Review of the expression of peroxisome proliferator-activated receptors alpha (PPARα), beta (PPARβ), and gamma (PPARγ) in rodent and human development

The peroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor superfamily and there are three primary subtypes, PPARα, β, and γ. These receptors regulate important physiological processes that impact lipid homeostasis, inflammation, adipogenesis, reproduction, wound healing, and carcinogenesis. These nuclear receptors have important roles in reproduction and development and their expression may influence the responses of an embryo exposed to PPAR agonists. PPARs are relevant to the study of the biological effects of the perfluorinated alkyl acids as these compounds, including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), activate PPARα. Exposure of the rodent to PFOA or PFOS during gestation results in neonatal deaths, developmental delay and growth deficits. Studies in PPARα knockout mice demonstrate that the developmental effects of PFOA, but not PFOS, depend on expression of PPARα. This review provides an overview of PPARα, β, and γ protein and mRNA expression during mouse, rat, and human development. The review presents the results from many published studies and the information is organized by organ system and collated to show patterns of expression at comparable developmental stages for human, mouse, and rat. The features of the PPAR nuclear receptor family are introduced and what is known or inferred about their roles in development is discussed relative to insights from genetically modified mice and studies in the adult.     

Puerarin pretreatment attenuates cardiomyocyte apoptosis induced by coronary microembolization in rats by activating the PI3K/Akt/GSK-3β signaling pathway

Coronary microembolization (CME) is associated with cardiomyocyte apoptosis and cardiac dysfunction. Puerarin confers protection against multiple cardiovascular diseases, but its effects and specific mechanisms on CME are not fully known. Hence, our study investigated whether puerarin pretreatment could alleviate cardiomyocyte apoptosis and improve cardiac function following CME. The molecular mechanism associated was also explored. A total of 48 Sprague-Dawley rats were randomly divided into CME, CME + Puerarin (CME + Pue), sham, and sham + Puerarin (sham + Pue) groups (with 12 rats per group). A CME model was established in CME and CME + Pue groups by injecting 42 μm microspheres into the left ventricle of rats. Rats in the CME + Pue and sham + Pue groups were intraperitoneally injected with puerarin at 120 mg/kg daily for 7 days before operation. Cardiac function, myocardial histopathology, and cardiomyocyte apoptosis index were determined via cardiac ultrasound, hematoxylin-eosin (H&E) and hematoxylin-basic fuchsin-picric acid (HBFP) stainings, and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. Western blotting was used to measure protein expression related to the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway. We found that, puerarin significantly ameliorated cardiac dysfunction after CME, attenuated myocardial infarct size, and reduced myocardial apoptotic index. Besides, puerarin inhibited cardiomyocyte apoptosis, as revealed by decreased Bax and cleaved caspase-3, and up-regulated Bcl-2 and PI3K/Akt/GSK-3β pathway related proteins. Collectively, puerarin can inhibit cardiomyocyte apoptosis and thus attenuate myocardial injury caused by CME. Mechanistically, these effects may be achieved through activation of the PI3K/Akt/GSK-3β pathway.     

Resveratrol attenuates intestinal injury in irradiated rats via PI3K/Akt/mTOR signaling pathway

Radiation‐induced enteritis is one of the greatest challenges in radiotherapy. The current study was designed to evaluate the ameliorative effect of resveratrol, which exhibits anti‐inflammatory property, against radiation‐induced intestinal injury in rats and to explore the underlying mechanism. Rats were exposed to a single dose of 5 Gy. Resveratrol (20 mg/kg/day) was orally administered to irradiated rats over 3 weeks. Results showed that resveratrol ameliorated the intestinal oxidative stress parameters; malondialdehyde (MDA) content, glutathione (GSH) level, and catalase (CAT) activity compared to irradiated group. Furthermore, resveratrol reduced the contents of inflammatory cytokines; tumor necrosis factor α (TNF‐α), nuclear factor‐kappa (NF‐κB), and interleukin 1β (IL‐1β) in intestine. Western blotting analysis revealed that resveratrol down‐regulated the proteins expression of phosphoinositide 3‐kinases (PI3K), protein kinase B (Akt) as well as the mammalian target of rapamycin (mTOR) in intestinal tissues of irradiated rats and thus reduced the inflammatory mediator production. These results were confirmed by histopathological investigation. In conclusion, resveratrol attenuated intestinal inflammation following irradiation via modulating PI3K/Akt/mTOR pathway and thereby could be a promising adjuvant in radiotherapy.     

