目的:观察通心脉方对大鼠离体心脏缺血再灌AKt及p38αMAPK(p38 a mitogen-activated protein kinase,MAPK)蛋白表达的影响,初步探讨通心脉方对心肌缺血再灌注损伤及细胞凋亡的作用机制。方法:采用Langendorff离体心脏灌流方法模拟缺血...目的:观察通心脉方对大鼠离体心脏缺血再灌AKt及p38αMAPK(p38 a mitogen-activated protein kinase,MAPK)蛋白表达的影响,初步探讨通心脉方对心肌缺血再灌注损伤及细胞凋亡的作用机制。方法:采用Langendorff离体心脏灌流方法模拟缺血再灌注模型;分光光度法观察心肌组织中超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、丙二醛(MDA)、caspase-8及caspase-3含量的变化,酶联免疫(ELISA)法观察心肌组织中肿瘤坏死因子-α(TNF-α)含量的变化,免疫印迹(Western blot)法检测心肌组织p-p38αMAPK(phosphoryl-ated p38αmitogen activated protein kinase)、p38αMAPK、p-AKt(phosphorylated AKt)及AKt蛋白表达的变化。结果:与缺血再灌注组对比,正常灌流组、通心脉方大、中剂量组及卡维地洛组MDA、TNF-α、caspase-8及caspase-3含量显著降低,差别有统计学意义(P<0.01或P<0.05),SOD及CAT含量显著升高,差别有统计学意义(P<0.05或P<0.01);p38αMAPK及AKt在各组表达相对恒定,与缺血再灌注组相比,差别无统计学意义(P>0.05),p-p38αMAPK在与缺血再灌注组明显激活,在通心脉方大、中剂量组及卡维地洛组表达明显降低,差别有统计学意义(P<0.01);p-AKt在与缺血再灌注组激活,而在通心脉方大、中剂量组及卡维地洛组表达进一步增加(P<0.05)。结论:通心脉方能保护心肌缺血再灌注损伤和细胞凋亡,其作用机制可能与通过抑制脂质过氧化,下调p-p38αMAPK表达,减少TNF-α的形成,进而抑制caspase-8及caspase-3活性以及激活细胞增殖信号AKt有关。展开更多
丝裂原活化蛋白激酶(mitogen-activated protein kinases,MAPK)是真核生物长期进化过程中高度保守的丝氨酸/苏氨酸蛋白激酶,MAPK在许多生物中发挥着重要作用,包括细胞生长、分化、凋亡、炎症反应、细胞骨架重排及应激刺激等。P38MAPK是...丝裂原活化蛋白激酶(mitogen-activated protein kinases,MAPK)是真核生物长期进化过程中高度保守的丝氨酸/苏氨酸蛋白激酶,MAPK在许多生物中发挥着重要作用,包括细胞生长、分化、凋亡、炎症反应、细胞骨架重排及应激刺激等。P38MAPK是其中重要的一个亚家族,其中P38α是P38MAPK中最重要的亚型,在雌性生殖系统中有着重要的作用。卵巢在受到体内激素或者外界因素等信号刺激时,通过激活P38αMAPK信号通路,表达各种细胞调控因子以调控颗粒细胞活动及卵母细胞减数分裂,进而影响生殖细胞的生长发育。激活颗粒细胞中P38αMAPK信号通路可以调控激素分泌及相关细胞因子的释放,从而有助于卵母细胞的成熟;P38αMAPK可能参与了卵母细胞的减数分裂过程,下调P38α的表达,可能导致成熟卵母细胞数目减少或者非整倍体卵母细胞的产生。展开更多
Colorectal cancer(CRC)remains one of the most common malignancies in the world.Although surgical resection combined with adjuvant therapy is effective at the early stages of the disease,resistance to conventional ther...Colorectal cancer(CRC)remains one of the most common malignancies in the world.Although surgical resection combined with adjuvant therapy is effective at the early stages of the disease,resistance to conventional therapies is frequently observed in advanced stages,where treatments become ineffective.Resistance to cisplatin,irinotecan and 5-fluorouracil chemotherapy has been shown to involve mitogen-activated protein kinase(MAPK)signaling and recent studies identified p38αMAPK as a mediator of resistance to various agents in CRC patients.Studies published in the last decade showed a dual role for the p38αpathway in mammals.Its role as a negative regulator of proliferation has been reported in both normal(including cardiomyocytes,hepatocytes,fibroblasts,hematopoietic and lung cells)and cancer cells(colon,prostate,breast,lung tumor cells).This function is mediated by the negative regulation of cell cycle progression and the transduction of some apoptotic stimuli.However,despite its anti-proliferative and tumor suppressor activity in some tissues,the p38αpathway may also acquire an oncogenic role involving cancer related-processes such as cell metabolism,invasion,inflammation and angiogenesis.In this review,we summarize current knowledge about the predominant role of the p38αMAPK pathway in CRC development and chemoresistance.In our view,this might help establish the therapeutic potential of the targeted manipulation of this pathway in clinical settings.展开更多
