开更多
Acute lung injury is featured as diffuse pulmonary edema and persistent hypoxemia caused by lung or systemic injury.It is believed that these pathological changes are associated with damage to the alveolar epithelium ...Acute lung injury is featured as diffuse pulmonary edema and persistent hypoxemia caused by lung or systemic injury.It is believed that these pathological changes are associated with damage to the alveolar epithelium and vascular endothelium,recruitment of inflammatory cells,and inflammatory factor storms.In recent years,the metabolic reprogramming of lung parenchymal cells and immune cells,particularly alterations in glycolysis,has been found to occur in acute lung injury.Inhibition of glycolysis can reduce the severity of acute lung injury.Thus,this review focuses on the interconnection between acute lung injury and glycolysis and the mechanisms of interaction,which may bring hope for the treatment of acute lung injury.展开更多
Objective Oral lichen planus(OLP)is one of the most common oral mucosa diseases,and is mainly mediated by T lymphocytes.The metabolic reprogramming of activated T cells has been shown to transform from oxidative phosp...Objective Oral lichen planus(OLP)is one of the most common oral mucosa diseases,and is mainly mediated by T lymphocytes.The metabolic reprogramming of activated T cells has been shown to transform from oxidative phosphorylation to aerobic glycolysis.The present study investigated the serum levels of glycolysis-related molecules(lactate dehydrogenase,LDH;pyruvic acid,PA;lactic acid,LAC)in OLP,and the correlation with OLP activity was assessed using the reticular,atrophic and erosive lesion(RAE)scoring system.Methods Univariate and multivariate linear regression functions based on scikit-learn were designed to predict the RAE scores in OLP patients,and the performance of these two machine learning functions was compared.Results The results revealed that the serum levels of PA and LAC were upregulated in erosive OLP(EOLP)patients,when compared to healthy volunteers.Furthermore,the LDH and LAC levels were significantly higher in the EOLP group than in the nonerosive OLP(NEOLP)group.All glycolysis-related molecules were positively correlated to the RAE scores.Among these,LAC had a strong correlation.The univariate function that involved the LAC level and the multivariate function that involved all glycolysis-related molecules presented comparable prediction accuracy and stability,but the latter was more time-consuming.Conclusion It can be concluded that the serum LAC level can be a user-friendly biomarker to monitor the OLP activity,based on the univariate function developed in the present study.The intervention of the glycolytic pathway may provide a potential therapeutic strategy.展开更多
BACKGROUND Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2(HER-2)-positive gastric cancer(GC).However,the efficacy of this treat...BACKGROUND Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2(HER-2)-positive gastric cancer(GC).However,the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance.While S-phase kinase associated protein 2(Skp2)overexpression has been implicated in the malignant progression of GC,its role in regulating trastuzumab resistance in this context remains uncertain.Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products,there has been a lack of successful commercialization of drugs specifically targeting Skp2.AIM To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment.METHODS Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells.Q-PCR,western blot,and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression.A cell counting kit-8 assay,flow cytometry,a amplex red glucose/glucose oxidase assay kit,and a lactate assay kit were utilized to measure the proliferation,apoptosis,and glycolytic activity of GC cells in vitro.A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo.RESULTS The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab.Thioridazine demonstrated the ability to directly bind to Skp2,resulting in a reduction in Skp2 expression at both the transcriptional and translational levels.Moreover,thioridazine effectively inhibited cell proliferation,exhibited antiapoptotic properties,and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways.The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo,surpassing the efficacy of either monotherapy.CONCLUSION Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance,particularly when used in conjunction with lapatinib.This compound has potential benefits for patients with Skp2-proficient tumors.展开更多
Background:Establishing an appropriate prognostic model for PCa is essential for its effective treatment.Glycolysis is a vital energy-harvesting mechanism for tumors.Developing a prognostic model for PCa based on glyc...Background:Establishing an appropriate prognostic model for PCa is essential for its effective treatment.Glycolysis is a vital energy-harvesting mechanism for tumors.Developing a prognostic model for PCa based on glycolysis-related genes is novel and has great potential.Methods:First,gene expression and clinical data of PCa patients were downloaded from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO),and glycolysis-related genes were obtained from the Molecular Signatures Database(MSigDB).Gene enrichment analysis was performed to verify that glycolysis functions were enriched in the genes we obtained,which were used in nonnegative matrix factorization(NMF)to identify clusters.The correlation between clusters and clinical features was discussed,and the differentially expressed genes(DEGs)between the two clusters were investigated.Based on the DEGs,we investigated the biological differences between clusters,including immune cell infiltration,mutation,tumor immune dysfunction and exclusion,immune function,and checkpoint genes.To establish the prognostic model,the genes were filtered based on univariable Cox regression,LASSO,and multivariable Cox regression.Kaplan–Meier analysis and receiver operating characteristic analysis validated the prognostic value of the model.A nomogram of the risk score calculated by the prognostic model and clinical characteristics was constructed to quantitatively estimate the survival probability for PCa patients in the clinical setting.Result:The genes obtained from MSigDB were enriched in glycolysis functions.Two clusters were identified by NMF analysis based on 272 glycolysis-related genes,and a prognostic model based on DEGs between the two clusters was finally established.The prognostic model consisted of LAMPS,SPRN,ATOH1,TANC1,ETV1,TDRD1,KLK14,MESP2,POSTN,CRIP2,NAT1,AKR7A3,PODXL,CARTPT,and PCDHGB2.All sample,training,and test cohorts from The Cancer Genome Atlas(TCGA)and the external validation cohort from GEO showed significant differences between the high-risk and low-risk groups.The area under the ROC curve showed great performance of this prognostic model.Conclusion:A prognostic model based on glycolysis-related genes was established,with great performance and potential significance to the clinical application.展开更多
