Effect of insulin and metformin on methylation and glycolipid metabolism of peroxisome proliferator-activated receptor γcoactivator-1A of rat offspring with gestational diabetes mellitus

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.

Association of β3 Adrenergic Receptor and Peroxisome Proliferator-activated Receptor Gamma 2 Polymorphisms With Insulin Sensitivity:A Twin Study

Objective To study the effect of β3 adrenergic receptor （β3AR） Trp64Arg and peroxisome proliferator activated receptor gamma 2 （PPAR72） Prol2Ala polymorphisms on insulin resistance. Methods One hundred and eight dizygotic twin pairs were enrolled in this study. Microsatellite polymorphism was used to diagnose zygosity of twins. Insulin sensitivity was estimated with logarithm transformed homeostasis model assessment （HOMA）. PCR-RFLP analysis was performed to detect the variants. As a supplement to the sib-pair method, identity by state （IBS） was used to analyze the association of polymorphisms with insulin sensitivity. Results The genotype frequencies of Trp64Trg, Trp64Arg, and Arg64Arg were 72.3%, 23.8%, and 3.9%, respectively, while the genotype frequencies of Pro12Pro, Pro12Ala, and Ala12Ala were 89.9%, 9.6%, and 0.5%, respectively. For β3AR Trp64Arg the interclass co-twin correlations of Waist-to-hip ratio （WHR）, blood glucose （GLU）, and insulin （INS）, homeostasis model assessment insulin resistance index （HOMA-IR） of the twin pairs sharing 2 alleles of IBS were greater than those sharing 0-1 allele of IBS, and HOMA4R had statistic significance. For PPAR3t2 Prol2Ala most traits of twin pairs sharing 2 alleles of IBS had greater correlations and statistic significance in body mass index （BMI）, WHR, percent of body fat （PBF） and GLU, but there were low correlations of either insulin or HOMA-IR of twin pairs sharing 1 or 2 alleles of IBS. The combined effects of the two variations showed less squared significant twin-pair differences of INS and HOMA-IR among twins sharing 4 alleles of IBS. Condusions β3AR Trp64Arg and PPAR）,2 Pro 12Ala polymorphisms might be associated with insulin resistance and obesity, and there might be slight synergistic effects between this two gene loci, and further studies are necessary to confirm this finding.

Peroxisome proliferator-activated receptor gamma inhibits hepatic fibrosis in rats

BACKGROUND:Hepatic fibrosis is a necessary step in the development of hepatic cirrhosis.In this study we used lentiviral vector-mediated transfection technology to evaluate the effect of peroxisome proliferator-activated receptor gamma(PPAR-γ) on rat hepatic fibrosis. METHODS:Hepatic fibrosis in rats was induced by CCl4 for 2 weeks(early fibrosis)and 8 weeks(sustained fibrosis).The rats were randomly divided into four groups:normal control, fibrosis,blank vector,and PPAR-γ.They were infected with the recombinant lentiviral expression vector carrying the rat PPAR-γgene by portal vein injection.The liver of the rats was examined histologically and hydroxyproline was assessed.In vitro primary hepatic stellate cells(HSCs)were infected with the recombinant lentiviral expression vector carrying the rat PPAR-γgene.The status of HSC proliferation was measured by the MTT assay.The protein levels of PPAR-γ,α-smooth muscle actin(α-SMA)and type I collagen expression were evaluated by the Western blotting method. RESULTS:In vitro studies revealed that expression of PPAR-γ inhibited expression ofα-SMA and type I collagen in activated HSCs(P<0.01)as well as HSC proliferation(P<0.01).In vivo experiments indicated that in the early hepatic fibrosis group,the hydroxyproline content and the level of collagen I protein in the liver in the PPAR-γtransfected group were not significantly different compared to the hepatic fibrosis group and the blank vector group;whereas the expressions of PPAR-γ andα-SMA were different compared to the hepatic fibrosis group(P<0.01).In the sustained hepatic fibrosis group,there were significant differences in the hydroxyproline content and the expression of PPAR-γ,α-SMA,and type I collagen between each group.CONCLUSION:PPAR-γcan inhibit HSC proliferation and hepatic fibrosis,and suppressα-SMA and type I collagen expression.

