Three-in-one agonists for PPAR-α, PPAR-γ, and PPAR-δ from traditional Chinese medicine

Nowadays, the occurrence of metabolic syndrome, which is characterized by obesity and clinical disorders, has been increasing rapidly over the world. It induces several serious chronic diseases such as cardiovascular disease, dyslipidemia, gall bladder disease, hypertension, osteoarthritis, sleep apnea, stroke, and type 2 diabetes mellitus. Peroxisome proliferator-activated receptors (PPARs), which have three isoforms: PPAR-α, PPAR-γ, and PPAR-δ, are key regulators of adipogenesis, lipid and carbohydrate metabolism, and are potential drug targets for treating metabolic syndrome. The traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) were employed to virtually screen for potential PPAR agonists, and structure-based pharmacophore models were generated to identify the key interactions for each PPAR protein. In addition, molecular dynamics (MD) simulation was performed to evaluate the stability of the PPAR-ligand complexes in a dynamic state. (S)-Tryptophan-betaxanthin and berberrubine, which have higher Dock Score than controls, form stable interactions during MD, and are further supported by the structure-based pharmacophore models in each PPAR protein. Key features include stable H-bonds with Thr279 and Ala333 of PPAR-α, with Thr252, Thr253 and Lys331 of PPAR-δ, and with Arg316 and Glu371 of PPAR-γ. Hence, we propose the top two TCM candidates as potential lead compounds in developing agonists targeting PPARs protein for treating metabolic syndrome.     

Three-in-one agonists for PPAR-α, PPAR-γ, and PPAR-δ from traditional Chinese medicine

Nowadays, the occurrence of metabolic syndrome, which is characterized by obesity and clinical disorders, has been increasing rapidly over the world. It induces several serious chronic diseases such as cardiovascular disease, dyslipidemia, gall bladder disease, hypertension, osteoarthritis, sleep apnea, stroke, and type 2 diabetes mellitus. Peroxisome proliferator-activated receptors (PPARs), which have three isoforms: PPAR-α, PPAR-γ, and PPAR-δ, are key regulators of adipogenesis, lipid and carbohydrate metabolism, and are potential drug targets for treating metabolic syndrome. The traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan (http://tcm.cmu.edu.tw/) were employed to virtually screen for potential PPAR agonists, and structure-based pharmacophore models were generated to identify the key interactions for each PPAR protein. In addition, molecular dynamics (MD) simulation was performed to evaluate the stability of the PPAR–ligand complexes in a dynamic state. (S)-Tryptophan-betaxanthin and berberrubine, which have higher Dock Score than controls, form stable interactions during MD, and are further supported by the structure-based pharmacophore models in each PPAR protein. Key features include stable H-bonds with Thr279 and Ala333 of PPAR-α, with Thr252, Thr253 and Lys331 of PPAR-δ, and with Arg316 and Glu371 of PPAR-γ. Hence, we propose the top two TCM candidates as potential lead compounds in developing agonists targeting PPARs protein for treating metabolic syndrome.     

PPAR-δ在动脉粥样硬化中的作用

过氧化物酶体增殖物激活受体(PPARs)是一类配体依赖的核受体超家族转录因子,包括α、β/δ和γ三种亚型.近年研究表明:PPAR-δ不仅在调节细胞生长、分化及组织损伤、修复过程中起重要作用,还参与脂质代谢、转运及胰岛素信号,并具有重要的血管生物学效应.因此,PPAR-δ可能成为代谢综合征及动脉粥样硬化病的潜在治疗靶点.     

PPAR-γ作用及其相关信号转导途径

过氧化物酶增殖物激活受体(peroxisomeproliferater-activatedreceptor,PPAR)是一类配体激活的核转录因子超家族成员,包括PPAR-α、PPAR-β/δ和PPAR-γ三种表型,其中以PPAR-γ的研究最为深入。PPAR-γ通过JAK-STAT、激活蛋白-1(AP-1)、NF-κB、活化T细胞核因子信号通路(NFAT)来抑制炎症反应;通过抑制泡沫细胞(foamcell)的分化、炎症反应以及细胞增殖来抑制动脉粥样硬化的发生发展;通过磷脂酰肌醇-3激酶(PI3K)、瘦素、脂链素等信号通路来参与糖稳态的调节;通过细胞周期的调控来影响肿瘤生长;参与脂肪细胞分化并与肥胖密切相关。明确这些相关信号通路以及相关细胞因子的作用,可对相关疾病机制及防治进一步提供有力依据和干预途径。     