Background:Pulmonary arterial hypertension(PAH)is a chronic and progressive disease that is strongly associated with dysregulation of glucose metabolism.Alterations in nuclear receptor subfamily 4 group A member 1(NR4...Background:Pulmonary arterial hypertension(PAH)is a chronic and progressive disease that is strongly associated with dysregulation of glucose metabolism.Alterations in nuclear receptor subfamily 4 group A member 1(NR4A1)activity alter the outcome of PAH.This study aimed to investigate the effects of NR4A1 on glycolysis in PAH and its underlying mechanisms.Methods:This study included twenty healthy volunteers and twenty-three PAH patients,and plasma samples were collected from the participants.To mimic the conditions of PAH in vitro,a hypoxia-induced model of pulmonary artery smooth muscle cell(PASMC)model was established.The proliferation of PASMCs was assessed using CCK8 assays.Results:Levels of NR4A1,hypoxia-inducible factor-1α(HIF-1α),and various glycolysis-related enzymes were measured.In addition,extracellular glucose and lactate production were assessed.The interaction between NR4A1 and HIF-1αwas evaluated by co-immunoprecipitation assays.Levels of NR4A1 and HIF-1αwas increased in PAH patients,and exposure to hypoxia resulted in increased levels of NR4A1 and HIF-1αin PASMCs.NR4A1 interacted with HIF-1α.NR4A1 overexpression enhanced hypoxia-induced expression of HIF-1α,GLUT1,PKM2,HK2,and CD36,decreased glucose levels,increased lactate levels and promoted hypoxic PASMC viability.Conversely,silencing NR4A1 decreased hypoxia-induced expression of HIF-1α,GLUT1,PKM2,HK2,and CD36,promoted glucose production,reduced lactate levels and inhibited hypoxic PASMC viability.Furthermore,overexpression of HIF-1αreversed the regulation of glycolysis caused by NR4A1 knockdown.Conclusion:NR4A1 enhances glycolysis in hypoxia-induced PASMCs by upregulating HIF-1α.Our findings indicate that the management of NR4A1 activity may be a promising strategy for PAH therapy.展开更多
BACKGROUND Resistance to sorafenib has become a challenge in clinical treatment of hepatocellular carcinoma(HCC).Physcion is a common bioactive anthraquinone that has potential as an anticancer agent.AIM To study the ...BACKGROUND Resistance to sorafenib has become a challenge in clinical treatment of hepatocellular carcinoma(HCC).Physcion is a common bioactive anthraquinone that has potential as an anticancer agent.AIM To study the effect of physcion on sensitizing HCC cells to sorafenib.METHODS Sorafenib-resistant HCC cells were established and treated with sorafenib and/or physcion.The cell viability,proliferation and apoptosis were measured by cell counting kit-8,colony formation,flow cytometry,and in vivo xenograft model.Glucose uptake,lactate acid production,extracellular acidification rate(ECAR),and oxygen consumption rate(OCR)were measured to analyze glycolysis.Expression of glycolysis-related regulators was assessed by western blotting.RESULTS The addition of physcion significantly enhanced the antitumor effects of sorafenib on sorafenib-resistant HCC cells,manifested by enhanced apoptosis and suppressed cell growth.The glucose uptake,lactate acid production,and ECAR were elevated,and OCR was suppressed by physcion treatment.The level of PIM1 was elevated and miR-370 was suppressed in sorafenib-resistant HCC cells compared with the parental cells,which was suppressed by physcion treatment.Inhibition of miR-370 notably reversed the effects of physcion on sorafenib-resistant HCC cells.CONCLUSION Our data indicated that physcion enhanced the sensitivity of HCC cells to sorafenib by enhancing miR-370 to suppress PIM1-promoted glycolysis.展开更多
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 lin...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.展开更多
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 ...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.展开更多
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 ...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.展开更多
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 mitocho...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.展开更多
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.Transfor...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.展开更多
In a series of our recent studies, stress was found to induce simultaneously hypothermia and hyperglycemia. These conditions are beneficial to obtain prompt force which depends on the glycolysis pathway and to escape ...In a series of our recent studies, stress was found to induce simultaneously hypothermia and hyperglycemia. These conditions are beneficial to obtain prompt force which depends on the glycolysis pathway and to escape emergency. Since we have noticed that such conditions resemble the internal environment seen in some cancer patients, it was investigated whe- ther such conditions were accompanied with other patients. We selected patients with early and advanced cancer. Body temperature and other parameters including blood gas contents were examined. A difference was seen in body temperature, namely, many patients showed hypothermia, irrespective of cancer stages. Fur- ther characterization of other parameters show- ed that hypothermia and hyperglycemia existed in many patients. They had immunosuppressive state and anemia. Blood gas analysis showed that oxygen contents were low and carbon dioxide contents were high in patients. These results suggest a possibility that the internal environment seen in patients is responsible to induce onset of disease and to maintain their cell growth, because cancer cells have an energy system of predominant glycolysis. Although hypothermia, hypoxia and hyperglycemia are important to activate the glycolysis pathway and to escape from emergency, such responses suppress the mitochondrial pathway for long span and may result in carcinogenesis.展开更多