基于不同组织和器官角度回顾PGC-1α在运动抗衰老中的作用

背景:过氧化物酶体增殖物激活受体γ共激活因子1α(peroxisome proliferators-activated receptors gamma co-activator 1α,PGC-1α)和衰老密切相关,且其在运动抗衰老中发挥着重要的调控作用,但缺乏从不同组织和器官视角下PGC-1α在运动抗衰老中作用的相关综述。目的:详细回顾PGC-1α在运动抗衰老中的作用,并从不同组织和器官的角度探讨其调控情况。方法:于2023-05-01/07-01进行文献检索。检索范围包括自各数据库建库至2023年7月,并在Web of Science、PubMed、中国知网、万方和维普数据库上进行检索。中文检索词:“PGC-1α,过氧化物酶体增殖物激活受体γ共激活因子1α,PPARGC1A,衰老,运动,老年人等”;英文检索词:“PGC-1α,aging,exercise,exercise training,older adults”。运用布尔逻辑运算符将检索词连接进行检索,并制定了相应的检索策略。根据纳入和排除标准进行筛选,最终纳入文献83篇进行综述分析。结果与结论:①PGC-1α是一个重要的转录共激活因子,在维持线粒体功能、调控能量代谢和适应不同代谢需求方面发挥着关键的调节作用。②在线粒体衰老中的多种功能,在多种细胞类型中的调节作用,在多种细胞类型中发挥着重要的调节作用,与炎症途径和氧化还原控制的关系及其相关蛋白修饰和表观遗传变化。③PGC-1α的表达水平能够被运动训练提高,并通过调节线粒体生物发生、能量代谢和抗氧化应激等途径发挥积极的作用,其在运动改善脂肪组织衰老、心血管老化、神经系统老化、肾脏衰老、骨骼肌衰老和肝脏老化等中发挥重要作用。④课题组专家建议未来研究方向包括探索不同类型、强度和时长的运动对PGC-1α表达的调节影响,研究PGC-1α的蛋白修饰和表观遗传变化的调节机制,以及加强对PGC-1α在不同衰老相关疾病中的作用机制的研究。

Association between peroxisome proliferator-activated receptor-γ coactivator-1α gene polymorphisms and type 2 diabetes in southern Chinese population:role of altered interaction with myocyte enhancer factor 2C

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.

Effect of dexamethasone on peroxisome proliferator activated receptor-gamma mRNA expression in 3T3-L1 adipocytes with the human recombinant adiponectin

Background The fat derived protein adiponectin plays an important role in the regulation of glucose metabolism. The aim of this study was to provide the experimental basis for further investigating on adiponectin （ADPN） function. Its eukaryotic recombinant was constructed and expressed in precursor cells of 3T3-L1 adipocytes. The effects of dexamethasone on peroxisome proliferator activated receptor-gamma （PPAR-y） mRNA expression in 3T3-L1 cells with human recombinant adiponectin were assessed. Methods The recombinant plasmid pMD18-T-hADPN and eukaryotic expression vector pcDNA3.1^＋ were digested by two restrictive endonucleases and adiponectin and linear pcDNA3.1^＋ were obtained. Then, they were ligated and translated into JM109. The recombinant pcDNA3.1^＋-hADPN so obtained was identified by digestion by restrictive endonuclease and nucleotide sequencing. The 3T3-L1 precursor cells were transfected using SuperFect Transfection Reagent （Qiagen）. Furthermore, 3T3-L1 cells with human recombinant adiponectin incubated with dexamethasone （0.5 mmol/L） for 24 hours, cells were collected and total RNA was extracted. The PPAR-γ mRNA expression was quantified by semiquantitative reverse transcription-polymerase chain reaction （RT-PCR）. Results After eukaryotic recombinant was digested by Hind Ⅲ and EcoR Ⅰ, fragments of 800 bp and 5.4 kb were identified by nucleotide sequence scanning and consistent with theoretical values. Electrophoretogram of RT-PCR in 3T3-L1 precursors showed only one band in front of 250 bp, which was consistent with theoretical value 234 bp. In the 3T3-L1 cells, 3T3-L1 cells with plasmid and 3T3-L1 cells human recombinant adiponectin, treatment with dexamethasone （0.5 mmol/L） decreased PPAR-y mRNA expression compared to untreated controls （P〈0.01）. Effect of dexamethasone on PPAR-γ mRNA expression in 3T3-L1 cells was reversed by stably transfected human recombinant adiponectin. Conclusion The 3T3-L1 cells stably transfected human recombinant adiponectin had increased PPAR-γ mRNA expression. Dexamethasone suppressed PPAR-γ mRNA expression in the 3T3-L1 cells. Effect of dexamethasone on PPAR-γ mRNA expression in 3T3-L1 cells was reversed by stably transfected human recombinant adiponectin.

