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PPARγ Antagonizes Hypoxia-Induced Activation of Hepatic Stellate Cell through Cross Mediating PI3K/AKT and cGMP/PKG Signaling. PPARγ通过交叉介导PI3K/AKT和cGMP/PKG信号通路拮抗缺氧诱导的肝星状细胞活化。
IF 2.9 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2018-03-01 eCollection Date: 2018-01-01 DOI: 10.1155/2018/6970407
Qinghui Zhang, Shihao Xiang, Qingqian Liu, Tao Gu, Yongliang Yao, Xiaojie Lu

Background and aims: Accumulating evidence reveals that PPARγ plays a unique role in the regulation of hepatic fibrosis and hepatic stellate cells (HSCs) activation. This study was aimed at investigating the role of PPARγ in hypoxia-induced hepatic fibrogenesis and its possible mechanism.

Methods: Rats used for CCl4-induced hepatic fibrosis model were exposed to hypoxia for 8 hours each day. Rats exposed to hypoxia were treated with or without the PPARγ agonist rosiglitazone. Liver sections were stained with HE and Sirius red staining 8 weeks later. HSCs were exposed to hypoxic environment in the presence or absence of rosiglitazone, and expression of PPARγ and two fibrosis markers, α-SMA and desmin, were measured using western blot and immunofluorescence staining. Next, levels of PPARγ, α-SMA, and desmin as well as PKG and cGMP activity were detected using PI3K/AKT and a cGMP activator or inhibitor.

Results: Hypoxia promoted the induction and progress of hepatic fibrosis and HSCs activation. Meanwhile, rosiglitazone significantly antagonized the effects induced by hypoxia. Signaling by sGC/cGMP/PKG promoted the inhibitory effect of PPARγ on hypoxia-induced activation of HSCs. Moreover, PI3K/AKT signaling or PDE5 blocked the above response of PPARγ.

Conclusion: sGC/cGMP/PKG and PI3K/AKT signals act on PPARγ synergistically to attenuate hypoxia-induced HSC activation.

背景与目的:越来越多的证据表明,PPARγ在肝纤维化和肝星状细胞(HSCs)活化的调控中起着独特的作用。本研究旨在探讨PPARγ在缺氧诱导的肝纤维化中的作用及其可能的机制。方法:ccl4致肝纤维化模型大鼠每天缺氧8小时。暴露于缺氧的大鼠分别给予或不给予PPARγ激动剂罗格列酮。8周后行HE染色和天狼星红染色。在罗格列酮存在或不存在的情况下,将hsc暴露于缺氧环境中,采用western blot和免疫荧光染色检测PPARγ和α-SMA和desmin两种纤维化标志物的表达。接下来,使用PI3K/AKT和cGMP激活剂或抑制剂检测PPARγ、α-SMA和desmin水平以及PKG和cGMP活性。结果:缺氧促进肝纤维化的诱导和进展,促进造血干细胞的活化。同时,罗格列酮对缺氧作用有明显的拮抗作用。sGC/cGMP/PKG信号通路促进了PPARγ对缺氧诱导的hsc活化的抑制作用。此外,PI3K/AKT信号或PDE5阻断了PPARγ的上述反应。结论:sGC/cGMP/PKG和PI3K/AKT信号协同作用于PPARγ,可减弱缺氧诱导的HSC活化。
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引用次数: 20
Research Advances in the Correlation between Peroxisome Proliferator-Activated Receptor-γ and Digestive Cancers. 过氧化物酶体增殖物激活受体-γ与消化道肿瘤相关性研究进展。
IF 2.9 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2018-02-01 eCollection Date: 2018-01-01 DOI: 10.1155/2018/5289859
Shuqi Xu, Xuanfu Xu

Peroxisome proliferator-activated receptor-γ (PPARγ) is a class of ligand-activated nuclear transcription factors, which is a member of type II nuclear receptor superfamily. Previous studies demonstrate that PPARγ is expressed in a variety of tumor tissues and is closely associated with the proliferation and prognosis of digestive system tumors by its roles in mediation of cell differentiation, induction of cell apoptosis, and inhibition of cell proliferation.