BACKGROUND Hepatic stellate cell(HSC)hyperactivation is a central link in liver fibrosis development.HSCs perform aerobic glycolysis to provide energy for their activation.Focal adhesion kinase(FAK)promotes aerobic gl...BACKGROUND Hepatic stellate cell(HSC)hyperactivation is a central link in liver fibrosis development.HSCs perform aerobic glycolysis to provide energy for their activation.Focal adhesion kinase(FAK)promotes aerobic glycolysis in cancer cells or fibroblasts,while FAK-related non-kinase(FRNK)inhibits FAK phosphorylation and biological functions.AIM To elucidate the effect of FRNK on liver fibrosis at the level of aerobic glycolytic metabolism in HSCs.METHODS Mouse liver fibrosis models were established by administering CCl4,and the effect of FRNK on the degree of liver fibrosis in the model was evaluated.Transforming growth factor-β1 was used to activate LX-2 cells.Tyrosine phosphorylation at position 397(pY397-FAK)was detected to identify activated FAK,and the expression of the glycolysis-related proteins monocarboxylate transporter 1(MCT-1)and enolase1(ENO1)was assessed.Bioinformatics analysis was performed to predict putative binding sites for c-myc in the ENO1 promoter region,which were validated with chromatin immunoprecipitation(ChIP)and dual luciferase reporter assays.RESULTS The pY397-FAK level was increased in human fibrotic liver tissue.FRNK knockout promoted liver fibrosis in mouse models.It also increased the activation,migration,proliferation and aerobic glycolysis of primary hepatic stellate cells(pHSCs)but inhibited pHSC apoptosis.Nevertheless,opposite trends for these phenomena were observed after exogenous FRNK treatment in LX-2 cells.Mechanistically,the FAK/Ras/c-myc/ENO1 pathway promoted aerobic glycolysis,which was inhibited by exogenous FRNK.CONCLUSION FRNK inhibits aerobic glycolysis in HSCs by inhibiting the FAK/Ras/c-myc/ENO1 pathway,thereby improving liver fibrosis.FRNK might be a potential target for liver fibrosis treatment.展开更多
AIM To investigate the effect of lycopene extracted from tomatoes(LycT) on ultrastructure, glycolytic enzymes, cell proliferation markers and hypoxia during N-Nitrosodiethylamine(NDEA)-induced hepatocarcinogenesis. ME...AIM To investigate the effect of lycopene extracted from tomatoes(LycT) on ultrastructure, glycolytic enzymes, cell proliferation markers and hypoxia during N-Nitrosodiethylamine(NDEA)-induced hepatocarcinogenesis. METHODS Female BALB/c mice were randomly divided into four groups: The Control, NDEA(200 mg NDEA/kg b.w. given i.p.), LycT(5 mg/kg b.w. given orally on alternate days) and Lyc T + NDEA group. The m RNA and protein expression of various cell proliferation markers(PCNA, Cyclin D1, and p21) were assessed by reverse transcription-polymerase chain reaction and enzyme linked immunosorbent assay, respectively. The ultrastructure of hepatic tissue was analyzed using scanning and transmission electron microscopy. The enzymatic activity of glycolytic enzymes was estimated using standardized protocols, while glucose-6-phosphate dehydrogenase activity level was estimated using a kit obtained from Reckon Diagnostic P. Ltd.(India). RESULTS Uncontrolled proliferation in the liver of NDEA(P ≤ 0.001) mice was evident from the high expression of cell-proliferation associated genes(PCNA, Cyclin D1, and p21) when compared to control and Lyc T mice. In addition, enhanced activities of hexokinase, phosphoglucoisomerase, aldolase, glucose-6-phosphatedehydrogenase and hypoxia-inducible factor-1α were observed in NDEA mice as compared to control(P ≤ 0.001) and Lyc T(P ≤ 0.001) mice. The alterations in hepatic ultrastructure observed in the NDEA group correlated with the changes in the above parameters. Lyc T pre-treatment in NDEA-challenged mice ameliorated the investigated pathways disrupted by NDEA treatment. Moreover, hepatic electron micrographs from the Lyc T + NDEA group showed increased macrophages, apoptotic bodies and well-differentiated hepatocellular carcinoma(HCC) in comparison to undifferentiated HCC as observed in the NDEA treated group. CONCLUSION This study demonstrates that dietary supplementation with Lyc T has a multidimensional role in preventing HCC development.展开更多
Dramatically increasing waste polyurethane rigid foam(WPRF)draws the attention of the world.A mixture of ethylene glycol(EG)and diethylene glycol(DEG)is used as glycolysis agents.WPRF was subjected to alcoholysis usin...Dramatically increasing waste polyurethane rigid foam(WPRF)draws the attention of the world.A mixture of ethylene glycol(EG)and diethylene glycol(DEG)is used as glycolysis agents.WPRF was subjected to alcoholysis using different catalysts which are titanium ethylene glycol and potassium hydroxide to obtain recycled polyol,respectively.The effect of a different catalyst on the viscosity and hydroxyl value of recycled polyol is discussed.The regenerated polyurethane(RPU)is performed using the recycled polyol.Infrared spectrum,compressive strength,apparent density,water absorption,scanning electron microscope,and thermogravimetric analysis are carried out to investigate the effect of WPRF degradation using different catalysts.The results show that titanium glycol is more efficient than potassium hydroxide in almost all conditions.The viscosity of the recycled polyol is relatively low,and the hydroxyl value meets the requirements of industrial use.When the titanium glycol titanium addition amount is 0.05%,the prepared RPU has a compressive strength of 0.24 MPa,an apparent density of 41.75 kg/m^(3),and a good foam structure.Besides,the water absorption rate of the RPU under the two catalytic systems is not much different,and the thermal stability is good.The recycled polyol can generally partially replace traditional polyols to prepare polyurethane rigid foams with good comprehensive properties.展开更多
The limitations of fluorine-18 fluorodeoxy-D-glucose(FDG)in detecting some cancers has prompted a longstandin search for other positron emission tomography(PET tracers to complement the imaging of glycolysis i oncolog...The limitations of fluorine-18 fluorodeoxy-D-glucose(FDG)in detecting some cancers has prompted a longstandin search for other positron emission tomography(PET tracers to complement the imaging of glycolysis i oncology, with much attention paid to lipogenesis base on observations that the production of various lipid an lipid-containing compounds is increased in most cancers Radiolabeled analogs of choline and acetate have now been used as oncologic PET probes for over a decade showing convincingly improved detection sensitivit over FDG for certain cancers. However, neither cholin nor acetate have been thoroughly validated as lipogeni biomarkers, and while acetyl-Co A produced from acetat is used in de-novo lipogenesis to synthesize fatty acids acetate is also consumed by various other syntheti and metabolic pathways, with recent experimenta observations challenging the assumption that lipogenesi is its predominant role in all cancers. Since tumor detected by acetate PET are also frequently detected b choline PET, imaging of choline metabolism might serv as an alternative albeit indirect marker of lipogenesis particularly if the fatty acids produced in cancer cell are mainly destined for membrane synthesis throug incorporation into phosphatidylcholines. Aerobic glycolysi may or may not coincide with changes in lipid metabolism resulting in combinatorial metabolic phenotypes that ma have different prognostic or therapeutic implications Consequently, PET imaging using dual metabolic tracers in addition to being diagnostically superior to imagin with individual tracers, could eventually play a greate role in supporting precision medicine, as efforts t develop small-molecule metabolic pathway inhibitors ar coming to fruition. To prepare for this advent, clinical an translational studies of metabolic PET tracers must g beyond simply estimating tracer diagnostic utility, and aim to uncover potential therapeutic avenues associated wit these metabolic alterations.展开更多
