Objective:To discuss the effect of insulin and metformin on amethylation and glycolipid metabolism of peroxisome proliferator-activated receptor γ coactivator-1A(PPARGC1A) of rat offspring with gestational diabetes m...Objective:To discuss the effect of insulin and metformin on amethylation and glycolipid metabolism of peroxisome proliferator-activated receptor γ coactivator-1A(PPARGC1A) of rat offspring with gestational diabetes mellitus(GDM).Methods:A total of 45 pregnant rats received the intraperitoneal injection of streptozotocin to establish the pregnant rat model of GDM.A total of 21 pregnant rats with GDM were randomly divided into three groups,with 7ruts in each group,namely the insulin group,metformin group and control group.Rats in the insulin group received the abdominal subcutaneous injection of 1 mL/kg recombinant insulin glargine at 18:00 every day.Rats in the metformin group received the intragastric infusion of metformin hydrochloride at 18:00 every day,with the first dose of 300 mg/kg.The doses of two groups were adjusted every 3 d to maintain the blood glucose level at 2.65-7.62 mmol/L.Rats in the control group received the intragastric infusion of 1 mL normal saline at 18:00 every day.After the natural delivery of pregnant rats.10 offspring rats were randomly selected from each group.At birth,4 wk and 8 wk after the birth of offspring rats,the weight of offspring rats was measured.The blood glucose level of offspring rats was measured at 4wk and 8 wk,while the level of serum insulin,triglyceride and leptin was measured at 8 wk.Results:The weight of offspring rats at birth in the insulin group and metformin group was significantly lower than the one in the control group(P<0.05),and there was no significant difference at 4 wk and 8 wk among three groups(P>0.05).The fasting blood glucose and random blood glucose in the insulin group and metformin group at 4 wk and 8 wk were all significantly lower than ones in the control group(P<0.05);there was no significant difference between the insulin group and metformin group(P>0.05).The expression of PPARGC1 A mRNA in the insulin group and metformin group was significantly higher and the methylation level of PPARGC1 A was significantly lower than the one in the control group(P<0.05),but there was no significant difference between the insulin group and metformin group(P>0.05).Insulin and leptin at 8 wk in the insulin group and metformin group were significantly higher,while triglyceride was significantly lower than the one in the control group(P<0.05);triglyceride level of rats in the insulin group was significantly higher than the one in the metformin group(P<0.05).There was no significant difference in insulin and leptin level of offspring rats between the insulin group and metformin group(P>0.05).Conclusions:GDM can induce the methylation of PPARGC1 A of offspring rats to reduce the expression of PPARGC1 A mRNA and then cause the disorder of glycolipid metabolism when the offspring rats grow up;the insulin or metformin in the treatment of pregnant rats with GDM can reduce the methylation level of PPARGC1 A and thus improve the abnormal glycolipid metabolism of offspring rats.展开更多
Death following situations of intense emotional stress has been linked to the cardiac pathology described as stress cardiomyopathy, whose pathomechanism is still not clear. In this study, we sought to determine, via a...Death following situations of intense emotional stress has been linked to the cardiac pathology described as stress cardiomyopathy, whose pathomechanism is still not clear. In this study, we sought to determine, via an animal model, whether the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α) and the amino peptide neuropeptide Y (NPY) play a role in the pathogenesis of this cardiac entity. Male Sprague-Dawley rats in the experimental group were subjected to immobilization in a plexy glass box for 1 h, which was followed by low voltage elec-tric foot shock for about 1h at 10s intervals in a cage fitted with metallic rods. After 25 days the rats were sacrificed and sections of their hearts were processed. Hematoxylin-eosin staining of cardiac tissues revealed the characteristic cardiac lesions of stress cardiomyopathy such as contraction band necrosis, inflammatory cell infiltration and fibrosis. The semi-quantitative RT-PCR analysis for PGC-1α mRNA expression showed significant overexpression of PGC1-α in the stress-subjected rats (P<0.05). Fluorescence immunohistochemistry revealed a higher production of NPY in the stress-subjected rats as compared to the control rats (P=0.0027). Thus, we are led to conclude that following periods of intense stress, an increased expression of PGC1-α in the heart and an overflow of NPY may lead to stress car-diomyopathy and even death in susceptible victims. Moreover, these markers can be used to identify stress cardiomyopathy as the cause of sudden death in specific cases.展开更多
Objective.To investigate the effect of peroxis ome proliferator-activated recept ors(PPARs )activators on plasminogen activator inhibitor ty pe-1(PAI-1)expression in human umbilical vein e ndothelial cells and the pos...Objective.To investigate the effect of peroxis ome proliferator-activated recept ors(PPARs )activators on plasminogen activator inhibitor ty pe-1(PAI-1)expression in human umbilical vein e ndothelial cells and the possi-ble mechanism.Methods.Human umbilical vein endothelial ce lls(HUVECs )were obtained from normal fetus,and cul-tured conventionally.Then the HUVECs were exposed to test agents(linolenic acid,linoleic acid,oleic acid,stearic acid and prostaglandin J 2 respectively)in varying concentrations with fresh media.RT -PCR and ELISA were applied to determine the expression of PPARs and PAI-1in HUVECs.Results.PPARα,PPARδand PPARγmRNA were detected by using RT-PCR in HUVECs.Treatment of HUVECs with PPARαand PPARγactivators---linolenic acid,linoleic acid,oleic acid and prostaglandin J 2 respectively,but not with stearic a cid could augment PAI-I mRNA expression and protein secretion in a concentration-dependent manner.However,the mRNA expressions of 3subclasses of PPAR with their activators in HUVECs were not changed compared w ith controls.Conclusion.HUVECs express PPARs.PPARs activators may increase PAI-1expression in ECs,but the underlying mechanism remains uncle ar.Although PPARs expression was not enhanced after stimulated by their activators in ECs,the role of functionally active PPARs in regulating PA I-1expression in ECs needs to be further investigated by using transient gen e transfection assay.展开更多
Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regul...Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor α (PPARα) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPARα may be a potential therapeutic target for the treatment of alcoholic liver disease.展开更多
Background Pancreatic beta-cell apoptosis induced by lipotoxicity, to a large extent, contributes to the progression of type 2 diabetes. To investigate the mechanism of free fatty acid induced apoptosis, we aimed to s...Background Pancreatic beta-cell apoptosis induced by lipotoxicity, to a large extent, contributes to the progression of type 2 diabetes. To investigate the mechanism of free fatty acid induced apoptosis, we aimed to study the effects of palmitic acid （PA） on the apoptosis and peroxisome proliferator-activated receptor y coactivator-1α （PGC-1α） expression in βTC3 cells as well as the possible role of nuclear factor-KB （NF-KB） in this process. Methods Hoechst 33258 was used to detect βTC3 cell apoptosis, which was induced by PA stimulation for 12 hours. PGC-1α expression was analyzed by reverse transcription polymerase chain reaction, IκB kinase β （IKKβ）, IκBα NF-KB-inducing kinase （NIK） and ReI-B expressions were analyzed by Western blotting. MGβ2 was employed to block the endogenous IκBαdegradation before PA administration, and then its effect on PA-inducing cell apoptosis and PGC-1α mRNA expression was analyzed. Results Significant increased cell apoptosis was found at the concentration of 0.5 mmol/L and 1.0 mmol/L PA administration. PA （0.5 mmol/L） could extensively reduced the expression of PGC-1α mRNA. After exposing βTC3 cells to 0.5 mmol/L PA for different time periods （0, 4, 6, 8, 10 and 12 hours）, IKKβ protein expression increased while IκBα NIK and ReI-B protein expression declined in a time-dependent manner. Pretreatment with MGβ2 to inhibit the degradation of IκBα partially prevented the down-regulation of PGC-1α mRNA expression after 12-hour PA treatment in accordance with the decrease of PA induced apoptosis. Conclusions NF-KB canonical pathway was activated in PA-mediated βTC3 cell apoptosis, whereas non-canonical pathway was inhibited. Reduced PGC-1α expression by PA in βTC3 cells could involve the activation of canonical NF-KB pathway, so as to deteriorate the PA induced apoptosis.展开更多
Background Some single nucleotide polymorphisms （SNPs） in the peroxisome proliferator-activated receptor-y coactivator （PGC）-1α gene have been reported to be associated with type 2 diabetes in different populatio...Background Some single nucleotide polymorphisms （SNPs） in the peroxisome proliferator-activated receptor-y coactivator （PGC）-1α gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1α and type 2 diabetes in the southern Chinese population and to determine whether the common variants： Gly482Ser and Thr394Thr, in the PGC-1α gene have any impacts on interaction with myocyte enhancer factor （MEF） 2C. Methods The SNPs in all exons of the PGC-1α gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism （PCR-SSCP） and direct sequencing. Thereafter, 263 type 2 diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP）. A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1α gene alter the interaction with MEF2C. Results Three frequent SNPs （Thr394Thr, Gly482Ser and Thr528Thr） were found in exons of the PGC-1α gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls （40.1% vs 29.3%, P〈0.01）. Even in controls, the 482Ser（A） carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly（G） carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr （A） had a synergic effect on the interaction between 482Ser variant and MEF2C. Conclusions The results suggested that the 482Ser variant of PGC-1α conferred the susceptibility to type 2 diabetes in the southern Chinese population. The underlying mechanism may be attributable, at least in part, to the altered interaction between the different variants （Gly482Ser, Thr394Thr） in the PGC-1α gene and MEF2C.展开更多
Hepatitis C virus(HCV)is still one of the main causes of liver disease worldwide.Metabolic disorders,including nonalcoholic fatty liver disease(NAFLD),induced by HCV have been shown to accelerate the progression of fi...Hepatitis C virus(HCV)is still one of the main causes of liver disease worldwide.Metabolic disorders,including nonalcoholic fatty liver disease(NAFLD),induced by HCV have been shown to accelerate the progression of fibrosis to cirrhosis and to increase the risk of hepatocellular carcinoma.An optimal peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PPARGC1A)activity is crucial to prevent NAFLD installation.The present study aims to investigate the associations between two common PPARGC1A polymorphisms(rs8192678 and rs12640088)and the outcomes of HCV infection in a North African context.A series of 592 consecutive Moroccan subjects,including 292 patients with chronic hepatitis C(CHC),100 resolvers and 200 healthy controls were genotyped using a TaqMan allelic discrimination assay.PPARGC1A variations at rs8192678 and rs12640088 were not associated with spontaneous clearance of HCV infection(adjusted ORs=0.76 and 0.79 respectively,P[0.05,for both).Furthermore,multivariable logistic regression analysis showed that both SNPs were not associated with fibrosis progression(OR=0.71;95%CI 0.20–2.49;P=0.739;OR=1.28;95%CI 0.25–6.54;P=0.512,respectively).We conclude that,in the genetic context of South Mediterranean patients,rs8192678 and rs12640088 polymorphisms of PPARGC1 A are neither associated with spontaneous clearance nor with disease progression in individuals infected with HCV.展开更多
Objective To investigate the effect of peroxisome proliferator-activated receptors (PPARs) activators on plasminogen activator inhibitor 1 (PAI-1) expression in human umbilical vein endothelial cells and elucidate a ...Objective To investigate the effect of peroxisome proliferator-activated receptors (PPARs) activators on plasminogen activator inhibitor 1 (PAI-1) expression in human umbilical vein endothelial cells and elucidate a possible mechanism. Methods Human umbilical vein endothelial cells (HUVECs) were obtained from normal fetus, and cultured conventionally. Then the HUVEC were exposed to fatty acids and prostaglandin J 2 in varying concentrations with fresh media. RT-PCR and ELISA were used to determine the expression of PPAR and PAI-1 in HUVECs. Transient co-transfection of PAI-1 promoter and PPARα gene or PPARγ gene to ECV304 was performed.Results PPARα, PPARδ and PPARγ mRNA in HUVECs were detected by RT-PCR. Treatment of HUVECs with PPARα and PPARγ activators-linolenic acid, linoleic acid, oleic acid and prostaglandin J 2, but not with stearic acid could augment PAI-I mRNA expression and protein secretion in a concentration-dependent manner. Proportional induction of PAI-1 promoter activity was observed through increasing amounts of PPARα DNA in HUVECs through a transient gene transfection assay, although the mRNA expression of the 3 subtypes of PPAR with their activators were not changed compared with controls.Conclusions HUVECs express PPARs. PPARs activators may increase PAI-1 expression in endothelial cells (EC). Although PPARs expression was not enhanced after being stimulated by their activators in EC, the functionally active PPARα is probably involved in regulating PAI-1 expression in EC.展开更多
Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR3...Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.展开更多
BACKGROUND Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities.The effects mediated by the silent i...BACKGROUND Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities.The effects mediated by the silent information regulator type 2 homolog-1(SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α(PGC-1α)axis present new opportunities for the treatment of type 2 diabetic peripheral neuropathy(T2DPN),potentially breaking this harmful cycle.AIM To validate the effectiveness of electroacupuncture(EA)in the treatment of T2DPN and investigate its potential mechanism based on the SIRT1/PGC-1αaxis.METHODS The effects of EA were evaluated through assessments of metabolic changes,morphological observations,and functional examinations of the sciatic nerve,along with measurements of inflammation and oxidative stress.Proteins related to the SIRT1/PGC-1αaxis,involved in the regulation of mitochondrial biogenesis and antioxidative stress,were detected in the sciatic nerve using Western blotting to explain the underlying mechanism.A counterevidence group was created by injecting a SIRT1 inhibitor during EA intervention to support the hypothesis.RESULTS In addition to diabetes-related metabolic changes,T2DPN rats showed significant reductions in pain threshold after 9 weeks,suggesting abnormal peripheral nerve function.EA treatment partially restored metabolic control and reduced nerve damage in T2DPN rats.The SIRT1/PGC-1αaxis,which was downregulated in the model group,was upregulated by EA intervention.The endogenous antioxidant system related to the SIRT1/PGC-1αaxis,previously inhibited in diabetic rats,was reactivated.A similar trend was observed in inflammatory markers.When SIRT1 was inhibited in diabetic rats,these beneficial effects were abolished.CONCLUSION EA can alleviate the symptoms of T2DNP in experimental rats,and its effects may be related to the mitochondrial biogenesis and endogenous antioxidant system mediated by the SIRT1/PGC-1αaxis.展开更多
AIM:To investigate the effects of heme oxygenase(HO)-1 on liver fibrosis and the expression of peroxisome proliferator-activated receptor gamma(PPARγ) and nuclear factor-kappa B(NF-κB) in rats.METHODS:Sixty Wistar r...AIM:To investigate the effects of heme oxygenase(HO)-1 on liver fibrosis and the expression of peroxisome proliferator-activated receptor gamma(PPARγ) and nuclear factor-kappa B(NF-κB) in rats.METHODS:Sixty Wistar rats were used to construct liver fibrosis models and were randomly divided into 5 groups:group A(normal,untreated),group B(model for 4 wk,untreated),group C(model for 6 wk,untreated),group D [model for 6 wk,treated with zinc protoporphyrin Ⅸ(ZnPP-Ⅸ) from week 4 to week 6],group E(model for 6 wk,treated with hemin from week 4 to week 6).Next,liver injury was assessed by measuring serum alanine aminotransferase(ALT),aspartate aminotransferase(AST) and albumin levels.The degree of hepatic fibrosis was evaluated by measuring serum hyaluronate acid(HA),type Ⅳ collagen(Ⅳ-C) and by histological examination.Hydroxyproline(Hyp) content in the liver homogenate was determined.The expres-sion levels of alpha-smooth muscle actin(α-SMA) in liver tissue were measured by real-time quantitative polymerase chain reaction(RT-PCR).The expression levels of PPARγ and NF-κB were determined by RT-PCR and Western blotting.RESULTS:The expression of HO-1 increased with the development of fibrosis.Induction of HO-1 by hemin significantly attenuated the severity of liver injury and the levels of liver fibrosis as compared with inhibition of HO-1 by ZnPP-Ⅸ.The concentrations of serum ALT,AST,HA and Ⅳ-C in group E decreased compared with group C and group D(P < 0.01).Amount of Hyp and α-SMA in the liver tissues in group E decreased compared with group C(0.62 ± 0.14 vs 0.84 ± 0.07,1.42 ± 0.17 vs 1.84 ± 0.17,respectively,P < 0.01) and group D(0.62 ± 0.14 vs 1.11 ± 0.16,1.42 ± 0.17 vs 2.56 ± 0.37,respectively,P < 0.01).The expression of PPARγ at levels of transcription and translation decreased with the development of fibrosis especially in group D;and it increased in group E compared with groups C and D(0.88 ± 0.15 vs 0.56 ± 0.19,0.88 ± 0.15 vs 0.41 ± 0.11,respectively,P < 0.01).The expression of NF-κB increased with the development of fibrosis especially in group D;and it decreased in group E compared with groups C and D(1.43 ± 0.31 vs 1.89 ± 0.29,1.43 ± 0.31 vs 2.53 ± 0.54,respectively,P < 0.01).CONCLUSION:Our data demonstrate a potential mechanism that HO-1 can prevent liver fibrosis by enhancing the expression of PPARγ and decreasing the expression of NF-κB in liver tissues.展开更多
A number of disparate diseases can lead to pulmonary hypertension(PH), a serious disorder with a high morbidity and mortality rate. Recent studies suggest that the associated metabolic dysregulation may be an importan...A number of disparate diseases can lead to pulmonary hypertension(PH), a serious disorder with a high morbidity and mortality rate. Recent studies suggest that the associated metabolic dysregulation may be an important factor adversely impacting the prognosis of PH. Furthermore, metabolic syndrome is associated with vascular diseases including PH. Inflammation plays a significant role both in PH and metabolic syndrome. Adipose tissue modulates lipid and glucose metabolism, and also produces pro-and anti-inflammatory adipokines that modulate vascular function and angiogenesis, suggesting a close functional relationship between the adipose tissue and the vasculature. Both caveolin-1, a cell membrane scaffolding protein and peroxisome proliferator-activated receptor(PPAR) γ, a ligandactivated transcription factor are abundantly expressed in the endothelial cells and adipocytes. Both caveolin-1 and PPARγ modulate proliferative and anti-apoptotic pathways, cell migration, inflammation, vascular homeostasis, and participate in lipid transport, triacylglyceride synthesis and glucose metabolism. Caveolin-1 and PPARγ regulate the production of adipokines and in turn are modulated by them. This review article summarizes the roles and inter-relationships of caveolin-1,PPARγ and adipokines in PH and metabolic syndrome.展开更多