白藜芦醇通过SIRT1/PGC-1α影响牛肌管细胞线粒体生物发生和肌纤维类型转化

以牛肌管细胞为研究对象,通过添加白藜芦醇探究其对牛肌管细胞肌纤维类型转化的影响及其作用机制。通过噻唑蓝法和比色法对细胞活力和相关代谢酶活力进行测定,对成肌调节因子、肌球蛋白重链(myosin heavy chains,MyHCs)以及线粒体生物发生相关分子的基因和蛋白表达量进行测定。结果表明,白藜芦醇处理显著提高了Myf5、Myf6、MyoG和MyoD的基因表达水平(P<0.05),促进了牛肌管细胞分化。白藜芦醇处理显著提高了慢肌纤维蛋白(slow MyHC)的表达,降低了快肌纤维蛋白(fast MyHC)表达,同时上调了MyHC I和MyHC IIa基因表达水平,下调了MyHC IIx和MyHC IIb基因表达水平(P<0.05)。白藜芦醇还能显著提高牛肌管细胞中的琥珀酸脱氢酶和苹果酸脱氢酶活性,降低乳酸脱氢酶活性(P<0.05),此外,白藜芦醇显著提高了沉默信息调节因子1(silent information regulator 1,SIRT1)、过氧化物酶体增殖物激活受体γ共激活因子1α(peroxisome proliferator-activated receptor-gamma coactivator-1α,PGC-1α)、核呼吸因子(nucleus respiratory factors,NRF)-1、线粒体转录因子A(mitochondrial transcription factor A,TFAM)的基因和蛋白表达水平(P<0.05)。添加SIRT1抑制剂6-氯-2,3,4,9-四氢-1H-咔唑-1-甲酰胺(1H-carbazole-1-carboxam,EX527)后,显著削弱了白藜芦醇诱导的肌纤维类型转化(P<0.05),白藜芦醇对SIRT1、PGC-1α、NRF-1和TFAM的基因和蛋白表达的促进作用被EX527显著削弱(P<0.05)。综上所述,白藜芦醇通过激活SIRT1/PGC-1α信号通路促进线粒体生物发生,进而促进牛肌管肌纤维类型的转化。