Objective To investigate the regulatory relationship of Protein Phosphatase 2 Regulatory Subunit B"Alpha(PPP2R3A)and hexokinase 1(HK1)in glycolysis of hepatocellular carcinoma(HCC).Methods In HepG2 and Huh7 cells...Objective To investigate the regulatory relationship of Protein Phosphatase 2 Regulatory Subunit B"Alpha(PPP2R3A)and hexokinase 1(HK1)in glycolysis of hepatocellular carcinoma(HCC).Methods In HepG2 and Huh7 cells,PPP2R3A expression was silenced by small interfering RNA(siRNA)and overexpression by plasmid transfection.The PPP2R3A-related genes were searched by RNA sequencing.Glycolysis levels were measured by glucose uptake and lactate production.QRT-PCR,ELISA,western blot and immunofluorescence assay were performed to detect the changes of PPP2R3A and HK1.Cell proliferation,migration and invasion assay were used to study the roles of HK1 regulation by PPP2R3A.Results RNA sequencing data revealed that PPP2R3A siRNA significantly downregulated the expression of HK1.PPP2R3A gene overexpression promotes,while gene silencing suppresses,the level of HK1 and glycolysis in HCC cells.In HCC tissue samples,PPP2R3A and HK1 were colocalized in the cytoplasm,and their expression showed a positive correlation.HK1 inhibition abrogated the promotion of glycolysis,proliferation,migration and invasion by PPP2R3A overexpression in liver cancer cells.Conclusion Our findings showed the correlation of PPP2R3A and HK1 in the glycolysis of HCC,which reveals a new mechanism for the oncogenic roles of PPP2R3A in cancer.展开更多
基金National Natural Science Foundation of China Regional Fund(No.82060844)Guangxi Natural Science Foundation General Project(No.2022GXNSFAA035461)+4 种基金Guangxi Clinical Medical Research Center for Tradit Chin Med Encephalopathy(No.Guike AD20238028)Academic Team Construction Project of the First Affiliated Hospital of Guangxi Univ Tradit Chin Med[Hospital Letter(2018)No.146]The 2020 Guangxi Higher Education High level Innovation Team and Outstanding Scholar Program[Guijiao Talent(2020)No.6]Guangxi Univ Tradit Chin Med"Qihuang Project"High level Talent Team Cultivation Project(No.2018003)Guangxi Key Discipline Construction Project of Tradit Chin Med(No.GZXK-Z-20-13)Alzheimer’s disease(AD)is an irreversible neurodegenerative disease.At present,the number of AD cases has exceeded 30 million and continues to rise in the world,especially in developing countries including China.Due to the superposition of factors such as an aging population,social pressure and improper lifestyle,it is speculated that the number of AD cases will double in the next 30 years[1].Although a large amount of money has been invested in the drug development and diagnosis and treatment of AD,the current medical methods can only delay the disease of AD but can not cure it completely.It is undeniable that AD is a recognized health problem and health problem in the current society.Therefore,it is particularly important to further study the molecular mechanism of AD in order to identify the pathogenic factors and therapeutic targets,and to explore effective treatment.Modern medicine believes that its pathological mechanism is complex and interact with each other,includingβ-amyloid(Aβ)toxic damage,abnormal modification of Tau protein,oxidative stress,neuroinflammation,mitochondrial dysfunction and so on[2].In fact,in the process of inevitable aging,the metabolic network is affected by related signal pathways,proteins and genes,which leads to the gradual down-regulation of aerobic glycolysis(AEG),which can directly or indirectly participate in the pathogenesis of the above-mentioned AD and affect its pathological changes.Therefore,taking AEG as the research target can provide a new idea for the prevention and treatment of AD.The name of AD disease is not seen in Tradit Chin Med,and it is Alzheimer's disease(AD)is an irreversible neurodegenerative disease with a variety of pathogenic factors and complex pathogenesis,so that the disease has a high prevalence and mortality in the world.Although the current diagnosis and treatment equipment and drug research and development keep pace with the times,the current medical technology still can not completely cure the disease,so it is of great significance to explore the pathogenesis and treatment target of AD.The disorder of energy metabolism is one of the characteristic changes in the pathological process of AD.Aerobic glycolysis(AEG)is a special metabolic pathway in the brain,which can rapidly consume glucose to produce energy and substrate for neurons,improve synaptic plasticity,neuroinflammation and oxidative damage,and contribute to the recovery of memory and cognitive function.In recent years,many literatures have reported the mechanism of AEG in AD and the intervention of Tradit Chin Med on this mechanism.The purpose of this paper is to summarize the role of AEG in AD and the related research on the regulation and control of AEG in the treatment of AD by Tradit Chin Med,in order to provide reference and ideas for the prevention and treatment of AD with Tradit Chin Med in the future。
文摘Alzheimer's disease (AD) is an irreversible neurodegenerative disease with a variety of pathogenic factors and complex pathogenesis, so that the disease has a high prevalence and mortality in the world. Although the current diagnosis and treatment equipment and drug research and development keep pace with the times, the current medical technology still can not completely cure the disease, so it is of great significance to explore the pathogenesis and treatment target of AD. The disorder of energy metabolism is one of the characteristic changes in the pathological process of AD. Aerobic glycolysis (AEG) is a special metabolic pathway in the brain, which can rapidly consume glucose to produce energy and substrate for neurons, improve synaptic plasticity, neuroinflammation and oxidative damage, and contribute to the recovery of memory and cognitive function. In recent years, many literatures have reported the mechanism of AEG in AD and the intervention of Tradit Chin Med on this mechanism. The purpose of this paper is to summarize the role of AEG in AD and the related research on the regulation and control of AEG in the treatment of AD by Tradit Chin Med, in order to provide reference and ideas for the prevention and treatment of AD with Tradit Chin Med in the future.