过氧化物酶体增殖体激活受体-γ (PPARγ)是一类配体激活的核转录因子,是II型核受体超家族的成员。既往研究表明,PPARγ在多种肿瘤组织中表达,并通过介导细胞分化、诱导细胞凋亡、抑制细胞增殖等作用与消化系统肿瘤的增殖和预后密切相关。
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引用次数: 7
Portulaca Extract Attenuates Development of Dextran Sulfate Sodium Induced Colitis in Mice through Activation of PPARγ. 马齿苋提取物通过激活PPARγ减轻硫酸葡聚糖钠诱导小鼠结肠炎的发展。
IF 2.9 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2018-02-01 eCollection Date: 2018-01-01 DOI: 10.1155/2018/6079101
Rui Kong, Hui Luo, Nan Wang, Jingjing Li, Shizan Xu, Kan Chen, Jiao Feng, Liwei Wu, Sainan Li, Tong Liu, Xiya Lu, Yujing Xia, Yanhong Shi, Yingqun Zhou, Weigang He, Qi Dai, Yuejuan Zheng, Jie Lu

Portulaca oleracea L. is a traditional Chinese medicine, which has been used as adjuvant therapy for inflammatory bowel disease (IBD). However, the mechanism of its activity in IBD still remains unclear. Since previous studies have documented the anti-inflammatory effect of peroxisome proliferator activated receptors-γ (PPAR-γ), Portulaca regulation of PPAR-γ in inflammation was examined in current study. Ulcerative colitis (UC) was generated by 5% dextran sulfate sodium (DSS) in mice and four groups were established as normal control, DSS alone, DSS plus mesalamine, and DSS plus Portulaca. Severity of UC was evaluated by body weight, stool blood form, and length of colorectum. Inflammation was examined by determination of inflammatory cytokines (TNF-a, IL-6, and IL-1a). Portulaca extract was able to attenuate development of UC in DSS model similar to the treatment of mesalazine. Moreover, Portulaca extract inhibited proinflammatory cytokines release and reduced the level of DSS-induced NF-κB phosphorylation. Furthermore, Portulaca extract restored PPAR-γ level, which was reduced by DSS. In addition, Portulaca extract protected DSS induced apoptosis in mice. In conclusion, Portulaca extract can alleviate colitis in mice through regulation of inflammatory reaction, apoptosis, and PPAR-γ level; therefore, Portulaca extract can be a potential candidate for the treatment of IBD.

马齿苋是一种中药,已被用作炎症性肠病(IBD)的辅助治疗。然而,其在IBD中的作用机制尚不清楚。鉴于已有研究证实过氧化物酶体增殖物激活受体-γ (PPAR-γ)具有抗炎作用,本研究探讨马齿苋对PPAR-γ在炎症中的调节作用。采用5%葡聚糖硫酸钠(DSS)致小鼠溃疡性结肠炎(UC),设正常对照组、DSS单用组、DSS联合美萨拉明组、DSS联合马齿苋组。UC的严重程度通过体重、粪便血液形态和结直肠长度来评估。通过检测炎症因子(TNF-a、IL-6和IL-1a)来检测炎症。马齿苋提取物对DSS模型UC的抑制作用与美萨拉嗪类似。马齿苋提取物可抑制促炎细胞因子的释放,降低dss诱导的NF-κB磷酸化水平。马齿苋提取物能恢复DSS降低的PPAR-γ水平。马齿苋提取物对DSS诱导的小鼠细胞凋亡具有保护作用。由此可见,马齿苋提取物可通过调节小鼠炎症反应、细胞凋亡及PPAR-γ水平减轻结肠炎;因此,马齿苋提取物可能是治疗IBD的潜在候选物。
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引用次数: 26
Peroxisome Proliferator-Activated Receptor γ and PGC-1α in Cancer: Dual Actions as Tumor Promoter and Suppressor. 过氧化物酶体增殖物激活受体γ和PGC-1α在癌症中的双重作用:肿瘤启动子和抑制子。
IF 2.9 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2018-01-21 eCollection Date: 2018-01-01 DOI: 10.1155/2018/6727421
Seong-Hoon Yun, Sang-Heum Han, Joo-In Park