Functional genomics of PPAR-γ in human immunomodulatory cells

Keeping in view the fact that peroxisome-proliferators activated receptors-PPARs (α,γ) play a crucial role in atherogenic inflammation, the present study was addressed to explore as to how selective and specific PPAR-γ gene silencing within human mononuclear cells affects genes involved in lipid metabolism and innate immune process. Such a study revealed that with respect to control cells, the PPAR-γ knock-out cells exhibited significant reduction in the expression of genes coding for PPAR- α, CD-36, LDL-R as well as significant increase in the expression of genes coding for IL-4, IL-8, IFN-γ, CX3CR1, hTERT. However, the expression of genes coding for LXR-α and Receptor-C _k could not be detected in PPAR-γ knock-out cells. Based on these results, we propose that PPAR-γ gene has the inherent capacity to influence the lipid mediated inflammation process in atherosclerotic lesions.     

PPAR-γ agonist protects against intestinal injury during necrotizing enterocolitis

Necrotizing enterocolitis (NEC) remains a lethal condition for many premature infants. Peroxisome proliferator-activated receptor-γ (PPAR-γ), a member of the nuclear hormone receptor family, has been shown to play a protective role in cellular inflammatory responses; however, its role in NEC is not clearly defined. We sought to examine the expression of PPAR-γ in the intestine using an ischemia-reperfusion (I/R) model of NEC, and to assess whether PPAR-γ agonist treatment would ameliorate I/R-induced gut injury. Swiss-Webster mice were randomized to receive sham (control) or I/R injury to the gut induced by transient occlusion of superior mesenteric artery for 45 min with variable periods of reperfusion. I/R injury resulted in early induction of PPAR-γ expression and activation of NF-κB in small intestine. Pretreatment with PPAR-γ agonist, 15d-PGJ₂, attenuated intestinal NF-κB response and I/R-induced gut injury. Activation of PPAR-γ demonstrated a protective effect on small bowel during I/R-induced gut injury.     

Regulatory T cells expressing PPAR-γ control inflammation in obesity

A recent study (Cipolletta et al., 2012) shows that regulatory T (Treg) cells expressing the peroxisome-proliferator- activated receptor (PPAR-γ) are engaged in suppressing adipose tissue inflammation in obesity, suggesting that Treg cells may be a target for treatment and prevention of adipose tissue inflammation and insulin resistance.     

非酒精性脂肪性肝病大鼠肝脏PPAR-γ的表达

目的：研究PPAR-γ在非酒精性脂肪性肝病（NAFLD）大鼠肝脏组织中的表达,探讨非酒精脂肪性肝病可能的发病机制。方法：雄性SD大鼠30只,随机分为A（正常组）15只普通饮食,B（高脂组）15只高脂饮食。8周后,自两组各随机抽取2只大鼠处死,光镜观察证实脂肪肝造模成功,继续喂养4周后处死所有大鼠,取血清做免疫生化检查,取肝组织标本,分别以光镜观察做出NAS评分,免疫组化和PCR法检测肝组织PPAR-γ蛋白的表达。结果：1.高脂饮食可以成功的复制NAFLD的大鼠模型;2.血清GLU、TC、TG、HDL-C、LDL-C在高脂组表达量较正常组明显升高,差异具有统计学意义（P〈0.05）;3.免疫组化显示：高脂组PPAR-γ表达量较正常组升高;结论：1.高脂饮食可成功复制NAFLD模型;2.PPAR-γ在NAFLD大鼠肝脏成脂性改变中具有重要作用。     