基金Supported by the Shaanxi Science and Technology overall Planning and Innovation Project,No.2016KTTSSF01-05Key R&D projects in Shaanxi Province,No.2022ZDLSF05-10Shaanxi University of Chinese Medicine Discipline Innovation Team Construction Project,No.2019-YL-05.
文摘BACKGROUND Gastric precancerous lesions(GPL)precede the development of gastric cancer(GC).They are characterized by gastric mucosal intestinal metaplasia and dysplasia caused by various factors such as inflammation,bacterial infection,and injury.Abnormalities in autophagy and glycolysis affect GPL progression,and their effective regulation can aid in GPL treatment and GC prevention.Xiaojianzhong decoction(XJZ)is a classic compound for the treatment of digestive system diseases in ancient China which can inhibit the progression of GPL.However,its specific mechanism of action is still unclear.AIM To investigate the therapeutic effects of XJZ decoction on a rat GPL model and the mechanisms underlying its effects on autophagy and glycolysis regulation in GPLs.METHODS Wistar rats were randomly divided into six groups of five rats each and all groups except the control group were subjected to GPL model construction for 18 wk.The rats’body weight was monitored every 2 wk starting from the beginning of modeling.Gastric histopathology was examined using hematoxylin-eosin staining and Alcian blue-periodic acid-Schiff staining.Autophagy was observed using transmission electron microscopy.The expressions of autophagy,hypoxia,and glycolysis related proteins in gastric mucosa were detected using immunohistochemistry and immunofluorescence.The expressions of the following proteins in gastric tissues:B cell lymphoma/Leukemia-2 and adenovirus E1B19000 interacting protein 3(Bnip-3),microtubule associated protein 1 light chain 3(LC-3),moesin-like BCL2-interacting protein 1(Beclin-1),phosphatidylinositol 3-kimase(PI3K),protein kinase B(AKT),mammalian target of rapamycin(mTOR),p53,AMP-activated protein kinase(AMPK),and Unc-51 like kinase 1(ULK1)were detected using western blot.The relative expressions of autophagy,hypoxia,and glycolysis related mRNA in gastric tissues was detected using reverse transcription-polymerase chain reaction.RESULTS Treatment with XJZ increased the rats’body weight and improved GPL-related histopathological manifestations.It also decreased autophagosome and autolysosome formation in gastric tissues and reduced Bnip-3,Beclin-1,and LC-3II expressions,resulting in inhibition of autophagy.Moreover,XJZ down-regulated glycolysis-related monocarboxylate transporter(MCT1),MCT4,and CD147 expressions.XJZ prevented the increase of autophagy level by decreasing gastric mucosal hypoxia,activating the PI3K/AKT/mTOR pathway,inhibiting the p53/AMPK pathway activation and ULK1 Ser-317 and Ser-555 phosphorylation.In addition,XJZ improved abnormal gastric mucosal glucose metabolism by ameliorating gastric mucosal hypoxia and inhibiting ULK1 expression.CONCLUSION This study demonstrates that XJZ may inhibit autophagy and glycolysis in GPL gastric mucosal cells by improving gastric mucosal hypoxia and regulating PI3K/AKT/mTOR and p53/AMPK/ULK1 signaling pathways,providing a feasible strategy for the GPL treatment.
基金supported by National Natural Science Foundation of China(No.81960351)High-level Talent Fund of Hainan Province(No.822RC835).
文摘Acute lung injury is featured as diffuse pulmonary edema and persistent hypoxemia caused by lung or systemic injury.It is believed that these pathological changes are associated with damage to the alveolar epithelium and vascular endothelium,recruitment of inflammatory cells,and inflammatory factor storms.In recent years,the metabolic reprogramming of lung parenchymal cells and immune cells,particularly alterations in glycolysis,has been found to occur in acute lung injury.Inhibition of glycolysis can reduce the severity of acute lung injury.Thus,this review focuses on the interconnection between acute lung injury and glycolysis and the mechanisms of interaction,which may bring hope for the treatment of acute lung injury.
基金This work was supported by grants from the National Natural Science Foundation of China(No.62171193)the Natural Science Foundation of Hubei Province(No.2021CFB399)+1 种基金the Foundation of Health Commission of Hubei Province(No.WJ2021M125)the Key Research and Development Project of Hubei Province of China(No.2022BCA033).
文摘Objective Oral lichen planus(OLP)is one of the most common oral mucosa diseases,and is mainly mediated by T lymphocytes.The metabolic reprogramming of activated T cells has been shown to transform from oxidative phosphorylation to aerobic glycolysis.The present study investigated the serum levels of glycolysis-related molecules(lactate dehydrogenase,LDH;pyruvic acid,PA;lactic acid,LAC)in OLP,and the correlation with OLP activity was assessed using the reticular,atrophic and erosive lesion(RAE)scoring system.Methods Univariate and multivariate linear regression functions based on scikit-learn were designed to predict the RAE scores in OLP patients,and the performance of these two machine learning functions was compared.Results The results revealed that the serum levels of PA and LAC were upregulated in erosive OLP(EOLP)patients,when compared to healthy volunteers.Furthermore,the LDH and LAC levels were significantly higher in the EOLP group than in the nonerosive OLP(NEOLP)group.All glycolysis-related molecules were positively correlated to the RAE scores.Among these,LAC had a strong correlation.The univariate function that involved the LAC level and the multivariate function that involved all glycolysis-related molecules presented comparable prediction accuracy and stability,but the latter was more time-consuming.Conclusion It can be concluded that the serum LAC level can be a user-friendly biomarker to monitor the OLP activity,based on the univariate function developed in the present study.The intervention of the glycolytic pathway may provide a potential therapeutic strategy.