Peroxisome proliferator-activated receptor γ (PPARγ) is part of a nuclear receptor superfamily that regulates gene expression involved in cell differentiation, proliferation, immune/inflammation response, and lipid metabolism. PPARγ coactivator-1α (PGC-1α), initially identified as a PPARγ-interacting protein, is an important regulator of diverse metabolic pathways, such as oxidative metabolism and energy homeostasis. The role of PGC-1α in diabetes, neurodegeneration, and cardiovascular disease is particularly well known. PGC-1α is also now known to play important roles in cancer, independent of the role of PPARγ in cancer. Though many researchers have studied the expression and clinical implications of PPARγ and PGC-1α in cancer, there are still many controversies about the role of PPARγ and PGC-1α in cancer. This review examines and summarizes some recent data on the role and action mechanisms of PPARγ and PGC-1α in cancer, respectively, particularly the recent progress in understanding the role of PPARγ in several cancers since our review was published in 2012.

过氧化物酶体增殖物激活受体γ (PPARγ)是核受体超家族的一部分,可调节参与细胞分化、增殖、免疫/炎症反应和脂质代谢的基因表达。PPARγ共激活因子-1α (PGC-1α)最初被确定为PPARγ相互作用蛋白,是多种代谢途径的重要调节因子,如氧化代谢和能量稳态。PGC-1α在糖尿病、神经变性和心血管疾病中的作用是众所周知的。PGC-1α现在也被认为在癌症中发挥重要作用,独立于PPARγ在癌症中的作用。尽管许多研究者研究了PPARγ和PGC-1α在癌症中的表达及其临床意义,但关于PPARγ和PGC-1α在癌症中的作用仍存在许多争议。本文回顾和总结了PPARγ和PGC-1α在癌症中的作用和作用机制,特别是自2012年我们的综述发表以来,对PPARγ在几种癌症中的作用的最新研究进展。
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引用次数: 41
Vascular Remodeling, Oxidative Stress, and Disrupted PPARγ Expression in Rats of Long-Term Hyperhomocysteinemia with Metabolic Disturbance. 长期高同型半胱氨酸血症伴代谢紊乱大鼠的血管重塑、氧化应激和 PPARγ 表达紊乱
IF 3.5 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2018-01-15 eCollection Date: 2018-01-01 DOI: 10.1155/2018/6738703
Yajing Huo, Xuqing Wu, Jing Ding, Yang Geng, Weiwei Qiao, Anyan Ge, Cen Guo, Jianing Lv, Haifeng Bao, Wei Fan

Hyperhomocysteinemia, a risk factor for vascular disease, is associated with metabolic syndrome. Our study was aimed at exploring the effect of long-term hyperhomocysteinemia with metabolic disturbances on vascular remodeling. We also studied oxidative stress and expression of PPARγ in the coronary arteriole as a possible mechanism underlying vascular remodeling. Rats were treated with standard rodent chow (Control) or diet enriched in methionine (Met) for 48 weeks. Plasma homocysteine, blood glucose, serum lipids, malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO) levels were measured. Coronary arteriolar and carotid arterial remodeling was assessed by histomorphometric techniques and the expression of PPARγ in vessel wall was investigated. In Met group, an increase in the level of fasting blood glucose, serum triglyceride, total cholesterol, MDA, and NO, a decline in the serum SOD level, and increased collagen deposition in coronary and carotid arteries were found. Moreover, we detected decreased expression of PPARγ in the coronary arterioles in Met group. In summary, our study revealed metabolic disturbances in this model of long-term hyperhomocysteinemia together with vascular remodeling and suggested that impaired oxidative stress, endothelium dysfunction, and decreased PPARγ expression in the vessel wall could be underlying mechanisms.