文摘目的:观察通心脉方对大鼠离体心脏缺血再灌AKt及p38αMAPK(p38 a mitogen-activated protein kinase,MAPK)蛋白表达的影响,初步探讨通心脉方对心肌缺血再灌注损伤及细胞凋亡的作用机制。方法:采用Langendorff离体心脏灌流方法模拟缺血再灌注模型;分光光度法观察心肌组织中超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、丙二醛(MDA)、caspase-8及caspase-3含量的变化,酶联免疫(ELISA)法观察心肌组织中肿瘤坏死因子-α(TNF-α)含量的变化,免疫印迹(Western blot)法检测心肌组织p-p38αMAPK(phosphoryl-ated p38αmitogen activated protein kinase)、p38αMAPK、p-AKt(phosphorylated AKt)及AKt蛋白表达的变化。结果:与缺血再灌注组对比,正常灌流组、通心脉方大、中剂量组及卡维地洛组MDA、TNF-α、caspase-8及caspase-3含量显著降低,差别有统计学意义(P<0.01或P<0.05),SOD及CAT含量显著升高,差别有统计学意义(P<0.05或P<0.01);p38αMAPK及AKt在各组表达相对恒定,与缺血再灌注组相比,差别无统计学意义(P>0.05),p-p38αMAPK在与缺血再灌注组明显激活,在通心脉方大、中剂量组及卡维地洛组表达明显降低,差别有统计学意义(P<0.01);p-AKt在与缺血再灌注组激活,而在通心脉方大、中剂量组及卡维地洛组表达进一步增加(P<0.05)。结论:通心脉方能保护心肌缺血再灌注损伤和细胞凋亡,其作用机制可能与通过抑制脂质过氧化,下调p-p38αMAPK表达,减少TNF-α的形成,进而抑制caspase-8及caspase-3活性以及激活细胞增殖信号AKt有关。
文摘目的:探讨p38α蛋白在脑缺血后2 h降低的原因以及p38α蛋白水平表达是否受调于microRNA-128。方法:首先通过qPCR和Western blotting来检测p38αmRNA和蛋白的表达水平,其次通过生物信息学软件预测出p38α的表达可能受调于microRNA-128,最后进行细胞水平验证,使用携带有microRNA-128序列质粒的慢病毒载体、携带有microRNA-128反义序列质粒的慢病毒载体以及相应空质粒的慢病毒载体转染SH-SY5Y细胞,观察p38α蛋白的表达情况。结果:小鼠脑缺血后2 h p38αmRNA水平无降低,但其蛋白水平却明显下降,microRNA-128的表达水平明显升高;转染实验发现,转染microRNA-128序列质粒的慢病毒载体的细胞p38α蛋白水平明显降低,转染microRNA-128反义序列质粒的慢病毒载体的细胞p38α蛋白水平明显升高。结论:脑缺血后p38α蛋白的表达水平下降并不是因为p38αmRNA水平的降低,microRNA-128可以调控p38α蛋白的表达,可能是通过结合p38α的mRNA从而抑制其蛋白的翻译表达。
文摘丝裂原活化蛋白激酶(mitogen-activated protein kinases,MAPK)是真核生物长期进化过程中高度保守的丝氨酸/苏氨酸蛋白激酶,MAPK在许多生物中发挥着重要作用,包括细胞生长、分化、凋亡、炎症反应、细胞骨架重排及应激刺激等。P38MAPK是其中重要的一个亚家族,其中P38α是P38MAPK中最重要的亚型,在雌性生殖系统中有着重要的作用。卵巢在受到体内激素或者外界因素等信号刺激时,通过激活P38αMAPK信号通路,表达各种细胞调控因子以调控颗粒细胞活动及卵母细胞减数分裂,进而影响生殖细胞的生长发育。激活颗粒细胞中P38αMAPK信号通路可以调控激素分泌及相关细胞因子的释放,从而有助于卵母细胞的成熟;P38αMAPK可能参与了卵母细胞的减数分裂过程,下调P38α的表达,可能导致成熟卵母细胞数目减少或者非整倍体卵母细胞的产生。
基金Supported by Italian Association for Cancer Research(AIRC)fellowship(to Grossi V)Italian Foundation for Cancer Research(FIRC)fellowships(to Peserico A and Tezil T)+1 种基金Investigator Grant 2010 No.IG10177 to Simone C from the Italian Association for Cancer Research(AIRC)FIRB"Futuro in Ricerca"RBFR12VP3Q_003(to Simone C)from the Italian MIUR
文摘Colorectal cancer(CRC)remains one of the most common malignancies in the world.Although surgical resection combined with adjuvant therapy is effective at the early stages of the disease,resistance to conventional therapies is frequently observed in advanced stages,where treatments become ineffective.Resistance to cisplatin,irinotecan and 5-fluorouracil chemotherapy has been shown to involve mitogen-activated protein kinase(MAPK)signaling and recent studies identified p38αMAPK as a mediator of resistance to various agents in CRC patients.Studies published in the last decade showed a dual role for the p38αpathway in mammals.Its role as a negative regulator of proliferation has been reported in both normal(including cardiomyocytes,hepatocytes,fibroblasts,hematopoietic and lung cells)and cancer cells(colon,prostate,breast,lung tumor cells).This function is mediated by the negative regulation of cell cycle progression and the transduction of some apoptotic stimuli.However,despite its anti-proliferative and tumor suppressor activity in some tissues,the p38αpathway may also acquire an oncogenic role involving cancer related-processes such as cell metabolism,invasion,inflammation and angiogenesis.In this review,we summarize current knowledge about the predominant role of the p38αMAPK pathway in CRC development and chemoresistance.In our view,this might help establish the therapeutic potential of the targeted manipulation of this pathway in clinical settings.