基金Supported by Youth Fund of National Natural Science Foundation of China,No.81803575,No.31902287Kaifeng Science and Technology Development Plan Project,No.2203008+2 种基金Key Specialized Research and Promotion Project of Henan Province in 2023,No.232102311205Henan Medical Science and Technology Research Program Project,No.LHGJ20210801College Students Innovation and Entrepreneurship Training Program of Henan University,No.20231022007.
文摘BACKGROUND Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2(HER-2)-positive gastric cancer(GC).However,the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance.While S-phase kinase associated protein 2(Skp2)overexpression has been implicated in the malignant progression of GC,its role in regulating trastuzumab resistance in this context remains uncertain.Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products,there has been a lack of successful commercialization of drugs specifically targeting Skp2.AIM To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment.METHODS Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells.Q-PCR,western blot,and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression.A cell counting kit-8 assay,flow cytometry,a amplex red glucose/glucose oxidase assay kit,and a lactate assay kit were utilized to measure the proliferation,apoptosis,and glycolytic activity of GC cells in vitro.A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo.RESULTS The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab.Thioridazine demonstrated the ability to directly bind to Skp2,resulting in a reduction in Skp2 expression at both the transcriptional and translational levels.Moreover,thioridazine effectively inhibited cell proliferation,exhibited antiapoptotic properties,and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways.The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo,surpassing the efficacy of either monotherapy.CONCLUSION Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance,particularly when used in conjunction with lapatinib.This compound has potential benefits for patients with Skp2-proficient tumors.
基金supported by the Public Health Research Project in Futian District,Shenzhen(Grant Nos.FTWS2020026,FTWS2021073).
文摘Background:Establishing an appropriate prognostic model for PCa is essential for its effective treatment.Glycolysis is a vital energy-harvesting mechanism for tumors.Developing a prognostic model for PCa based on glycolysis-related genes is novel and has great potential.Methods:First,gene expression and clinical data of PCa patients were downloaded from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO),and glycolysis-related genes were obtained from the Molecular Signatures Database(MSigDB).Gene enrichment analysis was performed to verify that glycolysis functions were enriched in the genes we obtained,which were used in nonnegative matrix factorization(NMF)to identify clusters.The correlation between clusters and clinical features was discussed,and the differentially expressed genes(DEGs)between the two clusters were investigated.Based on the DEGs,we investigated the biological differences between clusters,including immune cell infiltration,mutation,tumor immune dysfunction and exclusion,immune function,and checkpoint genes.To establish the prognostic model,the genes were filtered based on univariable Cox regression,LASSO,and multivariable Cox regression.Kaplan–Meier analysis and receiver operating characteristic analysis validated the prognostic value of the model.A nomogram of the risk score calculated by the prognostic model and clinical characteristics was constructed to quantitatively estimate the survival probability for PCa patients in the clinical setting.Result:The genes obtained from MSigDB were enriched in glycolysis functions.Two clusters were identified by NMF analysis based on 272 glycolysis-related genes,and a prognostic model based on DEGs between the two clusters was finally established.The prognostic model consisted of LAMPS,SPRN,ATOH1,TANC1,ETV1,TDRD1,KLK14,MESP2,POSTN,CRIP2,NAT1,AKR7A3,PODXL,CARTPT,and PCDHGB2.All sample,training,and test cohorts from The Cancer Genome Atlas(TCGA)and the external validation cohort from GEO showed significant differences between the high-risk and low-risk groups.The area under the ROC curve showed great performance of this prognostic model.Conclusion:A prognostic model based on glycolysis-related genes was established,with great performance and potential significance to the clinical application.
基金supported by the National Natural Science Foundation of China(No.82000300).
文摘Background:Pulmonary arterial hypertension(PAH)is a chronic and progressive disease that is strongly associated with dysregulation of glucose metabolism.Alterations in nuclear receptor subfamily 4 group A member 1(NR4A1)activity alter the outcome of PAH.This study aimed to investigate the effects of NR4A1 on glycolysis in PAH and its underlying mechanisms.Methods:This study included twenty healthy volunteers and twenty-three PAH patients,and plasma samples were collected from the participants.To mimic the conditions of PAH in vitro,a hypoxia-induced model of pulmonary artery smooth muscle cell(PASMC)model was established.The proliferation of PASMCs was assessed using CCK8 assays.Results:Levels of NR4A1,hypoxia-inducible factor-1α(HIF-1α),and various glycolysis-related enzymes were measured.In addition,extracellular glucose and lactate production were assessed.The interaction between NR4A1 and HIF-1αwas evaluated by co-immunoprecipitation assays.Levels of NR4A1 and HIF-1αwas increased in PAH patients,and exposure to hypoxia resulted in increased levels of NR4A1 and HIF-1αin PASMCs.NR4A1 interacted with HIF-1α.NR4A1 overexpression enhanced hypoxia-induced expression of HIF-1α,GLUT1,PKM2,HK2,and CD36,decreased glucose levels,increased lactate levels and promoted hypoxic PASMC viability.Conversely,silencing NR4A1 decreased hypoxia-induced expression of HIF-1α,GLUT1,PKM2,HK2,and CD36,promoted glucose production,reduced lactate levels and inhibited hypoxic PASMC viability.Furthermore,overexpression of HIF-1αreversed the regulation of glycolysis caused by NR4A1 knockdown.Conclusion:NR4A1 enhances glycolysis in hypoxia-induced PASMCs by upregulating HIF-1α.Our findings indicate that the management of NR4A1 activity may be a promising strategy for PAH therapy.