AIMTo determine whether small interfering RNA (siRNA) of PGC-1α could inhibit vascular endothelial growth factor (VEGF) expression and tube formation in human retinal vascular endothelial cells (hRVECs).ME...AIMTo determine whether small interfering RNA (siRNA) of PGC-1α could inhibit vascular endothelial growth factor (VEGF) expression and tube formation in human retinal vascular endothelial cells (hRVECs).METHODShRVECs transfected with peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) siRNA were incubated for 24h and then placed into a normoxic (20%, O<sub>2</sub>) or hypoxic (1%, O<sub>2</sub>) environment for another 16h. PGC-1α mRNA and protein levels were detected by real-time PCR and Western blot. VEGF mRNA and protein levels were detected by real-time PCR and ELISA. Cell proliferation was evaluated by BrdU incorporation assay. Forty-eight hours after siRNA transfection, hRVECs were planted into Matrigel-coated plates and cultured under normoxic (20%, O<sub>2</sub>) or hypoxic (1%, O<sub>2</sub>) conditions for another 48h. The tube formation of hRVECs was observed under an optical microscope and quantified by counting the number of branch points and calculating the total tube length.RESULTSPGC-1α mRNA and protein levels were significantly reduced by PGC-1α siRNA, and VEGF mRNA and protein levels also decreased significantly. The percentage of BrdU-labeled cells in siPGC-1α groups were significantly decreased compared with control siRNA groups under normoxia and hypoxia in cell proliferation assay. In the tube formation assay, PGC-1α siRNA treated cells formed significantly fewer tubes.CONCLUSIONBlocking PGC-1α expression can inhibit VEGF expression in hRVECs and inhibit their ability to form tubes under both normoxic and hypoxic conditions.展开更多
Objective： To investigate the role of peroxisome proliferator-activated receptors δ （PPARδ） in inflammatory reaction and its possible mechanism in adipocyte. Methods：Lentivirus-mediated RNA interference （RNAi）...Objective： To investigate the role of peroxisome proliferator-activated receptors δ （PPARδ） in inflammatory reaction and its possible mechanism in adipocyte. Methods：Lentivirus-mediated RNA interference （RNAi） was used to block the expression of PPARδ in 3T3-L1 cells. In order to induce inflammation in 3T3-L1, cells were stimulated with tumor necrosis factor-α（TNFα, 20 ng/ml） for 4 h. The expression of PPARδ, nuclear factor κB （NFκB） and C reactive protein （CRP） were determined by Western blot analysis. Results：The expression of PPARδ was reduced by 80% after RNAi. Blockage of PPARδ promoted the expression of CRP and NFκB in cells stimulated with TNFα but had no effect on normal cells. Conclusion： PPARδ is involved in inflammatory reaction in adipocyte. Blockage of PPARδ can promote the inflammation mediated by inflammatory factors and increase the expression of NFκB and CRP in 3T3-L1 cells stimulated with TNFα.展开更多
Endometrial carcinoma(EMC)is associated with obesity;however,the underlying mechanisms have not yet been elucidated.Peroxisome proliferator-activated receptor alpha(PPARα)is a nuclear receptor that is involved in lip...Endometrial carcinoma(EMC)is associated with obesity;however,the underlying mechanisms have not yet been elucidated.Peroxisome proliferator-activated receptor alpha(PPARα)is a nuclear receptor that is involved in lipid,glucose,and energy metabolism.PPARαreportedly functions as a tumor suppressor through its effects on lipid metabolism;however,the involvement of PPARαin the development of EMC remains unclear.The present study demonstrated that the immunohistochemical expression of nuclear PPARαwas lower in EMC than in normal endometrial tissues,suggesting the tumor suppressive nature of PPARα.A treatment with the PPARαactivator,irbesartan,inhibited the EMC cell lines,Ishikawa and HEC1A,by down-regulating sterol regulatory element-binding protein 1(SREBP1)and fatty acid synthase(FAS)and up-regulating the tumor suppressor genes p21 and p27,antioxidant enzymes,and AT-rich interaction domain 1A(ARID1A).These results indicate the potential of the activation of PPARαas a novel therapeutic approach against EMC.展开更多
Several metabolic gene expressions are regulated in concert with muscle glycogen status. We hypothesized that intermittent exercise performed at high but sub-maximal intensities with long recovery periods would induce...Several metabolic gene expressions are regulated in concert with muscle glycogen status. We hypothesized that intermittent exercise performed at high but sub-maximal intensities with long recovery periods would induce a low glycogen state that would stimul- ate peroxisome proliferator-activated receptor-γ coa- ctivator-1α (PGC1-α) and pyruvate dehydrogenase kinase-4 (PDK-4) gene expression in muscle. Nine young human subjects performed two intermittent exercise sessions. One session consisted of 60 s cycling bouts at VO2max (IE100%), and the other session consisted of 75 s cycling bouts at 80% VO2max (IE80%). Twelve bouts of exercise were completed in both sessions with a 4 min rest between each bout. Muscle specimens were obtained at pre-exercise and immediately, 1.5 h and 3 h post-exercise. Muscle gly- cogen was significantly decreased after both sessions (IE100%, 94.1 ± 5.8 to 38.7 ± 5.5 mmol/kg w.w.;IE80%, 94.6 ± 9.1 to 53.3 ± 4.8 mmol/kg w.w.;both P α and PDK- 4 mRNA expression were significantly increased after exercise in both IE100% and IE80% (PGC-1α: ~3.7 and ~2.9-fold, respectively;PDK-4: ~11.1 and ~3.5-fold, respectively;all P 100% than in IE80% (P a and PDK-4 mRNA expression, suggesting that increasing exercise intensity contributes to muscle glycogen depletion and PDK-4 mRNA expression in human skeletal muscle.展开更多
Mangoes (Mangifera indica L.) are one of the most important tropical foods. The seed is one of the main by-products of mango processing. Therefore, it is important to find an economically viable use for this waste (e....Mangoes (Mangifera indica L.) are one of the most important tropical foods. The seed is one of the main by-products of mango processing. Therefore, it is important to find an economically viable use for this waste (e.g., as a food additive or supplement with high nutraceutical value). We investigated the anti-obesity effects of mango seed kernel extract with hot water (MSKE-W) in 3T3-L1 adipocytes and in a high fat diet (HFD)-induced obesity rat model. MSKE-W caused a significant decrease in the activity of glycerol 2-phosphate dehydrogenase in 3T3-L1 adipocytes without eliciting cell cytotoxicity and inhibited cellular lipid accumulation through down-regulation of transcription factors such as PPARγ and C/EBPα. In the animal model, rats fed an HFD containing 1% MSKE-W gained less weight than rats fed an HFD alone. The visceral fat mass in rats fed an HFD containing 1% MSKE-W tended to be lower than that in rats fed an HFD alone. Furthermore, histological examination of rat livers from an HFD showed steatohepatitis. However, rats on an HFD containning 1% MSKE-W showed no histopathological changes in liver tissue. Our results indicate that MSKE-W influences anti-obesity effects, both in vitro and in vivo, and suggest that MSKE-W provides a novel preventive potential against obesity.展开更多