高同型半胱氨酸血症是血管疾病的危险因素,与代谢综合征有关。我们的研究旨在探讨长期高同型半胱氨酸血症与代谢紊乱对血管重塑的影响。我们还研究了氧化应激和 PPARγ 在冠状动脉中的表达,以此作为血管重塑的可能机制。我们用标准啮齿动物饲料(对照组)或富含蛋氨酸(Met)的饮食对大鼠进行了为期 48 周的治疗。测量血浆同型半胱氨酸、血糖、血清脂质、丙二醛(MDA)、超氧化物歧化酶(SOD)和一氧化氮(NO)水平。通过组织形态计量学技术评估了冠状动脉和颈动脉的重塑情况,并调查了血管壁中 PPARγ 的表达情况。在 Met 组中,空腹血糖、血清甘油三酯、总胆固醇、MDA 和 NO 水平升高,血清 SOD 水平下降,冠状动脉和颈动脉中胶原沉积增加。此外,我们还检测到 Met 组冠状动脉中 PPARγ 的表达减少。总之,我们的研究揭示了长期高同型半胱氨酸血症模型中的代谢紊乱和血管重塑,并提示氧化应激受损、内皮功能障碍和血管壁中 PPARγ 表达减少可能是潜在的机制。
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引用次数: 0
Quercetin and Quercetin-Rich Red Onion Extract Alter Pgc-1α Promoter Methylation and Splice Variant Expression 槲皮素和富含槲皮素的红洋葱提取物改变Pgc-1α启动子甲基化和剪接变异表达
IF 2.9 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2017-01-16 DOI: 10.1155/2017/3235693
Prasad P. Devarshi, Aarin D Jones, E. Taylor, B. Stefańska, T. Henagan
Pgc-1α and its various isoforms may play a role in determining skeletal muscle mitochondrial adaptations in response to diet. 8 wks of dietary supplementation with the flavonoid quercetin (Q) or red onion extract (ROE) in a high fat diet (HFD) ameliorates HFD-induced obesity and insulin resistance in C57BL/J mice while upregulating Pgc-1α and increasing skeletal muscle mitochondrial number and function. Here, mice were fed a low fat (LF), high fat (HF), high fat plus quercetin (HF + Q), or high fat plus red onion extract (HF + RO) diet for 9 wks and skeletal muscle Pgc-1α isoform expression and DNA methylation were determined. Quantification of various Pgc-1α isoforms, including isoforms Pgc-1α-a, Pgc-1α-b, Pgc-1α-c, Pgc-1α4, total NT-Pgc-1α, and FL-Pgc-1α, showed that only total NT-Pgc-1α expression was increased in LF, HF + Q, and HF + RO compared to HF. Furthermore, Q supplementation decreased Pgc-1α-a expression compared to LF and HF, and ROE decreased Pgc-1α-a expression compared to LF. FL-Pgc-1α was decreased in HF + Q and HF + RO compared to LF and HF. HF exhibited hypermethylation at the −260 nucleotide (nt) in the Pgc-1α promoter. Q and ROE prevented HFD-induced hypermethylation. −260 nt methylation levels were associated with NT-Pgc-1α expression only. Pgc-1α isoform expression may be epigenetically regulated by Q and ROE through DNA methylation.
Pgc-1α及其各种亚型可能在决定骨骼肌线粒体对饮食的适应中发挥作用。在高脂饮食(HFD)中添加8周的类黄酮槲皮素(Q)或红洋葱提取物(ROE)可改善C57BL/J小鼠HFD诱导的肥胖和胰岛素抵抗,同时上调Pgc-1α,增加骨骼肌线粒体数量和功能。小鼠分别饲喂低脂(LF)、高脂(HF)、高脂+槲皮素(HF + Q)或高脂+红洋葱提取物(HF + RO)饲粮9周,检测骨骼肌Pgc-1α异构体表达和DNA甲基化。定量分析各种Pgc-1α亚型,包括Pgc-1α-a、Pgc-1α-b、Pgc-1α-c、Pgc-1α4、总NT-Pgc-1α和FL-Pgc-1α,结果显示,与HF相比,LF、HF + Q和HF + RO中只有总NT-Pgc-1α表达增加。此外,与LF和HF相比,补充Q降低了Pgc-1α-a的表达,与LF相比,ROE降低了Pgc-1α-a的表达。HF + Q和HF + RO组FL-Pgc-1α较LF和HF组降低。HF在Pgc-1α启动子的- 260个核苷酸(nt)处表现出高甲基化。Q和ROE阻止了hfd诱导的超甲基化。−260 nt甲基化水平仅与nt - pgc -1α表达相关。Pgc-1α异构体的表达可能通过DNA甲基化受到Q和ROE的表观遗传调控。
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引用次数: 18
MicroRNAs-Dependent Regulation of PPARs in Metabolic Diseases and Cancers 代谢疾病和癌症中PPARs的microrna依赖性调控
IF 2.9 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2017-01-12 DOI: 10.1155/2017/7058424
Dorothea Portius, Cyril Sobolewski, Michelangelo Foti
Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-dependent nuclear receptors, which control the transcription of genes involved in energy homeostasis and inflammation and cell proliferation/differentiation. Alterations of PPARs' expression and/or activity are commonly associated with metabolic disorders occurring with obesity, type 2 diabetes, and fatty liver disease, as well as with inflammation and cancer. Emerging evidence now indicates that microRNAs (miRNAs), a family of small noncoding RNAs, which fine-tune gene expression, play a significant role in the pathophysiological mechanisms regulating the expression and activity of PPARs. Herein, the regulation of PPARs by miRNAs is reviewed in the context of metabolic disorders, inflammation, and cancer. The reciprocal control of miRNAs expression by PPARs, as well as the therapeutic potential of modulating PPAR expression/activity by pharmacological compounds targeting miRNA, is also discussed.
过氧化物酶体增殖物激活受体(PPARs)是一个配体依赖性核受体家族,控制参与能量稳态、炎症和细胞增殖/分化的基因转录。PPAR表达和/或活性的改变通常与肥胖、2型糖尿病、脂肪肝以及炎症和癌症等代谢紊乱有关。现在新出现的证据表明,微小RNA(miRNA)是一个微调基因表达的小型非编码RNA家族,在调节PPARs表达和活性的病理生理机制中发挥着重要作用。本文从代谢紊乱、炎症和癌症的角度综述了miRNA对PPARs的调节。还讨论了PPARs对miRNA表达的相互控制,以及靶向miRNA的药理学化合物调节PPARs表达/活性的治疗潜力。
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引用次数: 56
Bezafibrate Attenuates Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis 贝扎菲特减轻压力超载引起的心脏肥大和纤维化
IF 2.9 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2017-01-03 DOI: 10.1155/2017/5789714
Si-Chi Xu, Zhen-Guo Ma, Wen-ying Wei, Yu-Pei Yuan, Q. Tang
Background. Peroxisome proliferator-activated receptor-α (PPAR-α) is closely associated with the development of cardiac hypertrophy. Previous studies have indicated that bezafibrate (BZA), a PPAR-α agonist, could attenuate insulin resistance and obesity. This study was designed to determine whether BZA could protect against pressure overload-induced cardiac hypertrophy. Methods. Mice were orally given BZA (100 mg/kg) for 7 weeks beginning 1 week after aortic banding (AB) surgery. Cardiac hypertrophy was assessed based on echocardiographic, histological, and molecular aspects. Moreover, neonatal rat ventricular cardiomyocytes (NRVMs) were used to investigate the effects of BZA on the cardiomyocyte hypertrophic response in vitro. Results. Our study demonstrated that BZA could alleviate cardiac hypertrophy and fibrosis in mice subjected to AB surgery. BZA treatment also reduced the phosphorylation of protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) and mitogen-activated protein kinases (MAPKs). BZA suppressed phenylephrine- (PE-) induced hypertrophy of cardiomyocyte in vitro. The protective effects of BZA were abolished by the treatment of the PPAR-α antagonist in vitro. Conclusions. BZA could attenuate pressure overload-induced cardiac hypertrophy and fibrosis.
背景。过氧化物酶体增殖物激活受体-α (PPAR-α)与心肌肥厚的发生密切相关。先前的研究表明,苯扎贝特(BZA)是一种PPAR-α激动剂,可以减轻胰岛素抵抗和肥胖。本研究旨在确定BZA是否对压力过载引起的心脏肥厚具有保护作用。方法。从主动脉束带术后1周开始,小鼠口服BZA (100 mg/kg) 7周。基于超声心动图、组织学和分子方面评估心脏肥厚。此外,我们在体外用新生大鼠心室心肌细胞(nrvm)研究BZA对心肌细胞肥厚反应的影响。结果。我们的研究表明,BZA可以减轻AB手术小鼠的心脏肥大和纤维化。BZA还降低了蛋白激酶B (AKT)/糖原合成酶激酶3β (GSK3β)和丝裂原活化蛋白激酶(MAPKs)的磷酸化水平。BZA对苯肾上腺素(PE)诱导的心肌细胞肥大有抑制作用。体外PPAR-α拮抗剂可使BZA的保护作用消失。结论。BZA可减轻压力过载引起的心肌肥大和纤维化。
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引用次数: 19
Puerarin Protects against Cardiac Fibrosis Associated with the Inhibition of TGF-β1/Smad2-Mediated Endothelial-to-Mesenchymal Transition. 葛根素通过抑制TGF-β1/ smad2介导的内皮-间质转化来预防心脏纤维化。
IF 2.9 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2017-01-01 Epub Date: 2017-05-30 DOI: 10.1155/2017/2647129
Ya-Ge Jin, Yuan Yuan, Qing-Qing Wu, Ning Zhang, Di Fan, Yan Che, Zhao-Peng Wang, Yang Xiao, Sha-Sha Wang, Qi-Zhu Tang

