PI3K/Akt信号通路在肾小球足细胞损伤凋亡中的作用机制

[摘要]目的：初步探讨磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/Akt）信号通路在肾小球足细胞损伤凋亡中的作用机制。方法：采用荧光定量PCR技术、免疫印迹（Western blot）技术及激光共聚焦技术检测肾小球足细胞凋亡相关蛋白的表达和分布情况,流氏细胞仪检测肾小球足细胞凋亡率。结果：嘌呤霉素核苷酸（PAN）损伤足细胞后CD2相关蛋白（CD2AP）分子的表达明显降低,与p85的共定位异常;给予地塞米松（DEX）干预后,CD2AP的表达及分布趋于正常,足细胞磷酸化Akt（p-Akt）及磷酸化糖原合成酶激酶-3β（p-GSK3β）的表达与PAN浓度依赖性的下降,给予DEX干预后,p-Akt及p-GSK3β的表达逐渐恢复;PAN损伤足细胞后,其凋亡率明显升高,DEX干预后凋亡率较PAN组降低（P<0.05）。结论：PI3K/Akt信号通路在肾小球足细胞凋亡中发挥了重要作用,而糖皮质激素可能通过稳定PI3K/Akt信号通路发挥保护肾小球足细胞作用。     

PI3K/Akt信号通路与阿尔茨海默病关系的研究进展

神经系统活动的基础是神经元以及它们之间的联系。在生长发育过程中,如果这些结构出现变化就会导致相应的疾病发生,如轻度认知障碍(mild cognitive impairment,MIC)、阿尔茨海默病(Alzheimer′s disease,AD)、帕金森病(Parkinson disease,PD)等老化疾病。导致这些疾病发生的机制很多,包括基因水平改变、细胞内外部环境变化等。目前认为磷脂酰肌醇-3-激酶/丝/苏氨酸激酶(phosphatidylinositol-3-kinases/serine threonine kinase,PI3K/Akt)信号通路与细胞生存、细胞代谢以及细胞凋亡等机制密切相关。因     

PI3K/Akt信号通路在肿瘤发展和治疗中的作用

目前发现有多条信号网络通路参与调控肿瘤生成、增殖、凋亡等分子机制,PI3K/Akt是其中比较重要的一条信号传导途径,该通路与肿瘤的发生发展密切相关。该文就PI3K/Akt信号通路的结构组成与调控肿瘤机制进行阐述,并介绍了其在临床中的应用与前景。     

PI3K/Akt信号通路在肝癌中相关机制及药物研究进展

肝癌在我国的死亡率逐年提升,发病年龄也日趋年轻化,发现时大多已处于中、晚期,失去了最佳手术时机.随着近年来高通量测序技术水平的不断提高,多条信号通路的调控机制对肝癌的辅助治疗成为研究热点,对肝癌的靶点进行分子靶向治疗成为一项有效的手段.多条信号通路在肝癌的发病过程中发挥作用;其中,磷脂酰肌醇3-激酶(PI3K)/Akt...     