紫草素通过PI3K/Akt通路促进人乳腺癌MCF-7细胞自噬

目的研究紫草素(Shikonin)对人乳腺癌MCF-7细胞自噬的影响及其作用机制。方法 CCK-8法检测紫草素处理人乳腺癌MCF-7细胞24、48 h细胞的存活率,Western blot方法检测紫草素处理24 h和48 h时LC3、p62、PI3K、Akt、p-PI3K、p-Akt蛋白水平。结果 1μmol.L-1紫草素处理细胞48 h以及2.5、5μmol.L-1紫草素处理MCF-7细胞24 h和48 h时,MCF-7细胞的活力受到明显抑制,LC3-Ⅱ/LC3-Ⅰ值增加,p62表达减少,总PI3K、Akt、p-PI3K、p-Akt均减少。结论紫草素促进乳腺癌MCF-7细胞自噬,其作用机制可能与PI3K/Akt通路受到抑制有关。     

PI3K/Akt/mTOR信号传导通路与前列腺癌关系的研究进展

前列腺癌是威胁中老年男性健康的常见肿瘤,成为男性癌症死因的第二位。 PI3K/Akt/mTOR信号通路能够通过维持细胞生存、抑制细胞凋亡、促进细胞周期运行及血管生成等促进前列腺癌病程发展。本文综合国内外文献,阐述PI3K/Akt/mTOR信号通路在前列腺癌发生发展中的作用以及和通路相关的药物治疗进展。     

The PI3K/Akt/mTOR pathway: A potential pharmacological target in COVID-19

Coronavirus disease 2019 (COVID-19) has emerged as a serious threat to global health. The disregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) cell signaling pathway observed in patients with COVID-19 has attracted attention for the possible use of specific inhibitors of this pathway for the treatment of the disease. Here, we review emerging data on the involvement of the PI3K/Akt/mTOR pathway in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the clinical studies investigating its tailored inhibition in COVID-19. Current in silico, in vitro, and in vivo data convergently support a role for the PI3K/Akt/mTOR pathway in COVID-19 and suggest the use of specific inhibitors of this pathway that, by a combined mechanism entailing downregulation of excessive inflammatory reactions, cell protection, and antiviral effects, could ameliorate the course of COVID-19.     

PI3K/Akt信号通路抑制剂对人胃癌细胞增殖及相关基因表达的影响

目的 研究磷脂酰肌醇-3-激酶/蛋白激酶B(PI3K/Akt)信号通路抑制剂渥曼青霉素对人胃癌细胞增殖、细胞周期与凋亡的影响以及相关基因蛋白激酶B(pAkt)、磷酸化腺苷酸活化蛋白激酶(pAMPK)、S期激酶相关蛋白2(Skp2)及P27kip1蛋白表达的影响.方法 分别用不同浓度渥曼青霉素处理处于对数生长阶段的BGC823细胞12、24、48 h,利用MTT实验检测其对胃癌细胞增殖的影响,胃癌细胞凋亡及细胞周期的检测采用流式细胞术,Western-blotting检测p-Akt、p-AMPK、Skp2及P27kip1蛋白的表达变化.结果 渥曼青霉素可明显抑制BGC823细胞的增殖,在一定范围内具有时间和浓度依赖性.20 mmol/L渥曼青霉素作用细胞24 h时,细胞生长周期阻滞于G0/G1期,细胞凋亡率为(44.44±3.17)％;Western blot检测显示,pAkt、pAMPK及Skp2蛋白表达随着药物浓度的增加而减少,P27kip1蛋白表达随着药物浓度增加而增加.结论 PI3K/Akt信号通路抑制剂渥曼青霉素能够明显下调胃癌细胞的增殖活性,导致胃癌细胞周期被阻滞于G0/G1期并诱导细胞发生凋亡,进一步研究证实PI3K/Akt信号通路介导的Skp2及P27kip1蛋白调控在凋亡过程中发挥重要作用.     

Synthesis of tritium and carbon‐14 labelled NNC 61‐4655: a potent dual‐acting PPARα and PPARγ agonist

The synthesis of the potent dual‐acting PPARα and PPARγ agonist NNC 61‐4655 labelled with tritium and carbon‐14 is reported. Tritium labelled NNC 61‐4655 was obtained in three steps with introduction of tritium through catalytic tritium‐halogen exchange of an aryl bromide precursor. This provided [³H]NNC 61‐4655 in 39% overall radiochemical yield with a specific activity of 49 Ci/mmol. Carbon‐14 labelled NNC 61‐4655 was obtained in five steps starting from bromo[1‐¹⁴C]acetic acid. The synthetic sequence, which included a Horner–Wadsworth–Emmons olefination and a Mitsunobu alkylation, provided [¹⁴C]NNC 61‐4655 in 33% overall radiochemical yield with a specific activity of 57.4 mCi/mmol. Copyright © 2003 John Wiley & Sons, Ltd.     