基金supported by Shandong Natural Science Fund(Y2008c170)
文摘Objective:To discuss the effect of insulin and metformin on amethylation and glycolipid metabolism of peroxisome proliferator-activated receptor γ coactivator-1A(PPARGC1A) of rat offspring with gestational diabetes mellitus(GDM).Methods:A total of 45 pregnant rats received the intraperitoneal injection of streptozotocin to establish the pregnant rat model of GDM.A total of 21 pregnant rats with GDM were randomly divided into three groups,with 7ruts in each group,namely the insulin group,metformin group and control group.Rats in the insulin group received the abdominal subcutaneous injection of 1 mL/kg recombinant insulin glargine at 18:00 every day.Rats in the metformin group received the intragastric infusion of metformin hydrochloride at 18:00 every day,with the first dose of 300 mg/kg.The doses of two groups were adjusted every 3 d to maintain the blood glucose level at 2.65-7.62 mmol/L.Rats in the control group received the intragastric infusion of 1 mL normal saline at 18:00 every day.After the natural delivery of pregnant rats.10 offspring rats were randomly selected from each group.At birth,4 wk and 8 wk after the birth of offspring rats,the weight of offspring rats was measured.The blood glucose level of offspring rats was measured at 4wk and 8 wk,while the level of serum insulin,triglyceride and leptin was measured at 8 wk.Results:The weight of offspring rats at birth in the insulin group and metformin group was significantly lower than the one in the control group(P<0.05),and there was no significant difference at 4 wk and 8 wk among three groups(P>0.05).The fasting blood glucose and random blood glucose in the insulin group and metformin group at 4 wk and 8 wk were all significantly lower than ones in the control group(P<0.05);there was no significant difference between the insulin group and metformin group(P>0.05).The expression of PPARGC1 A mRNA in the insulin group and metformin group was significantly higher and the methylation level of PPARGC1 A was significantly lower than the one in the control group(P<0.05),but there was no significant difference between the insulin group and metformin group(P>0.05).Insulin and leptin at 8 wk in the insulin group and metformin group were significantly higher,while triglyceride was significantly lower than the one in the control group(P<0.05);triglyceride level of rats in the insulin group was significantly higher than the one in the metformin group(P<0.05).There was no significant difference in insulin and leptin level of offspring rats between the insulin group and metformin group(P>0.05).Conclusions:GDM can induce the methylation of PPARGC1 A of offspring rats to reduce the expression of PPARGC1 A mRNA and then cause the disorder of glycolipid metabolism when the offspring rats grow up;the insulin or metformin in the treatment of pregnant rats with GDM can reduce the methylation level of PPARGC1 A and thus improve the abnormal glycolipid metabolism of offspring rats.
基金supported by a grant from the National Natural Science Foundation of China(No.81172898)
文摘Death following situations of intense emotional stress has been linked to the cardiac pathology described as stress cardiomyopathy, whose pathomechanism is still not clear. In this study, we sought to determine, via an animal model, whether the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α) and the amino peptide neuropeptide Y (NPY) play a role in the pathogenesis of this cardiac entity. Male Sprague-Dawley rats in the experimental group were subjected to immobilization in a plexy glass box for 1 h, which was followed by low voltage elec-tric foot shock for about 1h at 10s intervals in a cage fitted with metallic rods. After 25 days the rats were sacrificed and sections of their hearts were processed. Hematoxylin-eosin staining of cardiac tissues revealed the characteristic cardiac lesions of stress cardiomyopathy such as contraction band necrosis, inflammatory cell infiltration and fibrosis. The semi-quantitative RT-PCR analysis for PGC-1α mRNA expression showed significant overexpression of PGC1-α in the stress-subjected rats (P<0.05). Fluorescence immunohistochemistry revealed a higher production of NPY in the stress-subjected rats as compared to the control rats (P=0.0027). Thus, we are led to conclude that following periods of intense stress, an increased expression of PGC1-α in the heart and an overflow of NPY may lead to stress car-diomyopathy and even death in susceptible victims. Moreover, these markers can be used to identify stress cardiomyopathy as the cause of sudden death in specific cases.
文摘Objective.To investigate the effect of peroxis ome proliferator-activated recept ors(PPARs )activators on plasminogen activator inhibitor ty pe-1(PAI-1)expression in human umbilical vein e ndothelial cells and the possi-ble mechanism.Methods.Human umbilical vein endothelial ce lls(HUVECs )were obtained from normal fetus,and cul-tured conventionally.Then the HUVECs were exposed to test agents(linolenic acid,linoleic acid,oleic acid,stearic acid and prostaglandin J 2 respectively)in varying concentrations with fresh media.RT -PCR and ELISA were applied to determine the expression of PPARs and PAI-1in HUVECs.Results.PPARα,PPARδand PPARγmRNA were detected by using RT-PCR in HUVECs.Treatment of HUVECs with PPARαand PPARγactivators---linolenic acid,linoleic acid,oleic acid and prostaglandin J 2 respectively,but not with stearic a cid could augment PAI-I mRNA expression and protein secretion in a concentration-dependent manner.However,the mRNA expressions of 3subclasses of PPAR with their activators in HUVECs were not changed compared w ith controls.Conclusion.HUVECs express PPARs.PPARs activators may increase PAI-1expression in ECs,but the underlying mechanism remains uncle ar.Although PPARs expression was not enhanced after stimulated by their activators in ECs,the role of functionally active PPARs in regulating PA I-1expression in ECs needs to be further investigated by using transient gen e transfection assay.