基于网络药理学和SIRT1/PGC-1α信号通路探究青光安Ⅱ号方的视神经保护作用

目的基于网络药理学和实验研究探讨青光安Ⅱ号方对青光眼视神经的保护作用机制。方法通过TCMSP数据库筛选青光安Ⅱ号方成分靶点,在GeneCards、Disgenet、CTD数据库挖掘青光眼相关靶点,进而筛选青光安Ⅱ号方作用于青光眼的靶点;制作蛋白质-蛋白质相互作用(protein-protein interaction,PPI)网络取其交集,并通过GO分析和KEGG富集分析。建立自发性慢性高眼压DBA/2J青光眼小鼠模型,将C57BL/6J小鼠设置为空白组(等体积蒸馏水),DBA/2J小鼠随机分为模型组(等体积蒸馏水)、益脉康组[0.31 g/(kg·d)]、青光安Ⅱ号方低浓度组[0.85 g/(kg·d)]、青光安Ⅱ号方中浓度组[1.7 g/(kg·d)]、青光安Ⅱ号方高浓度组[3.4 g/(kg·d)],每组8只,每日灌胃1次。干预4周后,触式眼压笔监测小鼠眼压;HE染色观察小鼠视网膜形态结构;Western blot检测沉默信息调节因子-1(silent information regulator type-1,SIRT1)、过氧化物酶体增殖物激活受体γ共激活因子-1α(peroxisome proliferationactivated receptor-γ-coactivator 1α,PGC-1α)的蛋白表达水平;qRT-PCR检测SIRT1、PGC-1α的mRNA表达水平。结果从青光安Ⅱ号方共筛选得到101个活性成分和245个相关靶点,2412个青光眼疾病相关基因靶点;药物-活性成分-靶点相互作用最强的5个靶点分别是前列腺素内过氧化物合成酶2、核受体共激活因子2、胃蛋白酶原Ⅱ、前列腺素内过氧化物合成酶1以及过氧化物酶体增殖物激活受体γ(peroxisome proliferative activated receptor gamma,PPARG);PPI网络显示较强的靶点是SIRT1、PPARG;GO分析和KEGG富集分析得到细胞衰老、IL-17等信号通路。与给药前相比,给药后用药组眼压显著降低(P<0.01)。给药后,与空白组相比,模型组眼压显著升高(P<0.01),视网膜中SIRT1、PGC-1αmRNA表达量和蛋白表达量均显著降低(P<0.01);与模型组相比,用药组眼压显著降低(P<0.01),SIRT1、PGC-1αmRNA表达量和蛋白表达量均显著升高(P<0.01)。与益脉康组和青光安Ⅱ号方低浓度组相比,青光安Ⅱ号方中、高浓度组SIRT1、PGC-1αmRNA表达量和SIRT1蛋白表达量显著升高(P<0.01);与青光安Ⅱ号方低浓度组相比,青光安Ⅱ号方高浓度组PGC-1α蛋白表达量均显著上升(P<0.01)。与青光安Ⅱ号方中浓度组相比,青光安Ⅱ号方高浓度组PGC-1αm RNA表达量和蛋白表达量显著升高(P<0.01)。结论青光安Ⅱ号方可有效调控SIRT1/PGC-1α信号通路,抑制RGC的丢失,主要在氧化应激、细胞衰老等方面对青光眼视神经发挥保护作用。

Activation of peroxisome proliferator-activated receptor α in human endothelial cells increases plasminogen activator inhibitor type-1 expression

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.

Protective effect of ghrelin on left ventricular remodeling in spontaneously hypertensive rats is associated with the peroxisome proliferator-activated receptor gamma-dependent pathway

Background Studies suggested that exogenous ghrelin administration could prevent early left ventricular remodeling in rats with myocardial infarction. We investigated herein whether ghrelin attenuated left ventricular remodeling induced by hypertension and whether ghrelin＇s effect was mediated through the peroxisome proliferator-activated receptor gamma （PPAR-y）-dependent pathway. Methods Spontaneously hypertensive rats （8-week-old males） were randomly divided into three groups with 12 rats in each： ghrelin group （received ghrelin 100 IJg/kg subcutaneously （sc） twice daily）; ghrelin＋GW9662 group （received the PPAR-y antagonist GW9662 at 2 mg/kg sc, and then ghrelin as above）; saline controls. Normal male Wistar Kyoto rats （n=-12） served as normal controls. Four weeks later, the effects of ghrelin on cardiac remodeling were evaluated by echocardiographic, hemodynamic, and histopathological examination, and gene expression analysis （PPAR-y protein and mRNA expression）. The serum levels of C-reactive protein （CRP） and tumor necrosis factor （TNF）-a were detected by enzyme linked immunosorbent assay. Results Ghrelin prevented ventricular remodeling, increased PPAR-y expression in the myocardium, suppressed collagen I and collagen Ill mRNA expression, and also decreased the serum levels of TNF-a, but not CRP. All abovementioned effects of ghrelin were inhibited by GW9662. Conclusion Ghrelin inhibited ventricular remodeling induced by hypertension, and the preventive effects of ghrelin may be mediated by the anti-inflammatory actions of the PPAR-y-dependent pathway.