BAFF/BAFF-R通过PI3K/Akt/mTOR信号转导通路调节B淋巴细胞功能在类风湿关节炎发病机制中的意义

B淋巴细胞活化和生存在类风湿关节炎(RA)病程中起关键作用。肿瘤坏死因子家族B细胞活化因子(BAFF)是维持B细胞功能的重要细胞因子。BAFF与其受体BAFF-R结合(BAFF/BAFF-R),能够激活PI3K/Akt/mTOR信号通路,调节B淋巴细胞的增殖、存活和活化。该文就B淋巴细胞、BAFF/BAFF-R以及PI3K/Akt/mTOR信号通路参与RA的发病机制加以综述。     

PI3K/AKT信号通路在银屑病发病机制中的研究进展

银屑病是一种免疫介导的多因素炎症性皮肤病,以表皮角质形成细胞异常增殖、毛细血管扩张、中性粒细胞浸润为主要病理表现。磷脂酰肌醇3-激酶（phosphatidylinositol 3-kinase,PI3K）/蛋白激酶B（protein kinase B,AKT）信号通路在表皮细胞增殖、细胞自噬、血管生成、脂质代谢等过程中...     

[14C] and [3H]‐labelling of Ragaglitazar: A dual acting PPARα and PPARγ agonist with hypolipidemic and anti‐diabetic activity

Currently, Ragaglitazar is being developed as a drug for the treatment of hyperglycaemia and hyperlipidemia in patients with type 2 diabetes. Here, we report the labelling of Ragaglitazar with carbon‐14 and tritium for in vivo and in vitro investigations. Two different carbon‐14 labelled as well as two different tritium labelled tracers of Ragaglitazar were synthesised. The carbon‐14 label was introduced from either ethyl bromo[2‐¹⁴C]acetate (5 steps/33% overall yield) or [U‐¹⁴C]phenoxazine (4 steps/48% overall yield). Tritium was incorporated either by catalytic tritiation of an alkene precursor followed by chiral HPLC separation (2 steps/17% overall yield) or by catalytic tritium–halogen exchange of an aryl bromide precursor (2 steps/68% overall yield). Copyright © 2003 John Wiley & Sons, Ltd.     

MicroRNA-141通过PI3K/Akt/mTOR信号通路促进PCOS卵巢颗粒细胞增殖的机制研究

目的　研究microRNA-141（miR-141）对卵巢颗粒细胞增殖的影响,并探讨其在多囊卵巢综合征（PCOS）发生发展中的作用机制。方法　采用实时荧光定量PCR检测20例PCOS患者的卵巢组织、20例对照组的正常卵巢组织、人卵巢颗粒细胞KGN及人正常卵巢上皮细胞IOSE80中miR-141 mRNA表达水平;KGN细胞分为miR-141 minics组、LY294002+miR-141 minics组、雷帕霉素（rapamycin）+miR-141 minics组、NC组、对照组。采用MTT法和平板克隆实验检测各组细胞增殖和克隆形成能力,采用Western blot法检测各组细胞磷脂酰肌醇3-激酶（PI3K）/蛋白激酶（Akt）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路相关蛋白表达水平。结果　PCOS卵巢组织miR-141 mRNA表达水平显著高于正常卵巢组织,人卵巢颗粒细胞KGN miR-141 mRNA表达水平高于人正常卵巢上皮细胞IOSE80（P＜0.05）;miR-141 minics组、LY294002+miR-141 minics组及rapamycin+miR-141 minics组miR-141 mRNA表达水平均高于NC组和对照组（P＜0.05）;LY294002+miR-141 minics组及rapamycin+miR-141 minics组转染后24、48、72、96 h OD值和克隆形成率均低于miR-141 minics组,但高于NC组和对照组（P＜0.05）;LY294002+miR-141 minics组转染后p-Akt、p-mTOR蛋白表达水平低于miR-141 minics组,但高于NC组、对照组（P＜0.05）。rapamycin+miR-141 minics组转染后p-mTOR蛋白表达水平低于miR-141 minics组,高于NC组、对照组（P＜0.05）。结论　miR-141可通过激活PI3K/Akt/mTOR信号通路促进卵巢颗粒细胞的增殖。     

PI3K/AKT/mTOR信号通路参与自身免疫性

自身免疫性疾病（autoimmune disease,AD）是机体因自身抗原免疫耐受障碍而对自身抗原产生免疫反应,从而引起机体组织损伤的一类疾病。近年研究发现,磷脂酰肌醇-3-激酶/蛋白激酶B/雷帕霉素靶蛋白（phosphatidylin ositol 3-kinase/protein kinase B/mechanistic target ofrapamycin kinase,PI3K/AKT/mTOR）信号通路与AD发病密切相关,其主要参与免疫细胞增殖分化、炎性细胞因子分泌、自噬及氧化应激等过程。本文重点概述PI3K/AKT/mTOR信号通路参与AD发病机理的研究进展。     

Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway

Pyrazinamide (PZA) causes serious hepatotoxicity, but little is known about the exact mechanism by which PZA induced liver injury. The peroxisome proliferator‐activated receptors alpha (PPARα) is highly expressed in the liver and modulates the intracellular lipidmetabolism. So far, the role of PPARα in the hepatotoxicity of PZA is unknown. In the present study, we described the hepatotoxic effects of PZA and the role of PPARα and its target genes in the downstream pathway including L‐Fabp, Lpl, Cpt‐1b, Acaa1, Apo‐A1 and Me1 in this process. We found PZA induced the liver lipid metabolism disorder and PPARα expressionwas down‐regulated which had a significant inverse correlation with liver injury degree. These changeswere ameliorated by fenofibrate, the co‐treatment that acts as a PPARα agonist. In contrast, short‐termstarvation significantly aggravated the severity of PZA‐induced liver injury. In conclusion, this study demonstrated the critical role played by PPARα in PZA‐induced hepatotoxicity and provided a better understanding of the molecular mechanisms underlying PZA‐induced liver injury. Copyright © 2016 John Wiley & Sons, Ltd.     

PI3K/Akt信号通路活化在曲妥珠单抗耐药机制意义的研究

目的探讨磷脂酰肌醇-3-激酶/丝苏氨酸蛋白激酶(PI3K/Akt)信号转导通路激活是曲妥珠单抗耐药的重要靶点之一,为乳腺癌曲妥珠单抗耐药的靶向治疗提供理论基础。方法对人乳腺癌细胞株BT474连续处理建立了耐曲妥珠单抗的耐药亚株BT-HerR,FISH法对耐药细胞株BT-HerR做Her-2表型分析,MTT法检测曲妥珠单抗对BT474和BT-HerR细胞的体外增殖抑制情况,流式细胞仪检测曲妥珠单抗干预后细胞的凋亡变化,PI3K/Akt抑制剂LY294002干预细胞后Western blot检测p-Akt表达。结果耐药细胞株BT-HerR Her-2基因表达为强阳性;曲妥珠单抗干预细胞72 h后,细胞的体外增殖受到抑制且随着浓度的升高而增强;经曲妥珠单抗处理后比较BT474与BT-HerR细胞凋亡率,差异具有显著性(P<0.01);曲妥珠单抗仅能抑制BT474的Akt蛋白磷酸化,LY294002则能同时抑制BT474的BT-HerR Akt蛋白磷酸化。结论曲妥珠单抗耐药细胞Akt蛋白磷酸化活化,PI3K/Akt抑制剂LY294002能明显抑制曲妥珠单抗耐药细胞Akt蛋白磷酸化,PI3K/Akt信号转导通路与曲妥珠单抗耐药存在明确相关性。     

Overexpressed Hsp70 alleviated formaldehyde‐induced apoptosis partly via PI3K/Akt signaling pathway in human bronchial epithelial cells

Formaldehyde (FA) is a ubiquitous environmental pollutant, which can induce apoptosis in lung cell and is related to the pathogenesis of asthma, pneumonia, and chronic obstructive pulmonary disease. Heat shock protein 70 (Hsp70) is an ATP‐dependent molecular chaperone and exhibits an anti‐apoptosis ability in a variety of cells. Previous studies reported that the expression of Hsp70 was induced when organisms were exposed to FA. Whether Hsp70 plays a role in the FA‐induced apoptosis and the involved cell signaling pathway remain largely unknown. In this study, human bronchial epithelial cells with overexpressed Hsp70 and the control were exposed to different concentrations of FA (0, 40, 80, and 160 μmol/L) for 24 hours. Apoptosis and the expression levels of PI3K, Akt, p‐Akt, MEK, p‐MEK, and GLI2 were detected by Annexin‐APC/7AAD double‐labeled flow cytometry and western blot. The results showed that overexpression of Hsp70 decreased the apoptosis induced by FA and alleviated the decline of PI3k and p‐Akt significantly. Inhibitor (LY 294002, a specific inhibitor of PI3K‐Akt) test result indicated that PI3K‐Akt signaling pathway was involved in the inhibition of FA‐induced apoptosis by Hsp70 overexpression and also active in the maintenance of GLI2 level. However, it also suggested that other signaling pathways activated by overexpressed Hsp70 participated in this process, which was needed to be elucidated in further research.     

PI3K/Akt信号通路与肝纤维化

PI3K/Akt信号通路为细胞内重要信号传导通路之一,在促进细胞增殖、抑制凋亡的过程中发挥重要作用。PI3K/Akt信号通路与肝纤维化的发生、发展密切相关。通过干预PI3K/Akt信号通路,研究肝纤维化的发病机制和药物治疗是有意义的途径。该文就PI3K/Akt信号通路的构成、转导途径及其在肝纤维化中的作用作一综述。