Background: Puerarin is a kind of flavonoids and is extracted from Chinese herb Kudzu root. Puerarin is widely used as an adjuvant therapy in Chinese clinics. But little is known about its effects on regulating cardiac fibrosis.

Methods: Mice were subjected to transverse aorta constriction (TAC) for 8 weeks; meanwhile puerarin was given 1 week after TAC. Cardiac fibrosis was assessed by pathological staining. The mRNA and protein changes of CD31 and vimentin in both animal and human umbilical vein endothelial cells (HUVECs) models were detected. Immunofluorescence colocalization of CD31 and vimentin and scratch test were carried out to examine TGF-β1-induced changes in HUVECs. The agonist and antagonist of peroxisome proliferator-activated receptor-γ (PPAR-γ) were used to explore the underlying mechanism.

Results: Puerarin mitigated TAC-induced cardiac fibrosis, accompanied with suppressed endothelial-to-mesenchymal transition (EndMT). The consistent results were achieved in HUVECs model. TGF-β1/Smad2 signaling pathway was blunted and PPAR-γ expression was upregulated in puerarin-treated mice and HUVECs. Pioglitazone could reproduce the protective effect in HUVECs, while GW9662 reversed this effect imposed by puerarin.

Conclusion: Puerarin protected against TAC-induced cardiac fibrosis, and this protective effect may be attributed to the upregulation of PPAR-γ and the inhibition of TGF-β1/Smad2-mediated EndMT.