Sestrin1参与调控小鼠肝脏细胞糖异生

目的研究应激诱导蛋白1(SESN1)在小鼠肝脏糖异生途径中的作用及调节机制。方法RT-qPCR检测SESN1在C57BL/6J小鼠禁食条件下肝脏组织以及用佛司可林(Fsk)与地塞米松(Dex)处理的原代肝细胞中的mRNA表达水平。通过质粒转染HepG2细胞,RT-qPCR检测SESN1过表达对糖异生相关基因PGC-1α,PEPCK,G6Pase的mRNA表达水平的影响。利用双荧光素酶报告系统研究SESN1在HepG2细胞中对PGC-1α的启动子活性的影响。在HepG2细胞中,通过过表达SESN1同时抑制SIRT1表达检测SESN1对PGC-1α去乙酰化状态的影响;通过敲低SIRT1表达检测其是否介导了SESN1诱导糖异生相关基因mRNA水平的变化。结果SESN1在饥饿的C57BL/6J小鼠肝脏组织和佛司可林(Fsk)和地塞米松(Dex)处理的原代肝细胞中的mRNA表达水平显著升高(P<0.001)。在HepG2细胞中过表达SESN1促进了PGC-1α,PEPCK,G6Pase的mRNA表达水平(P<0.001)并促进PGC-1α的启动子活性(P<0.001)。SESN1的过表达降低了原代肝细胞中PGC-1α的乙酰化水平,利用Sirt家族抑制剂NAM和shRNA腺病毒分别干扰SIRT1表达,均拮抗了SESN1对PGC-1α的去乙酰化作,同时SIRT1诱导的PGC-1α,PEPCK和G6Pase的表达也明显受损(P<0.0001)。结论SESN1参与调控小鼠肝脏细胞糖异生,可能依赖于SIRT1。

Anluohuaxianwan Alleviates Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats through Upregulation of Peroxisome Proliferator-Activated Receptor-Gamma and Downregulation of Nuclear Factor-Kappa B/IκBα Signaling Pathway

Objective:The aim of this study was to investigate the effects of traditional Chinese medicine Anluohuaxianwan(ALHXW)on peroxisome proliferator-activated receptor-gamma(PPARγ)and nuclear factor-kappa B(NF-κB)signaling pathways using a rat model of carbon model groups were gavaged with saline for 6 weeks.Liver function was measured,and liver fibrosis and necroinflammation were assessed.Protein and messenger RNA expression levels of PPARγ,NF-κB,and Inhibitorαof NF-κB(IκBα)were analyzed by Western blot and reverse transcription–quantitative polymerase chain reaction.Results:ALHXW markedly alleviated liver injury compared with the model group,as indicated by the improvements in disease status,the morphology of liver and spleen,the liver and spleen indexes,and liver function.The extent of liver fibrosis was improved,hepatic stellate cell activation was inhibited,the expression of PPARγand IκBαwas significantly higher,and the expression of NF-κB was significantly lower in the treatment group as compared with the model group.Conclusions:ALHXW treatment can alleviate CCl4-induced liver fibrosis in rats, and the potential antifibrogenic mechanisms may occur through the upregulation of PPARγ expression and downregulation of NF-κB/IκBα signaling pathway.