补骨脂素对绝经后大鼠骨质疏松及PI3K/Akt/mTOR信号通路的影响

目的:研究补骨脂素对绝经后大鼠骨质疏松及磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(Akt)/哺乳动物雷帕霉素靶蛋白(mTOR)信号通路的影响。方法:将60只健康雌性SD大鼠随机分为正常组、模型组、阳性对照组(0.09 mg/kg雌二醇)和补骨脂素低、中、高剂量组(22、44、88 mg/kg),每组10只。除正常组外,其余各组大鼠均采用卵巢摘除去势法建立绝经后骨质疏松模型。术后正常饲养2个月,正常组和模型组大鼠灌胃等体积生理盐水,各药物组大鼠灌胃相应药液;灌胃体积均为0.005 mL/g,每天1次,连续98天。末次给药24 h后,测定大鼠右侧下肢股骨和椎骨的骨密度,血清中钙离子、骨钙素、Ⅰ型前胶原N端前肽(P1NP)含量和骨形态发生蛋白2(BMP2)、血管内皮生长因子(VEGF)水平,以及股骨组织中PI3K、Akt、mTOR mRNA及蛋白的表达水平。结果:与正常组比较,模型组大鼠股骨和椎骨的骨密度以及血清中钙离子、骨钙素、P1NP含量和BMP2、VEGF水平均显著降低,PI3K、Akt、mTOR mRNA及蛋白的表达水平均显著升高(P<0.05或P<0.01)。与模型组比较,补骨脂素中、高剂量组和阳性对照组大鼠股骨和椎骨的骨密度以及血清中钙离子、骨钙素、P1NP含量和BMP2(补骨脂素中剂量组除外)、VEGF(补骨脂素中剂量组除外)水平均显著升高,各药物组PI3K、Akt、m TOR mRNA(补骨脂素低剂量组除外)及蛋白表达水平均显著降低(P<0.05或P<0.01),且高剂量组股骨骨密度和钙离子、BMP2水平以及PI3K蛋白表达水平均显著高于阳性对照组(P<0.05),mTOR mRNA表达水平显著低于阳性对照组(P<0.05)。结论:补骨脂素可改善绝经后大鼠的骨质疏松,其机制可能与抑制PI3K/Akt/mTOR信号通路有关。     

中医药调控PI3K/AKT信号通路防治慢性心力衰竭研究状况

慢性心力衰竭(CHF)是各种心血管疾病的终末期表现,是各种心脏结构或功能疾病所造成的心室充盈和(或)射血分数受损的一组综合征。该病的发病机制复杂多样,大多与细胞凋亡的活性增强有关。磷酸肌醇-3激酶/蛋白激酶B(PI3K/AKT)信号通路参与CHF的发生、发展和病理形成。相关研究表明,PI3K/AKT通路是中药治疗CHF的关键靶通路。本文对近年来中药调控PI3K/AKT通路干预CHF的机制和作用进行分析和总结,发现中药提取物、中成药及中药复方均可改善CHF的心肌细胞损伤,其作用机制与细胞凋亡、炎症因子、氧化应激和心室重构密切相关。同时创造性地总结了PI3K/AKT通路在防治CHF中存在的对立性争议,并分析了产生争议原因,以期为CHF的治疗和新药研发提供新思路。     

鱼腥草总黄酮调控PI3K/Akt信号通路诱导人乳腺癌细胞株MCF-7凋亡的实验研究

目的：探讨鱼腥草总黄酮调控磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（Akt）信号通路对人乳腺癌细胞株MCF-7凋亡的诱导作用。方法：取对数期MCF-7细胞,随机分为4组（5个复孔）,低、中、高剂量组分别用3,6,9 g·L^-1鱼腥草总黄酮处理,对照组用磷酸盐缓冲液（PBS）处理。干预48 h后进行细胞形态学观察;对比干预12,24,48 h时的细胞凋亡率;对比干预48 h时PI3K、Akt、B淋巴细胞瘤-2基因（Bcl-2）、Bcl-2相关X蛋白（Bax）mRNA和PI3K、Akt、磷酸化Akt（pAkt）、Bcl-2、Bax蛋白相对表达量。结果：Hoechst 33258染色结果显示,干预后3剂量组部分细胞体积缩小、染色质浓缩,出现凋亡小体,且中剂量组凋亡现象最为明显;细胞凋亡率、Bax mRNA和蛋白相对表达量组间比较,中剂量组最高、高剂量组其次、低剂量组其稍低、对照组最低,且每2组间比较差异均有显著性（P<0.05）;细胞凋亡率组内比较,对照组随时间的延长变化不显著（P>0.05）,3剂量组均随时间的延长显著增加（P<0.05）;PI3K、Bcl-2 mRNA和PI3K、pAkt、Bcl-2蛋白相对表达量组间比较,中剂量组最低、高剂量组其次、低剂量组稍高、对照组最高,且每2组间比较差异均有显著性（P<0.05）;Akt mRNA和蛋白相对表达量组间比较差异均不显著（P>0.05）。结论：鱼腥草总黄酮可促进人乳腺癌细胞株MCF-7的凋亡,其中浓度为6 g·L^-1时促凋亡作用最强,推测是通过下调PI3K、Bcl-2 mRNA和PI3K、pAkt、Bcl-2蛋白表达,上调Bax mRNA和蛋白的表达,与PI3K/Akt信号通路有关。     

