丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路是真核细胞功能高度保守的调节因子,在细胞受到外界刺激引起的炎症反应、应激反应等生理病理过程中起着重要调控作用。P38丝裂原活化蛋白激酶(p38 mitogen-activated...丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路是真核细胞功能高度保守的调节因子,在细胞受到外界刺激引起的炎症反应、应激反应等生理病理过程中起着重要调控作用。P38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38-MAPK)信号通路是MAPK通路的亚族之一,在细胞炎症、组织再生、免疫反应中起着重要的作用。p38-MAPK信号通路的激活在染色质重塑和关键肌生成转录因子的激活中起着关键作用,而肌卫星细胞的激活又影响着骨骼肌的再生修复。本文对p38-MAPK信号通路的调控机制及其介导骨骼肌再生的研究进展进行了综述,以期为深入了解相关机制提供理论依据,并为进一步治疗骨骼肌损伤提供一定的临床参考。展开更多
脓毒性心肌病是脓毒症和脓毒性休克的严重并发症,多种分子机制参与了脓毒症诱导的心肌功能障碍(sepsis-induced myocardial dysfunction,SIMD)。丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号转导途径是体内重要的信...脓毒性心肌病是脓毒症和脓毒性休克的严重并发症,多种分子机制参与了脓毒症诱导的心肌功能障碍(sepsis-induced myocardial dysfunction,SIMD)。丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号转导途径是体内重要的信号转导通路。MAPK家族中的p38-MAPK参与了SIMD分子信号及凋亡机制。探讨p38-MAPK的分子结构,p38-MAPK信号转导通路的特点,以及p38-MAPK在SIMD发病机制中的作用。展开更多
AIM To investigate the role of the complement 5a(C5a)/C5 a receptor(C5a R) pathway in the pathogenesis of acute liver failure(ALF) in a mouse model.METHODS BALB/c mice were randomly assigned to different groups, and i...AIM To investigate the role of the complement 5a(C5a)/C5 a receptor(C5a R) pathway in the pathogenesis of acute liver failure(ALF) in a mouse model.METHODS BALB/c mice were randomly assigned to different groups, and intraperitoneal injections of lipopolysaccharide(LPS)/D-galactosamine(D-Gal N)(600 mg/kg and 10 μg/kg) were used to induce ALF. The KaplanMeier method was used for survival analysis. Serum alanine aminotransferase(ALT) levels, at different time points within a 1-wk period, were detected with a biochemistry analyzer. Pathological examination of liver tissue was performed 36 h after ALF induction. Serum complement 5(C5), C5 a, tumor necrosis factor-α(TNF-α), interleukin(IL)-1β, IL-6, high-mobility group protein B1(HMGB1) and sphingosine-1-phosphatelevels were detected by enzyme-linked immunosorbant assay. Hepatic morphological changes at 36 h after ALF induction were assessed by hematoxylin and eosin staining. Expression of C5 a R, sphingosine kinase 1(Sph K1), p38-MAPK and p-p38-MAPK in liver tissue, peripheral blood mononuclear cells(PBMCs) and peritoneal exudative macrophages(PEMs) of mice or RAW 264.7 cells was analyzed by western blotting. C5 a R m RNA levels were detected by quantitative real-time PCR.RESULTS Activation of C5 and up-regulation of C5 a R were observed in liver tissue and PBMCs of mice with ALF. Blockade of C5 a R with a C5 a R antagonist(C5a Ra C5 a Ra) significantly reduced the levels of serum ALT, inflammatory cytokines(TNF-α, IL-1β and IL-6) and HMGB1, as well as the liver tissue damage, but increased the survival rates(P < 0.01 for all). Blockade of C5 a R decreased Sph K1 expression in both liver tissue and PBMCs significantly at 0.5 h after ALF induction. C5 a Ra pretreatment significantly downregulated the phosphorylation of p38-MAPK in liver tissues of ALF mice and C5 a stimulated PEMs or RAW 264.7 cells. Moreover, inhibition of p38-MAPK activity with SB203580 reduced Sph K1 protein production significantly in PEMs after C5 a stimulation.CONCLUSION The C5a/C5 a R pathway is essential for up-regulating Sph K1 expression through p38 MAPK activation in ALF in mice, which provides a potential immunotherapeutic strategy for ALF in patients.展开更多