Peroxisome proliferator-activated receptor gamma signaling in human sperm physiology

Peroxisome proliferator-activated receptor gamma （PPARy） is a member of the PPARs, which are transcription factors of the steroid receptor superfamily. PPARy acts as an important molecule for regulating energy homeostasis, modulates the hypothalamic-pituitary-gonadal （HPG） axis, and is reciprocally regulated by HPG. In the human, PPARγprotein is highly expressed in ejaculated spermatozoa, implying a possible role of PPARγ signaling in regulating sperm energy dissipation. PPARγ protein is also expressed in Sertoli cells and germ cells （spermatocytes）. Its activation can be induced during capacitation and the acrosome reaction. This mini-review will focus on how PPARy signaling may affect fertility and sperm quality and the potential reversibility of these adverse effects.

田蓟苷调节AMPK/SIRT1/PGC1α信号通路对脑出血大鼠认知功能和神经元损伤的影响

目的:探讨田蓟苷(TIL)对脑出血(ICH)大鼠认知功能、神经元损伤及腺苷酸激活蛋白激酶(AMPK)/沉默调节蛋白1(SIRT1)/过氧化物酶体增殖活化受体γ辅助活化因子1α(PGC1α)信号通路的影响。方法:采用Ⅳ型胶原酶注射法构建ICH大鼠模型,将造模成功的ICH大鼠随机分为模型组(ICH组)、TIL组(16 mg/kg)、AMPK抑制剂组(Compound C组,250μg/kg)、TIL+AMPK抑制剂组(TIL+Compound C组),另设假手术组(Sham组),每组12只。采用改良的Garcia JH法、Morris水迷宫实验和敞箱实验评价大鼠的神经功能和认知功能;苏木素-伊红(HE)和脱氧核糖核苷酸末端转移酶介导的缺口末端标记(TUNEL)法行脑组织病理学和神经元凋亡观察;蛋白质印迹法(Western Blot)检测AMPK/SIRT1/PGC1α通路蛋白表达。结果:与Sham组相比,ICH组大鼠脑组织出现细胞核皱缩、排列紊乱等损伤,神经功能评分、穿越平台次数、垂直活动得分和水平活动得分、磷酸化AMPK(p-AMPK)/AMPK、SIRT1、PGC1α蛋白水平均明显下降(P<0.05),找寻平台时间、神经元凋亡率、半胱氨酸蛋白酶-3(Caspase-3)、B淋巴细胞瘤-2(Bcl-2)蛋白表达水平均明显增加(P<0.05);与ICH组相比,TIL组大鼠脑组织损伤减轻,神经功能评分、穿越平台次数、垂直活动得分和水平活动得分、p-AMPK/AMPK、SIRT1、PGC1α蛋白水平均明显增加(P<0.05),找寻平台时间、神经元凋亡率、Caspase-3、Bcl-2蛋白表达水平均明显降低(P<0.05);而Compound C组大鼠以上指标呈现相反的趋势。且TIL对ICH大鼠脑组织及认知功能的保护作用均被AMPK抑制剂Compound C减弱(P<0.05)。结论:TIL可能通过激活AMPK/SIRT1/PGC1α通路,改善ICH大鼠认知功能,减轻神经元损伤。

