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
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
Objective： To explore the relationship between peroxisome proliferator activated receptor-gamma （PPARγ） and peroxisome proliferator-activated receptor-gamma coactivator-1 （PGC-1） expression in gastric carcinoma ...Objective： To explore the relationship between peroxisome proliferator activated receptor-gamma （PPARγ） and peroxisome proliferator-activated receptor-gamma coactivator-1 （PGC-1） expression in gastric carcinoma （GC）, and analyze their correlations with clinicopathological features and clinical outcomes of patients. Methods：The two-step immunohistochemical method was used to detect the expression of PPARγ and PGC-1 in 179 cases of GC, and 108 cases of matched normal gastric mucosa. Besides, 16 cases of fresh GC specimens and corresponding normal gastric mucosa were detected for PGC-1 expression with Western blotting. Results： The positive rates of PPART and PGC-1 expression were significantly lower in GC （54.75%, 49.16%） than in normal gastric mucosa （70.37%, 71.30%）, respectively （P〈0.05）. The decreased expression of PGC-1 in GC was confirmed ha our Western blot analysis （P=0.004）. PPAR7 and PGC-1 expressions were related to Lauren＇s types ofGC （P〈0.05）. Positive correlation was found between PPART and PGC-1 expression in GC （rk=0.422, P〈0.001）. The survival time of PPART negative and positive patients was 36.6±3.0 vs. 38.5_＋2.7 months, and no statistical difference was found between the 5-year survival rates of two groups （34.4% vs. 44.1%, P=0.522, log-rank test）; the survival time of PGC-1 negative and positive patients was 36.2±2.8 vs. 39.9±2.9 months, while no statistical difference was found between the 5-year survival rates of the two groups （32.0% vs. 48.2%, P=0.462, log-rank test） Conclusions＇. Decreased expression of PPARγand PGC-1 in GC was related to the Lauren＇s classification. Their expressions in GC were positively correlated, indicating that their fimctions in gastric carcinogenesis may be closely related.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
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
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.
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.
基金supported by the National Natural Science Foundation of China(No.8107165030973503)the Supporting Project for Climbing Scholars in Liaoning Provincial Universities,China(2009-2012)
文摘Objective： To explore the relationship between peroxisome proliferator activated receptor-gamma （PPARγ） and peroxisome proliferator-activated receptor-gamma coactivator-1 （PGC-1） expression in gastric carcinoma （GC）, and analyze their correlations with clinicopathological features and clinical outcomes of patients. Methods：The two-step immunohistochemical method was used to detect the expression of PPARγ and PGC-1 in 179 cases of GC, and 108 cases of matched normal gastric mucosa. Besides, 16 cases of fresh GC specimens and corresponding normal gastric mucosa were detected for PGC-1 expression with Western blotting. Results： The positive rates of PPART and PGC-1 expression were significantly lower in GC （54.75%, 49.16%） than in normal gastric mucosa （70.37%, 71.30%）, respectively （P〈0.05）. The decreased expression of PGC-1 in GC was confirmed ha our Western blot analysis （P=0.004）. PPAR7 and PGC-1 expressions were related to Lauren＇s types ofGC （P〈0.05）. Positive correlation was found between PPART and PGC-1 expression in GC （rk=0.422, P〈0.001）. The survival time of PPART negative and positive patients was 36.6±3.0 vs. 38.5_＋2.7 months, and no statistical difference was found between the 5-year survival rates of two groups （34.4% vs. 44.1%, P=0.522, log-rank test）; the survival time of PGC-1 negative and positive patients was 36.2±2.8 vs. 39.9±2.9 months, while no statistical difference was found between the 5-year survival rates of the two groups （32.0% vs. 48.2%, P=0.462, log-rank test） Conclusions＇. Decreased expression of PPARγand PGC-1 in GC was related to the Lauren＇s classification. Their expressions in GC were positively correlated, indicating that their fimctions in gastric carcinogenesis may be closely related.
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.
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.