文摘Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor α (PPARα) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPARα may be a potential therapeutic target for the treatment of alcoholic liver disease.
文摘Background Pancreatic beta-cell apoptosis induced by lipotoxicity, to a large extent, contributes to the progression of type 2 diabetes. To investigate the mechanism of free fatty acid induced apoptosis, we aimed to study the effects of palmitic acid （PA） on the apoptosis and peroxisome proliferator-activated receptor y coactivator-1α （PGC-1α） expression in βTC3 cells as well as the possible role of nuclear factor-KB （NF-KB） in this process. Methods Hoechst 33258 was used to detect βTC3 cell apoptosis, which was induced by PA stimulation for 12 hours. PGC-1α expression was analyzed by reverse transcription polymerase chain reaction, IκB kinase β （IKKβ）, IκBα NF-KB-inducing kinase （NIK） and ReI-B expressions were analyzed by Western blotting. MGβ2 was employed to block the endogenous IκBαdegradation before PA administration, and then its effect on PA-inducing cell apoptosis and PGC-1α mRNA expression was analyzed. Results Significant increased cell apoptosis was found at the concentration of 0.5 mmol/L and 1.0 mmol/L PA administration. PA （0.5 mmol/L） could extensively reduced the expression of PGC-1α mRNA. After exposing βTC3 cells to 0.5 mmol/L PA for different time periods （0, 4, 6, 8, 10 and 12 hours）, IKKβ protein expression increased while IκBα NIK and ReI-B protein expression declined in a time-dependent manner. Pretreatment with MGβ2 to inhibit the degradation of IκBα partially prevented the down-regulation of PGC-1α mRNA expression after 12-hour PA treatment in accordance with the decrease of PA induced apoptosis. Conclusions NF-KB canonical pathway was activated in PA-mediated βTC3 cell apoptosis, whereas non-canonical pathway was inhibited. Reduced PGC-1α expression by PA in βTC3 cells could involve the activation of canonical NF-KB pathway, so as to deteriorate the PA induced apoptosis.
文摘Background Some single nucleotide polymorphisms （SNPs） in the peroxisome proliferator-activated receptor-y coactivator （PGC）-1α gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1α and type 2 diabetes in the southern Chinese population and to determine whether the common variants： Gly482Ser and Thr394Thr, in the PGC-1α gene have any impacts on interaction with myocyte enhancer factor （MEF） 2C. Methods The SNPs in all exons of the PGC-1α gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism （PCR-SSCP） and direct sequencing. Thereafter, 263 type 2 diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP）. A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1α gene alter the interaction with MEF2C. Results Three frequent SNPs （Thr394Thr, Gly482Ser and Thr528Thr） were found in exons of the PGC-1α gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls （40.1% vs 29.3%, P〈0.01）. Even in controls, the 482Ser（A） carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly（G） carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr （A） had a synergic effect on the interaction between 482Ser variant and MEF2C. Conclusions The results suggested that the 482Ser variant of PGC-1α conferred the susceptibility to type 2 diabetes in the southern Chinese population. The underlying mechanism may be attributable, at least in part, to the altered interaction between the different variants （Gly482Ser, Thr394Thr） in the PGC-1α gene and MEF2C.
文摘Hepatitis C virus(HCV)is still one of the main causes of liver disease worldwide.Metabolic disorders,including nonalcoholic fatty liver disease(NAFLD),induced by HCV have been shown to accelerate the progression of fibrosis to cirrhosis and to increase the risk of hepatocellular carcinoma.An optimal peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PPARGC1A)activity is crucial to prevent NAFLD installation.The present study aims to investigate the associations between two common PPARGC1A polymorphisms(rs8192678 and rs12640088)and the outcomes of HCV infection in a North African context.A series of 592 consecutive Moroccan subjects,including 292 patients with chronic hepatitis C(CHC),100 resolvers and 200 healthy controls were genotyped using a TaqMan allelic discrimination assay.PPARGC1A variations at rs8192678 and rs12640088 were not associated with spontaneous clearance of HCV infection(adjusted ORs=0.76 and 0.79 respectively,P[0.05,for both).Furthermore,multivariable logistic regression analysis showed that both SNPs were not associated with fibrosis progression(OR=0.71;95%CI 0.20–2.49;P=0.739;OR=1.28;95%CI 0.25–6.54;P=0.512,respectively).We conclude that,in the genetic context of South Mediterranean patients,rs8192678 and rs12640088 polymorphisms of PPARGC1 A are neither associated with spontaneous clearance nor with disease progression in individuals infected with HCV.
基金hisstudywassupportedbyagrantfromNatureScienceFoundationofChina (No 39970 30 1)
文摘Objective To investigate the effect of peroxisome proliferator-activated receptors (PPARs) activators on plasminogen activator inhibitor 1 (PAI-1) expression in human umbilical vein endothelial cells and elucidate a possible mechanism. Methods Human umbilical vein endothelial cells (HUVECs) were obtained from normal fetus, and cultured conventionally. Then the HUVEC were exposed to fatty acids and prostaglandin J 2 in varying concentrations with fresh media. RT-PCR and ELISA were used to determine the expression of PPAR and PAI-1 in HUVECs. Transient co-transfection of PAI-1 promoter and PPARα gene or PPARγ gene to ECV304 was performed.Results PPARα, PPARδ and PPARγ mRNA in HUVECs were detected by RT-PCR. Treatment of HUVECs with PPARα and PPARγ activators-linolenic acid, linoleic acid, oleic acid and prostaglandin J 2, but not with stearic acid could augment PAI-I mRNA expression and protein secretion in a concentration-dependent manner. Proportional induction of PAI-1 promoter activity was observed through increasing amounts of PPARα DNA in HUVECs through a transient gene transfection assay, although the mRNA expression of the 3 subtypes of PPAR with their activators were not changed compared with controls.Conclusions HUVECs express PPARs. PPARs activators may increase PAI-1 expression in endothelial cells (EC). Although PPARs expression was not enhanced after being stimulated by their activators in EC, the functionally active PPARα is probably involved in regulating PAI-1 expression in EC.