基金Supported by National Natural Science Foundation of China,No.81960782.
文摘BACKGROUND Resistance to sorafenib has become a challenge in clinical treatment of hepatocellular carcinoma(HCC).Physcion is a common bioactive anthraquinone that has potential as an anticancer agent.AIM To study the effect of physcion on sensitizing HCC cells to sorafenib.METHODS Sorafenib-resistant HCC cells were established and treated with sorafenib and/or physcion.The cell viability,proliferation and apoptosis were measured by cell counting kit-8,colony formation,flow cytometry,and in vivo xenograft model.Glucose uptake,lactate acid production,extracellular acidification rate(ECAR),and oxygen consumption rate(OCR)were measured to analyze glycolysis.Expression of glycolysis-related regulators was assessed by western blotting.RESULTS The addition of physcion significantly enhanced the antitumor effects of sorafenib on sorafenib-resistant HCC cells,manifested by enhanced apoptosis and suppressed cell growth.The glucose uptake,lactate acid production,and ECAR were elevated,and OCR was suppressed by physcion treatment.The level of PIM1 was elevated and miR-370 was suppressed in sorafenib-resistant HCC cells compared with the parental cells,which was suppressed by physcion treatment.Inhibition of miR-370 notably reversed the effects of physcion on sorafenib-resistant HCC cells.CONCLUSION Our data indicated that physcion enhanced the sensitivity of HCC cells to sorafenib by enhancing miR-370 to suppress PIM1-promoted glycolysis.
基金Supported by the National Natural Science Foundation of China,No.30800511
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.
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.
基金Supported by National Natural Science Foundation of China,No.81300329 and No.81401992
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.
基金Supported by Grant to Dr.Jung-Hwan Yoonthe Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education,Science and Technology,No.20100007381by the Liver Research Foundation of Korea
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.
基金by National Natural Science Foundation of China,No.82060116,No.81860115 and No.81960118Guizhou Science and Technology Support Project Fund,No.[2021]058.
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.
文摘In a series of our recent studies, stress was found to induce simultaneously hypothermia and hyperglycemia. These conditions are beneficial to obtain prompt force which depends on the glycolysis pathway and to escape emergency. Since we have noticed that such conditions resemble the internal environment seen in some cancer patients, it was investigated whe- ther such conditions were accompanied with other patients. We selected patients with early and advanced cancer. Body temperature and other parameters including blood gas contents were examined. A difference was seen in body temperature, namely, many patients showed hypothermia, irrespective of cancer stages. Fur- ther characterization of other parameters show- ed that hypothermia and hyperglycemia existed in many patients. They had immunosuppressive state and anemia. Blood gas analysis showed that oxygen contents were low and carbon dioxide contents were high in patients. These results suggest a possibility that the internal environment seen in patients is responsible to induce onset of disease and to maintain their cell growth, because cancer cells have an energy system of predominant glycolysis. Although hypothermia, hypoxia and hyperglycemia are important to activate the glycolysis pathway and to escape from emergency, such responses suppress the mitochondrial pathway for long span and may result in carcinogenesis.
基金the National Natural Science Foundation of China,No.81860115,No.82060116 and No.81960118the Science and Technology Support Project of Guizhou Province,No.[2021]094.
文摘BACKGROUND Hepatic stellate cell(HSC)hyperactivation is a central link in liver fibrosis development.HSCs perform aerobic glycolysis to provide energy for their activation.Focal adhesion kinase(FAK)promotes aerobic glycolysis in cancer cells or fibroblasts,while FAK-related non-kinase(FRNK)inhibits FAK phosphorylation and biological functions.AIM To elucidate the effect of FRNK on liver fibrosis at the level of aerobic glycolytic metabolism in HSCs.METHODS Mouse liver fibrosis models were established by administering CCl4,and the effect of FRNK on the degree of liver fibrosis in the model was evaluated.Transforming growth factor-β1 was used to activate LX-2 cells.Tyrosine phosphorylation at position 397(pY397-FAK)was detected to identify activated FAK,and the expression of the glycolysis-related proteins monocarboxylate transporter 1(MCT-1)and enolase1(ENO1)was assessed.Bioinformatics analysis was performed to predict putative binding sites for c-myc in the ENO1 promoter region,which were validated with chromatin immunoprecipitation(ChIP)and dual luciferase reporter assays.RESULTS The pY397-FAK level was increased in human fibrotic liver tissue.FRNK knockout promoted liver fibrosis in mouse models.It also increased the activation,migration,proliferation and aerobic glycolysis of primary hepatic stellate cells(pHSCs)but inhibited pHSC apoptosis.Nevertheless,opposite trends for these phenomena were observed after exogenous FRNK treatment in LX-2 cells.Mechanistically,the FAK/Ras/c-myc/ENO1 pathway promoted aerobic glycolysis,which was inhibited by exogenous FRNK.CONCLUSION FRNK inhibits aerobic glycolysis in HSCs by inhibiting the FAK/Ras/c-myc/ENO1 pathway,thereby improving liver fibrosis.FRNK might be a potential target for liver fibrosis treatment.