Objective To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia(T-ALL) cells and potential molecular mechanisms. Methods The anti-proliferation effect of resverat...Objective To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia(T-ALL) cells and potential molecular mechanisms. Methods The anti-proliferation effect of resveratrol-induced, apoptosis and autophagy on T-ALL cells were detected by using MTT test, immunofluorescence, electronic microscope, and flow cytometry, respectively. Western blotting was performed for detecting changes of apoptosis-associated proteins, cell cycle regulatory proteins and state of activation of Akt, mTOR, p70S6K, 4E-BP1, and p38-MAPK. Results Resveratrol inhibited the proliferation and induced apoptosis and autophagy in T-ALL cells in a dose and time-dependent manner. It also induced cell cycle arrest at G0/G1 phase via up regulating cyclin-dependent kinase(CDK) inhibitors p21 and p27 and down regulating cyclin A and cyclin D1. Western blotting revealed that resveratrol significantly decreased the expression of antiapoptotic proteins(Mcl-1 and Bcl-2) and increased the expression of proapoptotic proteins(Bax, Bim, and Bad), and induced cleaved-caspase-3 in a time-dependent manner. Significant increase in ratio of LC3-II/LC3-I and Beclin 1 was also detected. Furthermore, resveratrol induced significant dephosphorylation of Akt, mTOR, p70S6K, and 4E-BP1, but enhanced specific phosphorylation of p38-MAPK which could be blocked by SB203580. When autophagy was suppressed by 3-MA, apoptosis in T-ALL cells induced by resveratrol was enhanced.Conclusion Our findings have suggested that resveratrol induces cell cycle arrest,apoptosis,and autophagy in T-ALL cells through inhibiting Akt/mTOR/p70S6K/4E-BP1 and activating p38-MAPK signaling pathways.Autophagy might play a role as a self-defense mechanism in T-ALL cells treated by resveratrol.Therefore,the reasonable inhibition of autophagy in T-ALL cells may serve as a promising strategy for resveratrol induced apoptosis and can be used as adjuvant chemotherapy for T-ALL.展开更多
文摘丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路是真核细胞功能高度保守的调节因子,在细胞受到外界刺激引起的炎症反应、应激反应等生理病理过程中起着重要调控作用。P38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38-MAPK)信号通路是MAPK通路的亚族之一,在细胞炎症、组织再生、免疫反应中起着重要的作用。p38-MAPK信号通路的激活在染色质重塑和关键肌生成转录因子的激活中起着关键作用,而肌卫星细胞的激活又影响着骨骼肌的再生修复。本文对p38-MAPK信号通路的调控机制及其介导骨骼肌再生的研究进展进行了综述,以期为深入了解相关机制提供理论依据,并为进一步治疗骨骼肌损伤提供一定的临床参考。
文摘脓毒性心肌病是脓毒症和脓毒性休克的严重并发症,多种分子机制参与了脓毒症诱导的心肌功能障碍(sepsis-induced myocardial dysfunction,SIMD)。丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号转导途径是体内重要的信号转导通路。MAPK家族中的p38-MAPK参与了SIMD分子信号及凋亡机制。探讨p38-MAPK的分子结构,p38-MAPK信号转导通路的特点,以及p38-MAPK在SIMD发病机制中的作用。
基金Supported by the National Natural Science Foundation of China,No.81260455 and No.81160065
文摘AIM To investigate the role of the complement 5a(C5a)/C5 a receptor(C5a R) pathway in the pathogenesis of acute liver failure(ALF) in a mouse model.METHODS BALB/c mice were randomly assigned to different groups, and intraperitoneal injections of lipopolysaccharide(LPS)/D-galactosamine(D-Gal N)(600 mg/kg and 10 μg/kg) were used to induce ALF. The KaplanMeier method was used for survival analysis. Serum alanine aminotransferase(ALT) levels, at different time points within a 1-wk period, were detected with a biochemistry analyzer. Pathological examination of liver tissue was performed 36 h after ALF induction. Serum complement 5(C5), C5 a, tumor necrosis factor-α(TNF-α), interleukin(IL)-1β, IL-6, high-mobility group protein B1(HMGB1) and sphingosine-1-phosphatelevels were detected by enzyme-linked immunosorbant assay. Hepatic morphological changes at 