基金supported by the National Notural Science Foundation of China,Nos.82071556 and 82271291 (both to WM)
文摘Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.
基金National Natural Science Foundation of China,No.82074532,No.82374577,No.82305375,No.82305376,and No.82405567The Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘BACKGROUND Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities.The effects mediated by the silent information regulator type 2 homolog-1(SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α(PGC-1α)axis present new opportunities for the treatment of type 2 diabetic peripheral neuropathy(T2DPN),potentially breaking this harmful cycle.AIM To validate the effectiveness of electroacupuncture(EA)in the treatment of T2DPN and investigate its potential mechanism based on the SIRT1/PGC-1αaxis.METHODS The effects of EA were evaluated through assessments of metabolic changes,morphological observations,and functional examinations of the sciatic nerve,along with measurements of inflammation and oxidative stress.Proteins related to the SIRT1/PGC-1αaxis,involved in the regulation of mitochondrial biogenesis and antioxidative stress,were detected in the sciatic nerve using Western blotting to explain the underlying mechanism.A counterevidence group was created by injecting a SIRT1 inhibitor during EA intervention to support the hypothesis.RESULTS In addition to diabetes-related metabolic changes,T2DPN rats showed significant reductions in pain threshold after 9 weeks,suggesting abnormal peripheral nerve function.EA treatment partially restored metabolic control and reduced nerve damage in T2DPN rats.The SIRT1/PGC-1αaxis,which was downregulated in the model group,was upregulated by EA intervention.The endogenous antioxidant system related to the SIRT1/PGC-1αaxis,previously inhibited in diabetic rats,was reactivated.A similar trend was observed in inflammatory markers.When SIRT1 was inhibited in diabetic rats,these beneficial effects were abolished.CONCLUSION EA can alleviate the symptoms of T2DNP in experimental rats,and its effects may be related to the mitochondrial biogenesis and endogenous antioxidant system mediated by the SIRT1/PGC-1αaxis.
文摘AIM:To investigate the effects of heme oxygenase(HO)-1 on liver fibrosis and the expression of peroxisome proliferator-activated receptor gamma(PPARγ) and nuclear factor-kappa B(NF-κB) in rats.METHODS:Sixty Wistar rats were used to construct liver fibrosis models and were randomly divided into 5 groups:group A(normal,untreated),group B(model for 4 wk,untreated),group C(model for 6 wk,untreated),group D [model for 6 wk,treated with zinc protoporphyrin Ⅸ(ZnPP-Ⅸ) from week 4 to week 6],group E(model for 6 wk,treated with hemin from week 4 to week 6).Next,liver injury was assessed by measuring serum alanine aminotransferase(ALT),aspartate aminotransferase(AST) and albumin levels.The degree of hepatic fibrosis was evaluated by measuring serum hyaluronate acid(HA),type Ⅳ collagen(Ⅳ-C) and by histological examination.Hydroxyproline(Hyp) content in the liver homogenate was determined.The expres-sion levels of alpha-smooth muscle actin(α-SMA) in liver tissue were measured by real-time quantitative polymerase chain reaction(RT-PCR).The expression levels of PPARγ and NF-κB were determined by RT-PCR and Western blotting.RESULTS:The expression of HO-1 increased with the development of fibrosis.Induction of HO-1 by hemin significantly attenuated the severity of liver injury and the levels of liver fibrosis as compared with inhibition of HO-1 by ZnPP-Ⅸ.The concentrations of serum ALT,AST,HA and Ⅳ-C in group E decreased compared with group C and group D(P < 0.01).Amount of Hyp and α-SMA in the liver tissues in group E decreased compared with group C(0.62 ± 0.14 vs 0.84 ± 0.07,1.42 ± 0.17 vs 1.84 ± 0.17,respectively,P < 0.01) and group D(0.62 ± 0.14 vs 1.11 ± 0.16,1.42 ± 0.17 vs 2.56 ± 0.37,respectively,P < 0.01).The expression of PPARγ at levels of transcription and translation decreased with the development of fibrosis especially in group D;and it increased in group E compared with groups C and D(0.88 ± 0.15 vs 0.56 ± 0.19,0.88 ± 0.15 vs 0.41 ± 0.11,respectively,P < 0.01).The expression of NF-κB increased with the development of fibrosis especially in group D;and it decreased in group E compared with groups C and D(1.43 ± 0.31 vs 1.89 ± 0.29,1.43 ± 0.31 vs 2.53 ± 0.54,respectively,P < 0.01).CONCLUSION:Our data demonstrate a potential mechanism that HO-1 can prevent liver fibrosis by enhancing the expression of PPARγ and decreasing the expression of NF-κB in liver tissues.
文摘A number of disparate diseases can lead to pulmonary hypertension(PH), a serious disorder with a high morbidity and mortality rate. Recent studies suggest that the associated metabolic dysregulation may be an important factor adversely impacting the prognosis of PH. Furthermore, metabolic syndrome is associated with vascular diseases including PH. Inflammation plays a significant role both in PH and metabolic syndrome. Adipose tissue modulates lipid and glucose metabolism, and also produces pro-and anti-inflammatory adipokines that modulate vascular function and angiogenesis, suggesting a close functional relationship between the adipose tissue and the vasculature. Both caveolin-1, a cell membrane scaffolding protein and peroxisome proliferator-activated receptor(PPAR) γ, a ligandactivated transcription factor are abundantly expressed in the endothelial cells and adipocytes. Both caveolin-1 and PPARγ modulate proliferative and anti-apoptotic pathways, cell migration, inflammation, vascular homeostasis, and participate in lipid transport, triacylglyceride synthesis and glucose metabolism. Caveolin-1 and PPARγ regulate the production of adipokines and in turn are modulated by them. This review article summarizes the roles and inter-relationships of caveolin-1,PPARγ and adipokines in PH and metabolic syndrome.