背景:葛根素是一种黄酮类化合物,从中药葛根中提取。葛根素在我国临床被广泛用作辅助治疗。但它对调节心脏纤维化的作用知之甚少。方法:小鼠横断主动脉缩窄术(TAC) 8周;同时在TAC后1周给予葛根素治疗。病理染色评价心脏纤维化程度。检测动物和人脐静脉内皮细胞(HUVECs)模型中CD31和vimentin mRNA和蛋白的变化。采用CD31和vimentin的免疫荧光共定位和划痕实验检测TGF-β1诱导HUVECs的变化。使用过氧化物酶体增殖物激活受体-γ (PPAR-γ)的激动剂和拮抗剂来探索其潜在的机制。结果:葛根素减轻了tac诱导的心脏纤维化,并伴有抑制内皮细胞向间质转化(EndMT)。在HUVECs模型中得到了一致的结果。葛根素处理小鼠和huvec中TGF-β1/Smad2信号通路钝化,PPAR-γ表达上调。吡格列酮可以复制HUVECs的保护作用,而GW9662可以逆转葛根素的作用。结论:葛根素对tac诱导的心肌纤维化具有保护作用,这种保护作用可能与上调PPAR-γ和抑制TGF-β1/ smad2介导的EndMT有关。
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引用次数: 24
Fimasartan Ameliorates Nonalcoholic Fatty Liver Disease through PPARδ Regulation in Hyperlipidemic and Hypertensive Conditions. 非马沙坦通过调节高脂血症和高血压病患者的PPARδ改善非酒精性脂肪肝
IF 2.9 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2017-01-01 Epub Date: 2017-03-13 DOI: 10.1155/2017/8048720
Yong-Jik Lee, Yoo-Na Jang, Yoon-Mi Han, Hyun-Min Kim, Jong-Min Jeong, Hong Seog Seo

To investigate the effects of fimasartan on nonalcoholic fatty liver disease in hyperlipidemic and hypertensive conditions, the levels of biomarkers related to fatty acid metabolism were determined in HepG2 and differentiated 3T3-L1 cells treated by high fatty acid and liver and visceral fat tissue samples of spontaneously hypertensive rats (SHRs) given high-fat diet. In HepG2 cells and liver tissues, fimasartan was shown to increase the protein levels of peroxisome proliferator-activated receptor delta (PPARδ), phosphorylated 5' adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylated acetyl-CoA carboxylase (p-ACC), malonyl-CoA decarboxylase (MCD), medium chain acyl-CoA dehydrogenase (MCAD), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and it led to a decrease in the protein levels of 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSDH1), fatty acid synthase (FAS), and tumor necrosis factor-alpha (TNF-α). Fimasartan decreased lipid contents in HepG2 and differentiated 3T3-L1 cells and liver tissues. In addition, fimasartan increased the adiponectin level in visceral fat tissues. The antiadipogenic effects of fimasartan were offset by PPARδ antagonist (GSK0660). Consequently, fimasartan ameliorates nonalcoholic fatty liver disease mainly through the activation of oxidative metabolism represented by PPARδ-AMPK-PGC-1α pathway.

为了研究非马沙坦对高脂血症和高血压患者非酒精性脂肪肝疾病的影响,研究人员在高脂肪饮食的自发性高血压大鼠(SHRs)的肝脏和内脏脂肪组织样本中,检测了高脂肪酸处理的HepG2和分化的3T3-L1细胞中脂肪酸代谢相关生物标志物的水平。在HepG2细胞和肝组织中,非马沙坦可增加过氧化物酶体增殖物激活受体δ (PPARδ)、磷酸化5'腺苷单磷酸活化蛋白激酶(p-AMPK)、磷酸化乙酰辅酶a羧化酶(p-ACC)、丙二酰辅酶a脱羧酶(MCD)、中链酰基辅酶a脱氢酶(MCAD)和过氧化物酶体增殖物激活受体γ辅助激活因子1- α (PGC-1α)的蛋白水平。导致11β-羟基类固醇脱氢酶1 (11β- hsdh1)、脂肪酸合成酶(FAS)、肿瘤坏死因子-α (TNF-α)蛋白水平降低。非马沙坦降低HepG2的脂质含量,使3T3-L1细胞和肝组织分化。此外,非马沙坦增加了内脏脂肪组织中的脂联素水平。非马沙坦的抗脂肪作用被PPARδ拮抗剂(GSK0660)所抵消。因此,非马沙坦主要通过激活以PPARδ-AMPK-PGC-1α途径为代表的氧化代谢来改善非酒精性脂肪性肝病。
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引用次数: 9
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