36 h after ALF induction were assessed by hematoxylin and eosin staining. Expression of C5 a R, sphingosine kinase 1(Sph K1), p38-MAPK and p-p38-MAPK in liver tissue, peripheral blood mononuclear cells(PBMCs) and peritoneal exudative macrophages(PEMs) of mice or RAW 264.7 cells was analyzed by western blotting. C5 a R m RNA levels were detected by quantitative real-time PCR.RESULTS Activation of C5 and up-regulation of C5 a R were observed in liver tissue and PBMCs of mice with ALF. Blockade of C5 a R with a C5 a R antagonist(C5a Ra C5 a Ra) significantly reduced the levels of serum ALT, inflammatory cytokines(TNF-α, IL-1β and IL-6) and HMGB1, as well as the liver tissue damage, but increased the survival rates(P < 0.01 for all). Blockade of C5 a R decreased Sph K1 expression in both liver tissue and PBMCs significantly at 0.5 h after ALF induction. C5 a Ra pretreatment significantly downregulated the phosphorylation of p38-MAPK in liver tissues of ALF mice and C5 a stimulated PEMs or RAW 264.7 cells. Moreover, inhibition of p38-MAPK activity with SB203580 reduced Sph K1 protein production significantly in PEMs after C5 a stimulation.CONCLUSION The C5a/C5 a R pathway is essential for up-regulating Sph K1 expression through p38 MAPK activation in ALF in mice, which provides a potential immunotherapeutic strategy for ALF in patients.
基金supported by grants from the Department of Science and Technology of Sichuan Province,China (No.2008JY0029-1 and No.07FG002-024)research funds from the Program for Changjiang Scholars and Innovative-Research Team in University (No.IRT0935)
文摘Objective To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia(T-ALL) cells and potential molecular mechanisms. Methods The anti-proliferation effect of resveratrol-induced, apoptosis and autophagy on T-ALL cells were detected by using MTT test, immunofluorescence, electronic microscope, and flow cytometry, respectively. Western blotting was performed for detecting changes of apoptosis-associated proteins, cell cycle regulatory proteins and state of activation of Akt, mTOR, p70S6K, 4E-BP1, and p38-MAPK. Results Resveratrol inhibited the proliferation and induced apoptosis and autophagy in T-ALL cells in a dose and time-dependent manner. It also induced cell cycle arrest at G0/G1 phase via up regulating cyclin-dependent kinase(CDK) inhibitors p21 and p27 and down regulating cyclin A and cyclin D1. Western blotting revealed that resveratrol significantly decreased the expression of antiapoptotic proteins(Mcl-1 and Bcl-2) and increased the expression of proapoptotic proteins(Bax, Bim, and Bad), and induced cleaved-caspase-3 in a time-dependent manner. Significant increase in ratio of LC3-II/LC3-I and Beclin 1 was also detected. Furthermore, resveratrol induced significant dephosphorylation of Akt, mTOR, p70S6K, and 4E-BP1, but enhanced specific phosphorylation of p38-MAPK which could be blocked by SB203580. When autophagy was suppressed by 3-MA, apoptosis in T-ALL cells induced by resveratrol was enhanced.Conclusion Our findings have suggested that resveratrol induces cell cycle arrest,apoptosis,and autophagy in T-ALL cells through inhibiting Akt/mTOR/p70S6K/4E-BP1 and activating p38-MAPK signaling pathways.Autophagy might play a role as a self-defense mechanism in T-ALL cells treated by resveratrol.Therefore,the reasonable inhibition of autophagy in T-ALL cells may serve as a promising strategy for resveratrol induced apoptosis and can be used as adjuvant chemotherapy for T-ALL.