非酒精性脂肪性肝病大鼠肝脏PPAR-γ的表达

目的:研究PPAR-Y在非酒精性脂肪性肝病(NAFLD)大鼠肝脏组织中的表达,探讨非酒精脂肪性肝病可能的发病机制.方法:雄性SD大鼠30只,随机分为A(正常组)15只普通饮食,B(高脂组)15只高脂饮食.8周后,自两组各随机抽取2只大鼠处死,光镜观察证实脂肪肝造模成功,继续喂养4周后处死所有大鼠,取血清做免疫生化检查,取肝组织标本,分别以光镜观察做出NAS评分,免疫组化和PCR法检测肝组织PPAR-Y蛋白的表达.结果:1.高脂饮食可以成功的复制NAFLD的大鼠模型;2.血清GLU、TC、TG、HDL-C、LDLC在高脂组表达量较正常组明显升高,差异具有统计学意义(P＜0.05);3.免疫组化显示:高脂组PPAR-Y表达量较正常组升高;结论:1.高脂饮食可成功复制NAFLD模型;2.PPAR-Y在NAFLD大鼠肝脏成脂性改变中具有重要作用.     

姜黄素激活PPAR-γ通路改变巨噬细胞的极化状态

过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptorγ,PPAR-γ)通路是调节替换活化的(alternatively activated)M2型巨噬细胞极化的中心环节.姜黄素是PPAR-γ的天然激动剂,有着良好的抗炎作用.本研究通过建立巨噬细胞株的体外炎症模型,用姜黄素及PPAR-γ的特异性抑制剂GW9662对其进行干预,观察巨噬细胞株极化状态的改变.结果显示,姜黄素可以促使巨噬细胞向M2型极化,当特异性抑制PPAR-γ通路后,姜黄素促进巨噬细胞向M2型极化的作用受到抑制.结果表明,姜黄素可能是通过激动PPAR-γ通路促使巨噬细胞向M2型极化,为进一步研究姜黄素的抗炎机制及治疗慢性低度炎症相关的代谢性疾病提供了一个新的思路.     

Phenolics from Glycyrrhiza glabra roots and their PPAR-γ ligand-binding activity

Bioassay-guided fractionation of the EtOH extract of licorice (Glycyrrhiza glabra roots), using a GAL-4-PPAR-γ chimera assay method, resulted in the isolation of 39 phenolics, including 10 new compounds (1–10). The structures of the new compounds were determined by analysis of their spectroscopic data. Among the isolated compounds, 5′-formylglabridin (5), (2R,3R)-3,4′,7-trihydroxy-3′-prenylflavane (7), echinatin, (3R)-2′,3′,7-trihydroxy-4′-methoxyisoflavan, kanzonol X, kanzonol W, shinpterocarpin, licoflavanone A, glabrol, shinflavanone, gancaonin L, and glabrone all exhibited significant PPAR-γ ligand-binding activity. The activity of these compounds at a sample concentration of 10 μg/mL was three times more potent than that of 0.5 μM troglitazone.     

Dipeptidyl-peptidase-IV by cleaving neuropeptide Y induces lipid accumulation and PPAR-γ expression

We evaluated the effects of dipeptidyl peptidase-IV (DPPIV), and its inhibitor, vildagliptin, on adipogenesis and lipolysis in a pre-adipocyte murine cell line (3T3-L1). The exogenous rDPPIV increased lipid accumulation and PPAR-γ expression, whereas an inhibitor of DPPIV, the anti-diabetic drug vildagliptin, suppresses the stimulatory role of DPPIV on adipogenesis and lipid accumulation, but had no effect on lipolysis. NPY immunoneutralization or NPY Y(2) receptor blockage inhibited DPPIV stimulatory effects on lipid accumulation, collectively, indicating that DPPIV has an adipogenic effect through NPY cleavage and subsequent NPY Y(2) activation. Vildagliptin inhibits PPAR-γ expression and lipid accumulation without changing lipolysis, suggesting that this does not impair the ability of adipose tissue to store triglycerides inside lipid droplets. These data indicate that DPPIV and NPY interact on lipid metabolism to promote adipose tissue depot.     