胰岛素PI3K/PKB信号转导通路研究进展

糖尿病是一种以高血糖为主要症状的代谢性紊乱疾病,其重要病理机制为胰岛素分泌不足或外周组织胰岛素抵抗。因此,阐明胰岛素的作用机制对于研发降低血糖、治疗糖尿病药物具有重要意义。胰岛素磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(PKB)信号转导通路在胰岛素作用途径中具有极其重要的作用,它参与介导胰岛素作用的葡萄糖转运、抑制脂肪分解,糖原、蛋白和脂肪的合成以及细胞分化、增殖和凋亡等。本文参阅国内外文献,综述了胰岛素在PI3K/PKB途径中的信号转导过程的最新进展。     

温阳解郁汤对肾阳虚型抑郁大鼠PI3K/Akt信号通路及神经递质的影响

目的 探讨温阳解郁汤对肾阳虚抑郁症大鼠磷脂酰肌醇3激酶（PI3K）/蛋白激酶B(Akt)信号通路及神经递质的影响。方法 将雄性SD大鼠分为空白组、模型组、氟西汀组（西药阳性对照,4.17 mg/kg）、逍遥散组（中药阳性对照,1.88 g/kg）和温阳解郁汤低、中、高剂量组（1.25、2.50、5.00 g/kg）,每组15只。除空白组外,其余各组均皮下注射皮质酮20 mg/kg以复制肾阳虚型抑郁大鼠模型,并同时灌胃相应药液,每天1次,连续28 d。观察大鼠的一般情况,检测其糖水偏好率、强迫游泳静止不动时间,计算其脏器指数,检测其血清中神经递质水平/含量,检测其海马组织中PI3K/Akt通路相关蛋白的表达量和树突棘数量。结果 与空白组比较,模型组大鼠出现了掉毛、畏冷扎堆、蜷缩等症状,糖水偏好率,肾上腺、胸腺、脾指数,血清环磷酸腺苷（cAMP）、脑源性神经营养因子、γ氨基丁酸水平,cAMP与环磷酸鸟苷比值,去甲肾上腺素、多巴胺、5-羟色胺含量,PI3K、Akt、哺乳动物雷帕霉素靶蛋白的表达量,以及海马组织中树突棘数量均显著降低（P<0.01）;静止不动时间、谷氨酸水平、糖原合成酶激...     

甲状腺腺瘤与PI3K/Akt信号转导途径的关系

目的 探讨甲状腺腺瘤疾病与磷脂酰肌醇3激酶／蛋白激酶B（P13K／Akt）信号转导途径之间的关系。方法 外科手术中获取19例单发结节型甲状腺腺瘤组织及瘤旁组织,采用RT-PCR技术及免疫组化方法检测腺瘤及瘤旁组织中P13K、ARt的表达。结果 （1）甲状腺腺瘤组织中P13K、ARt基因的mRNA表达水平均显著高于瘤旁组织（P〈0．01）;（2）免疫组化P13K、ARt染色均分布于细胞胞浆中,腺瘤组织中P13K、ARt的平均积分光度值均显著高于瘤旁组织（P〈0．01）。结论 P13K／Akt信号转导途径功能异常可能参与甲状腺腺瘤增殖的病理生理机制。     

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.     

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.     