多囊卵巢综合征病人血清Ⅲ型纤连蛋白域蛋白5、过氧化物酶体增殖物激活受体γ辅助激活因子-1α水平与胰岛素抵抗的关系

目的探究多囊卵巢综合征(PCOS)病人血清Ⅲ型纤连蛋白域蛋白5(FNDC5)、过氧化物酶体增殖物激活受体γ辅助激活因子-1α(PGC-1α)表达水平与胰岛素抵抗的关系。方法选取2017年1月至2021年12月在重庆松山医院接受治疗的118例PCOS病人为PCOS组,另选取与PCOS病人年龄、身体质量指数(BMI)、腰臀比相匹配的同期健康体检者94例作为对照组。酶联免疫吸附测定(ELISA)检测两组血清FNDC5、PGC-1α表达水平;全自动生化分析仪检测空腹胰岛素(FINS)、空腹血糖(FBG)水平,并计算胰岛素抵抗相关指标胰岛β细胞功能指数(HOMA-β)和胰岛素抵抗指数(HOMA-IR);Pearson相关性分析研究病人血清FNDC5、PGC-1α水平与胰岛素抵抗相关指标之间的关系。结果与对照组相比,PCOS组FBG、FINS、三酰甘油(TG)、HOMA-β、HOMA-IR显著升高(P<0.05);与对照组相比,PCOS组FNDC5[(18.46±2.76)μg/L比(30.25±5.87)μg/L]、PGC-1α[(1.87±0.45)μg/L比(4.91±1.34)μg/L]表达水平显著降低(P<0.05)。Pearson相关性分析结果显示,PCOS病人血清FNDC5、PGC-1α水平均与FBG、FINS、HOMA-β、HOMA-IR呈显著负相关(P<0.05)。结论PCOS病人血清FNDC5、PGC-1α表达水平降低,与胰岛素抵抗存在负相关。

芍药苷调节SIRT1/PGC-1α/Nrf2信号通路对过氧化氢诱导皮肤成纤维细胞氧化应激损伤的影响

目的:探讨芍药苷(PF)调节沉默信息调节因子2同系物1(SIRT1)/氧化物酶体增殖物激活受体γ共激活剂-1α(PGC-1α)/核因子E2相关因子2(Nrf2)信号通路对过氧化氢(H_(2)O_(2))诱导皮肤成纤维细胞(HSF)氧化应激损伤的影响。方法:以HSF细胞为研究对象,将其分为Control组、H_(2)O_(2)组、L-PF、M-PF、H-PF组、PF+EX527组;CCK-8检测HSF细胞增殖;β-半乳糖苷酶染色法检测HSF细胞衰老;流式细胞仪检测HSF细胞凋亡;ELISA法检测HSF细胞中ROS、SOD、GSH、MDA的表达;WB检测HSF细胞中SIRT1、PGC-1α、Nrf2蛋白表达。结果:H_(2)O_(2)组HSF细胞的存活率、SOD、GSH、SIRT1、PGC-1α、Nrf2表达低于Control组,衰老细胞比例、凋亡率、ROS、MDA表达高于Control组(P<0.05);与H_(2)O_(2)组比较,L-PF组、M-PF组、H-PF组存活率、SOD、GSH、SIRT1、PGC-1α、Nrf2表达升高,衰老细胞比例、凋亡率、ROS、MDA表达降低(P<0.05);PF+EX527组存活率、SOD、GSH、SIRT1、PGC-1α、Nrf2表达低于H-PF组,衰老细胞比例、凋亡率、ROS、MDA表达高于H-PF组(P<0.05)。结论:PF可以抑制H_(2)O_(2)诱导的HSF细胞氧化应激损伤,其机制可能是激活SIRT1/PGC-1α/Nrf2信号通路实现的。