高血压对大鼠心肌PPAR-γ表达水平的影响及其意义

以自发性高血压大鼠（SHR）为模型,Wistar-Kyoto大鼠（WKY）为正常对照,探讨过氧化物酶体增殖物激活受体γ（PPAR-γ）表达水平,在高血压肥厚心肌中的变化及其意义.4周龄(4w)、16周龄(16w) SHR及WKY称量体重（BM）后取心脏,分别测量左心室（LV）、室间隔（IS）、右心室（RV）湿重（WM）,并应用免疫组织化学技术,检测大鼠心肌细胞PPAR-γ表达;应用蛋白质印迹和RT-PCR技术,检测 4w、16w SHR LV、IS、RV PPAR-γ蛋白质和mRNA水平.发现4w SHR LVWM/BM、ISWM/BM、RVWM/BM与同龄WKY相比无显著性差异（P＞0.05）,PPAR-γ的蛋白质和mRNA表达水平亦相似（P＞0.05）;16w SHR LVWM/BM和ISWM/BM较同龄WKY明显增高（P＜0.01）,而PPAR-γ的蛋白质和mRNA水平显著降低（P＜0.01）,16w SHR RVWM/BM与16wWKY相比差异无显著性（P＞0.05）,PPAR-γ的蛋白质表达水平亦无显著性差异（P＞0.05）,mRNA水平较WKY略减弱（P＜0.05）.实验结果提示,长期压力负荷过重导致SHR LV和IS心肌代偿性肥厚,肥厚心肌中PPAR-γ蛋白质和mRNA表达水平显著降低,推测心肌细胞PPAR-γ表达受抑制,可能参与了高血压心室重塑的发生机制.     

Ursolic acid is a PPAR-α agonist that regulates hepatic lipid metabolism

In this study, we confirmed that ursolic acid, a plant triterpenoid, activates peroxisome proliferator-activated receptor (PPAR)-α in vitro. Surface plasmon resonance and time-resolved fluorescence resonance energy transfer analyses do not show direct binding of ursolic acid to the ligand-binding domain of PPAR-α; however, ursolic acid enhances the binding of PPAR-α to the peroxisome proliferator response element in PPAR-α-responsive genes, alters the expression of key genes in lipid metabolism, significantly reducing intracellular triglyceride and cholesterol concentrations in hepatocytes. Thus, ursolic acid is a PPAR-α agonist that regulates the expression of lipid metabolism genes, but it is not a direct ligand of PPAR-α.     

黄精多糖对帕金森病大鼠脑组织中PPAR-γ表达的影响

目的:探讨黄精多糖治疗帕金森病(Parkinson disease,PD)大鼠的疗效和作用机理。方法:建立帕金森病模型,随机分成4组:正常对照组(CG)、模型组(MG)、低剂量治疗组(LDG)和高剂量治疗组(HDG),每组12只。CG组和MG组予以等量注射用水,LDG组和HDG组分别予以4%和16%的黄精多糖溶液灌胃,连续6周。8周时分别观察各组阿扑吗啡诱导的旋转行为的变化,western检测过氧化物酶体增殖物激活受体-γ(peroxisome proliferator-activated receptor-γ,PPAR-γ)蛋白表达,组织化学方法检测酪氨酸羟化酶(tyrosin hydroxylase,TH)表达并计数阳性细胞数。结果:治疗8周后,LDG组和HDG组旋转次数均明显下降(P<0.05),PPAR-γ蛋白表达上调,与MG比较,差异具有显著性(P<0.01)。同时,LDG组和HDG组TH的表达均上调,TH阳性细胞数增多,与MG组比较,差异具有显著性(P<0.01)。结论:黄精多糖具有明显改善PD大鼠行为的作用,机制可能与黄精多糖上调PPAR-γ表达相关,进而抑制炎症反应和细胞凋亡,促进多巴胺神经元...     

Design and synthesis of marine fungal phthalide derivatives as PPAR-γ agonists

On the basis of a marine fungal phthalide (paecilocin A) skeleton, we synthesized 20 analogs and evaluated them for peroxisome proliferator-activated receptor gamma (PPAR-γ) binding and activation. Among these analogs, 6 and 7 had significant PPAR-γ binding activity, and 7 showed further PPAR-γ activation in rat liver Ac2F cells. In docking simulation, 7 formed H bonds with key amino acid residues of the PPAR-γ binding domain, and the overall positioning was similar to rosiglitazone. This new phthalide derivative is considered an interesting new molecular class of PPAR-γ ligands.