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。     

PI3K/Akt信号通路在小檗碱联合人参皂苷Rg3诱导鼻咽癌细胞凋亡中的调控作用

目的研究PI3K/Akt信号通路在小檗碱联合人参皂苷Rg3诱导鼻咽癌细胞凋亡中的作用。方法RTCA法检测小檗碱联合人参皂苷Rg3对鼻咽癌CNE2、6-10B细胞增殖的影响;Hoechst 33342染色法、荧光双染流式细胞仪检测药物对CNE2细胞凋亡的影响;Western blot法检测PI3K/Akt信号通路关键蛋白及凋亡相关蛋白表达的变化。结果小檗碱联合人参皂苷Rg3可抑制鼻咽癌CNE2、6-10B细胞的增殖,诱导CNE2细胞的凋亡。与单独用药组相比,联合用药组细胞的PI3K/Akt信号通路关键蛋白PI3K p110α和p-Akt的表达明显下调(P<0.05)。加入PI3K/Akt信号通路的激活剂SC79后,小檗碱联合人参皂苷Rg3抑制CNE2细胞增殖和诱导细胞凋亡的效应降低,p-Akt、Survivin、PCNA及Bcl-2表达量增加,Bax的表达下降。结论小檗碱联合人参皂苷Rg3可通过PI3K/Akt信号通路发挥抑制鼻咽癌细胞增殖和诱导细胞凋亡的作用。     

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。     

Urolithin A suppresses tumor progression and induces autophagy in gastric cancer via the PI3K/Akt/mTOR pathway

Urolithin A (UA) is a microbial metabolite of natural polyphenols ellagitannins and ellagic acid with well-established antitumor properties against various malignancies. However, the exact role of UA in gastric cancer (GC) progression remains largely unclear. In the present study, we investigated the effects and potential mechanisms of UA in GC in vitro and in vivo. Our results revealed that UA could suppress GC cell proliferation, inhibit migration and invasion, promote apoptosis, and induce autophagy via the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway in vitro. The autophagy inhibitors 3-methyladenine and chloroquine augmented the inhibitory effect of UA on proliferation and promoted apoptosis, implying that UA mediated the cytoprotective role of autophagy. Meanwhile, the in vivo experiments showed that UA effectively suppressed tumor growth, enhanced the therapeutic effects, and alleviated chemotherapy toxicity in xenograft models. Overall, these findings offer novel insights into the role of UA in tumor therapy and suggest that UA may possess potential therapeutic applications for GC.     

Nerve growth factor induces cord formation of mesenchymal stem cell by promoting proliferation and activating the PI3K/Akt signaling pathway

Aim:

To investigate whether nerve growth factor (NGF) induced angiogenesis of bone marrow mesenchymal stem cells (MSCs) and the underlying mechanisms.

Methods:

Bone marrow MSCs were isolated from femors or tibias of Sprague-Dawley rat, and cultured. The cells were purified after 3 to 5 passages, seeded on Matrigel-coated 24-well plates and treated with NGF. Tube formation was observed 24 h later. Tropomyosin-related kinase A (TrkA) and p75NTR gene expression was examined using PCR analysis and flow cytometry. Growth curves were determined via cell counting. Expression of VEGF and pAkt/Akt were analyzed with Western blot.

Results:

NGF (25, 50, 100 and 200 μg/L) promoted tube formation of MSCs. The tubular length reached the maximum of a 2.24-fold increase, when the cells were treated with NGF (50 μg/L). NGF (50 μg/L) significantly enhanced Akt phosphorylation. Pretreatment with the specific PI3K inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 (10 μmol/L) blocked NGF-stimulated Akt phosphorylation, tube formation and angiogenesis. NGF (25–200 μg/L) did not affect the expression of TrkA and vascular endothelial growth factor (VEGF), but significantly suppressed the expression of p75NTR. NGF (50 μg/L) markedly increased the proliferation of MSCs.

Conclusion:

NGF promoted proliferation of MSCs and activated the PI3K/Akt signaling pathway, which may be responsible for NGF induction of MSC angiogenesis.     

PI3K/Akt/mTOR通路在炎症相关疾病中分子机制研究进展

炎症是一种机体应对感染、组织损伤或者细胞应激的反应,并且可以通过修复机制恢复组织功能。炎症发生时会引起多条信号通路的激活,包括核转录因子-κB（NF-κB）通路、Janus激酶/信号转导与转录激活子（JAK/STAT）通路、丝裂原活化蛋白激酶（MAPK）通路以及磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白（PI3K/Akt/mTOR）通路等。本文综述了近年来磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白通路在炎症相关疾病中的分子作用机制,为研发以磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白为靶点的药物提供理论依据。