血清PGC-1α水平在脓毒症致急性肾损伤诊断中的价值

目的 探讨血清过氧化物酶增殖激活受体γ辅助激活物1α(PGC-1α)对脓毒症患者继发急性肾损伤(AKI)的早期诊断价值。方法 选取2019年10月至2022年1月绍兴第二医院重症医学科收治的107例脓毒症患者为研究对象,依据是否继发AKI将患者分为AKI组(n=68)和非AKI组(n=39)。比较两组患者基线临床资料;收集确诊脓毒症时患者空腹静脉血和尿液标本,检测血清PGC-1α、降钙素原(PCT)、乳酸(Lac)、肌酐(sCr)、中性粒细胞明胶酶相关脂质运载蛋白(NGAL)水平并估算肾小球滤过率(eGFR);采用二元logistic回归分析脓毒症患者继发AKI的危险因素;采用Spearman相关性分析血清PGC-1α水平与其他临床指标的相关性;采用受试者工作特征(ROC)曲线分析PGC-1α水平对脓毒症患者发生AKI的预测价值。结果 两组患者年龄、性别、BMI、合并基础病史、原发感染部位比例及Lac水平差异无统计学意义(P> 0.05)。AKI组患者急性生理学和慢性健康状况评价Ⅱ(APACHEⅡ)评分、脓毒症相关性器官功能衰竭(SOFA)评分及PCT、sCr、NGAL等水平均显著高于非AKI组(P <0.05),而eGFR、PGC-1α则显著低于非AKI组(P <0.05)。二元logistc回归分析模型显示,sCr、NGAL、eGFR、PGC-1α是脓毒症患者继发AKI的独立危险因素。Spearman相关性分析显示,脓毒症患者血清PGC-1α水平与sCr、NGAL呈负相关性(r=-0.302、-0.635,均P <0.05),而与eGFR呈正相关(r=0.475,P <0.05)。ROC曲线分析结果显示,血清PGC-1α水平对脓毒症患者继发AKI的诊断效能优于NGAL和eGFR。结论 PGC-1α在脓毒症继发AKI患者的早期血清中明显升高,其或可作为脓毒症致急性肾损伤早期诊断的有效预测指标。

Down-regulated expressions of PPAR_γ and its coactivator PGC-1 are related to gastric carcinogenesis and Lauren's classification 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.

川穹嗪调节SIRT1/AMPK/PGC1α信号通路对偏头痛大鼠镇痛作用及神经元损伤的影响

目的 探究川穹嗪(TMP)通过调控沉默信息调节因子2相关酶1(SIRT1)/腺苷酸活化蛋白激酶(AMPK)/过氧化物酶体增殖物激活受体γ共激活因子1α(PGC1α)信号通路对偏头痛大鼠发挥镇痛和神经元损伤的保护作用。方法 通过硝酸甘油诱导建立偏头痛大鼠模型,造模成功后随机分为模型(M)组、TMP低剂量(TMP-L)组(50 mg/kg)、TMP中剂量(TMP-M)组(100 mg/kg)、TMP高剂量(TMP-H)组(200 mg/kg)、TMP(200 mg/kg)+SIRT1抑制剂(EX527,5 mg/kg)组,每组10只;另取10只作为正常对照(NC)组。连续灌胃2周。给药结束24 h后,记录各组大鼠在连续30 min内出现挠头、爬笼的次数,进行行为学评分;测定机械性刺激及热刺激痛阈;酶联免疫吸附试验法检测血清中一氧化氮(NO)、白细胞介素(IL)-6、IL-1β含量和脑组织中5-羟色胺(5-HT)、去甲肾上腺素(NE)、多巴胺(DA)含量;TUNEL染色观察脑组织神经元凋亡情况;Western blot法检测脑组织中SIRT1、AMPK、p-AMPK、PGC1α蛋白表达。结果 与NC组比较,M组大鼠行为学评分,血清中NO、IL-6、IL-1β水平,神经元凋亡率升高(P<0.05);机械性刺激痛阈值降低,热刺激潜伏期缩短(P<0.05);脑组织中5-HT、NE、DA水平,p-AMPK/AMPK比值,SIRT1、PGC1α蛋白表达降低(P<0.05)。与M组比较,TMP各剂量组大鼠行为学评分,血清中NO、IL-6、IL-1β水平,神经元凋亡率降低(P<0.05);机械性刺激痛阈值升高,热刺激潜伏期延长(P<0.05);脑组织中5-HT、NE、DA水平,pAMPK/AMPK比值,SIRT1、PGC1α蛋白表达升高(P<0.05);与TMP-H组比较,TMP+EX527组可显著逆转TMP对偏头痛大鼠的作用。结论 TMP可能通过调节SIRT1/AMPK/PGC1α信号通路的表达,改善神经元损伤,发挥对偏头痛大鼠的镇痛作用。