基金Supported by National Natural Science Fundation of China(No.81000387)
文摘AIMTo determine whether small interfering RNA (siRNA) of PGC-1α could inhibit vascular endothelial growth factor (VEGF) expression and tube formation in human retinal vascular endothelial cells (hRVECs).METHODShRVECs transfected with peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) siRNA were incubated for 24h and then placed into a normoxic (20%, O<sub>2</sub>) or hypoxic (1%, O<sub>2</sub>) environment for another 16h. PGC-1α mRNA and protein levels were detected by real-time PCR and Western blot. VEGF mRNA and protein levels were detected by real-time PCR and ELISA. Cell proliferation was evaluated by BrdU incorporation assay. Forty-eight hours after siRNA transfection, hRVECs were planted into Matrigel-coated plates and cultured under normoxic (20%, O<sub>2</sub>) or hypoxic (1%, O<sub>2</sub>) conditions for another 48h. The tube formation of hRVECs was observed under an optical microscope and quantified by counting the number of branch points and calculating the total tube length.RESULTSPGC-1α mRNA and protein levels were significantly reduced by PGC-1α siRNA, and VEGF mRNA and protein levels also decreased significantly. The percentage of BrdU-labeled cells in siPGC-1α groups were significantly decreased compared with control siRNA groups under normoxia and hypoxia in cell proliferation assay. In the tube formation assay, PGC-1α siRNA treated cells formed significantly fewer tubes.CONCLUSIONBlocking PGC-1α expression can inhibit VEGF expression in hRVECs and inhibit their ability to form tubes under both normoxic and hypoxic conditions.
文摘Objective： To investigate the role of peroxisome proliferator-activated receptors δ （PPARδ） in inflammatory reaction and its possible mechanism in adipocyte. Methods：Lentivirus-mediated RNA interference （RNAi） was used to block the expression of PPARδ in 3T3-L1 cells. In order to induce inflammation in 3T3-L1, cells were stimulated with tumor necrosis factor-α（TNFα, 20 ng/ml） for 4 h. The expression of PPARδ, nuclear factor κB （NFκB） and C reactive protein （CRP） were determined by Western blot analysis. Results：The expression of PPARδ was reduced by 80% after RNAi. Blockage of PPARδ promoted the expression of CRP and NFκB in cells stimulated with TNFα but had no effect on normal cells. Conclusion： PPARδ is involved in inflammatory reaction in adipocyte. Blockage of PPARδ can promote the inflammation mediated by inflammatory factors and increase the expression of NFκB and CRP in 3T3-L1 cells stimulated with TNFα.
基金supported by JSPS KAKENHI Grant Number 18K09285.
文摘Endometrial carcinoma(EMC)is associated with obesity;however,the underlying mechanisms have not yet been elucidated.Peroxisome proliferator-activated receptor alpha(PPARα)is a nuclear receptor that is involved in lipid,glucose,and energy metabolism.PPARαreportedly functions as a tumor suppressor through its effects on lipid metabolism;however,the involvement of PPARαin the development of EMC remains unclear.The present study demonstrated that the immunohistochemical expression of nuclear PPARαwas lower in EMC than in normal endometrial tissues,suggesting the tumor suppressive nature of PPARα.A treatment with the PPARαactivator,irbesartan,inhibited the EMC cell lines,Ishikawa and HEC1A,by down-regulating sterol regulatory element-binding protein 1(SREBP1)and fatty acid synthase(FAS)and up-regulating the tumor suppressor genes p21 and p27,antioxidant enzymes,and AT-rich interaction domain 1A(ARID1A).These results indicate the potential of the activation of PPARαas a novel therapeutic approach against EMC.
文摘Several metabolic gene expressions are regulated in concert with muscle glycogen status. We hypothesized that intermittent exercise performed at high but sub-maximal intensities with long recovery periods would induce a low glycogen state that would stimul- ate peroxisome proliferator-activated receptor-γ coa- ctivator-1α (PGC1-α) and pyruvate dehydrogenase kinase-4 (PDK-4) gene expression in muscle. Nine young human subjects performed two intermittent exercise sessions. One session consisted of 60 s cycling bouts at VO2max (IE100%), and the other session consisted of 75 s cycling bouts at 80% VO2max (IE80%). Twelve bouts of exercise were completed in both sessions with a 4 min rest between each bout. Muscle specimens were obtained at pre-exercise and immediately, 1.5 h and 3 h post-exercise. Muscle gly- cogen was significantly decreased after both sessions (IE100%, 94.1 ± 5.8 to 38.7 ± 5.5 mmol/kg w.w.;IE80%, 94.6 ± 9.1 to 53.3 ± 4.8 mmol/kg w.w.;both P α and PDK- 4 mRNA expression were significantly increased after exercise in both IE100% and IE80% (PGC-1α: ~3.7 and ~2.9-fold, respectively;PDK-4: ~11.1 and ~3.5-fold, respectively;all P 100% than in IE80% (P a and PDK-4 mRNA expression, suggesting that increasing exercise intensity contributes to muscle glycogen depletion and PDK-4 mRNA expression in human skeletal muscle.
文摘Mangoes (Mangifera indica L.) are one of the most important tropical foods. The seed is one of the main by-products of mango processing. Therefore, it is important to find an economically viable use for this waste (e.g., as a food additive or supplement with high nutraceutical value). We investigated the anti-obesity effects of mango seed kernel extract with hot water (MSKE-W) in 3T3-L1 adipocytes and in a high fat diet (HFD)-induced obesity rat model. MSKE-W caused a significant decrease in the activity of glycerol 2-phosphate dehydrogenase in 3T3-L1 adipocytes without eliciting cell cytotoxicity and inhibited cellular lipid accumulation through down-regulation of transcription factors such as PPARγ and C/EBPα. In the animal model, rats fed an HFD containing 1% MSKE-W gained less weight than rats fed an HFD alone. The visceral fat mass in rats fed an HFD containing 1% MSKE-W tended to be lower than that in rats fed an HFD alone. Furthermore, histological examination of rat livers from an HFD showed steatohepatitis. However, rats on an HFD containning 1% MSKE-W showed no histopathological changes in liver tissue. Our results indicate that MSKE-W influences anti-obesity effects, both in vitro and in vivo, and suggest that MSKE-W provides a novel preventive potential against obesity.