基金Supported by University Grant Commission,New Delhi,No.2060930310
文摘AIM To investigate the effect of lycopene extracted from tomatoes(LycT) on ultrastructure, glycolytic enzymes, cell proliferation markers and hypoxia during N-Nitrosodiethylamine(NDEA)-induced hepatocarcinogenesis. METHODS Female BALB/c mice were randomly divided into four groups: The Control, NDEA(200 mg NDEA/kg b.w. given i.p.), LycT(5 mg/kg b.w. given orally on alternate days) and Lyc T + NDEA group. The m RNA and protein expression of various cell proliferation markers(PCNA, Cyclin D1, and p21) were assessed by reverse transcription-polymerase chain reaction and enzyme linked immunosorbent assay, respectively. The ultrastructure of hepatic tissue was analyzed using scanning and transmission electron microscopy. The enzymatic activity of glycolytic enzymes was estimated using standardized protocols, while glucose-6-phosphate dehydrogenase activity level was estimated using a kit obtained from Reckon Diagnostic P. Ltd.(India). RESULTS Uncontrolled proliferation in the liver of NDEA(P ≤ 0.001) mice was evident from the high expression of cell-proliferation associated genes(PCNA, Cyclin D1, and p21) when compared to control and Lyc T mice. In addition, enhanced activities of hexokinase, phosphoglucoisomerase, aldolase, glucose-6-phosphatedehydrogenase and hypoxia-inducible factor-1α were observed in NDEA mice as compared to control(P ≤ 0.001) and Lyc T(P ≤ 0.001) mice. The alterations in hepatic ultrastructure observed in the NDEA group correlated with the changes in the above parameters. Lyc T pre-treatment in NDEA-challenged mice ameliorated the investigated pathways disrupted by NDEA treatment. Moreover, hepatic electron micrographs from the Lyc T + NDEA group showed increased macrophages, apoptotic bodies and well-differentiated hepatocellular carcinoma(HCC) in comparison to undifferentiated HCC as observed in the NDEA treated group. CONCLUSION This study demonstrates that dietary supplementation with Lyc T has a multidimensional role in preventing HCC development.
基金the 2019 Graduate Student Innovative Research Project of Qiqihar University Heilongjiang Province,China(YJSCX2019063)Qiqihar Science and Technology Bureau Project(GYGG-201902)Heilongjiang Provincial Department of Education Project(135409301).
文摘Dramatically increasing waste polyurethane rigid foam(WPRF)draws the attention of the world.A mixture of ethylene glycol(EG)and diethylene glycol(DEG)is used as glycolysis agents.WPRF was subjected to alcoholysis using different catalysts which are titanium ethylene glycol and potassium hydroxide to obtain recycled polyol,respectively.The effect of a different catalyst on the viscosity and hydroxyl value of recycled polyol is discussed.The regenerated polyurethane(RPU)is performed using the recycled polyol.Infrared spectrum,compressive strength,apparent density,water absorption,scanning electron microscope,and thermogravimetric analysis are carried out to investigate the effect of WPRF degradation using different catalysts.The results show that titanium glycol is more efficient than potassium hydroxide in almost all conditions.The viscosity of the recycled polyol is relatively low,and the hydroxyl value meets the requirements of industrial use.When the titanium glycol titanium addition amount is 0.05%,the prepared RPU has a compressive strength of 0.24 MPa,an apparent density of 41.75 kg/m^(3),and a good foam structure.Besides,the water absorption rate of the RPU under the two catalytic systems is not much different,and the thermal stability is good.The recycled polyol can generally partially replace traditional polyols to prepare polyurethane rigid foams with good comprehensive properties.
文摘The limitations of fluorine-18 fluorodeoxy-D-glucose(FDG)in detecting some cancers has prompted a longstandin search for other positron emission tomography(PET tracers to complement the imaging of glycolysis i oncology, with much attention paid to lipogenesis base on observations that the production of various lipid an lipid-containing compounds is increased in most cancers Radiolabeled analogs of choline and acetate have now been used as oncologic PET probes for over a decade showing convincingly improved detection sensitivit over FDG for certain cancers. However, neither cholin nor acetate have been thoroughly validated as lipogeni biomarkers, and while acetyl-Co A produced from acetat is used in de-novo lipogenesis to synthesize fatty acids acetate is also consumed by various other syntheti and metabolic pathways, with recent experimenta observations challenging the assumption that lipogenesi is its predominant role in all cancers. Since tumor detected by acetate PET are also frequently detected b choline PET, imaging of choline metabolism might serv as an alternative albeit indirect marker of lipogenesis particularly if the fatty acids produced in cancer cell are mainly destined for membrane synthesis throug incorporation into phosphatidylcholines. Aerobic glycolysi may or may not coincide with changes in lipid metabolism resulting in combinatorial metabolic phenotypes that ma have different prognostic or therapeutic implications Consequently, PET imaging using dual metabolic tracers in addition to being diagnostically superior to imagin with individual tracers, could eventually play a greate role in supporting precision medicine, as efforts t develop small-molecule metabolic pathway inhibitors ar coming to fruition. To prepare for this advent, clinical an translational studies of metabolic PET tracers must g beyond simply estimating tracer diagnostic utility, and aim to uncover potential therapeutic avenues associated wit these metabolic alterations.
基金supported by National Natural Science Foundation of China [81372595]
文摘Objective To investigate the regulatory relationship of Protein Phosphatase 2 Regulatory Subunit B"Alpha(PPP2R3A)and hexokinase 1(HK1)in glycolysis of hepatocellular carcinoma(HCC).Methods In HepG2 and Huh7 cells,PPP2R3A expression was silenced by small interfering RNA(siRNA)and overexpression by plasmid transfection.The PPP2R3A-related genes were searched by RNA sequencing.Glycolysis levels were measured by glucose uptake and lactate production.QRT-PCR,ELISA,western blot and immunofluorescence assay were performed to detect the changes of PPP2R3A and HK1.Cell proliferation,migration and invasion assay were used to study the roles of HK1 regulation by PPP2R3A.Results RNA sequencing data revealed that PPP2R3A siRNA significantly downregulated the expression of HK1.PPP2R3A gene overexpression promotes,while gene silencing suppresses,the level of HK1 and glycolysis in HCC cells.In HCC tissue samples,PPP2R3A and HK1 were colocalized in the cytoplasm,and their expression showed a positive correlation.HK1 inhibition abrogated the promotion of glycolysis,proliferation,migration and invasion by PPP2R3A overexpression in liver cancer cells.Conclusion Our findings showed the correlation of PPP2R3A and HK1 in the glycolysis of HCC,which reveals a new mechanism for the oncogenic roles of PPP2R3A in cancer.
