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
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 resve...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 MTI- 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 dose and time-dependent manner. It also induced cyclin-dependent kinase （CDK） inhibitors p21 and induced apoptosis and autophagy in T-ALL cells in a cell cycle arrest at G0/G1 phase via up regulating 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 LC3-11/LC3-1 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/p7OS6K/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
Electroacupuncture attenuates cerebral hypoxia and neuronal apoptosis induced by cerebral ischemia/reperfusion injury.To further identify the involved mechanisms,we assumed that electroacupuncture used to treat cerebr...Electroacupuncture attenuates cerebral hypoxia and neuronal apoptosis induced by cerebral ischemia/reperfusion injury.To further identify the involved mechanisms,we assumed that electroacupuncture used to treat cerebral ischemia/reperfusion injury was associated with the p38 mitogen-activated protein kinase（MAPK） signaling pathway.We established rat models of cerebral ischemia/reperfusion injury using the modified Zea-Longa＇s method.At 30 minutes before model establishment,p38 MAPK blocker SB20358 was injected into the left lateral ventricles.At 1.5 hours after model establishment,electroacupuncture was administered at acupoints of Chize（LU5）,Hegu（LI4）,Zusanli（ST36）,and Sanyinjiao（SP6） for 20 minutes in the affected side.Results showed that the combination of EA and SB20358 injection significantly decreased neurologic impairment scores,but no significant differences were determined among different interventional groups.Hematoxylin-eosin staining also showed reduced brain tissue injuries.Compared with the SB20358 group,the cells were regularly arranged,the structures were complete,and the number of viable neurons was higher in the SB20358 ＋ electroacupuncture group.Terminal deoxynucleotidyl transferase（Td T）-mediated d UTP nick-end labeling assay showed a decreased apoptotic index in each group,with a significant decrease in the SB20358 ＋ electroacupuncture group.Immunohistochemistry revealed reduced phosphorylated p38 expression at 3 days in the electroacupuncture group and SB20358 ＋ electroacupuncture group compared with the ischemia/reperfusion group.There was no significant difference in phosphorylated p38 expression between the ischemia/reperfusion group and SB20358 group.These findings confirmed that the electroacupuncture effects on mitigating cerebral ischemia/reperfusion injury are possibly associated with the p38 MAPK signaling pathway.A time period of 3 days could promote the repair of ischemic cerebral nerves.展开更多
Mitogen-activated protein kinases(MAPKs)are a family of proteins that constitute signaling pathways involved in processes that control gene expression,cell division, cell survival,apoptosis,metabolism,differentiation ...Mitogen-activated protein kinases(MAPKs)are a family of proteins that constitute signaling pathways involved in processes that control gene expression,cell division, cell survival,apoptosis,metabolism,differentiation and motility.The MAPK pathways can be divided into conventional and atypical MAPK pathways.The first group converts a signal into a cellular response through a relay of three consecutive phosphorylation events exerted by MAPK kinase kinases,MAPK kinase,and MAPK.Atypical MAPK pathways are not organized into this three-tiered cascade.MAPK that belongs to both conventional and atypical MAPK pathways can phosphorylate both non-protein kinase substrates and other protein kinases.The latter are referred to as MAPK-activated protein kinases.This review focuses on one such MAPK-activated protein kinase,MAPK-activated protein kinase 5(MK5)or p38-regulated/activated protein kinase(PRAK).This protein is highly conserved throughout the animal kingdom and seems to be the target of both conventional and atypical MAPK pathways.Recent findings on the regulation of the activity and subcellular localization,bona fide interaction partners and physiological roles of MK5/PRAK are discussed.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
Rutin has anti-inflammatory, antioxidant, anti-viral, anti-tumor and immune regulatory effects. However, the neuroprotective effects of rutin in spinal cord injury are unknown. The p38 mitogen activated protein kinase...Rutin has anti-inflammatory, antioxidant, anti-viral, anti-tumor and immune regulatory effects. However, the neuroprotective effects of rutin in spinal cord injury are unknown. The p38 mitogen activated protein kinase （p38 MAPK） pathway is the most important member of the MAPK family that controls inflammation. We assumed that the mechanism of rutin in the repair of spinal cord injury is associated with the inhibition of p38 MAPK pathway. Allen’s method was used to establish a rat model of spinal cord injury. The rat model was intraperitoneally injected with rutin （30 mg/kg） for 3 days. After treatment with rutin, Basso, Beattie and Bresnahan locomotor function scores increased. Water content, tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 levels, p38 MAPK protein expression and caspase-3 and -9 activities in T8–9 spinal cord decreased. Oxidative stress related markers superoxide dismutase and glutathione peroxidase levels increased in peripheral blood. Rutin exerts neuroprotective effect through anti-oxidation, anti-inflammation, anti-apoptosis and inhibition of p38 MAPK pathway.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。
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 MTI- 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 dose and time-dependent manner. It also induced cyclin-dependent kinase （CDK） inhibitors p21 and induced apoptosis and autophagy in T-ALL cells in a cell cycle arrest at G0/G1 phase via up regulating 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 LC3-11/LC3-1 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/p7OS6K/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.
基金supported by the National Natural Science Foundation of China,No.81173355
文摘Electroacupuncture attenuates cerebral hypoxia and neuronal apoptosis induced by cerebral ischemia/reperfusion injury.To further identify the involved mechanisms,we assumed that electroacupuncture used to treat cerebral ischemia/reperfusion injury was associated with the p38 mitogen-activated protein kinase（MAPK） signaling pathway.We established rat models of cerebral ischemia/reperfusion injury using the modified Zea-Longa＇s method.At 30 minutes before model establishment,p38 MAPK blocker SB20358 was injected into the left lateral ventricles.At 1.5 hours after model establishment,electroacupuncture was administered at acupoints of Chize（LU5）,Hegu（LI4）,Zusanli（ST36）,and Sanyinjiao（SP6） for 20 minutes in the affected side.Results showed that the combination of EA and SB20358 injection significantly decreased neurologic impairment scores,but no significant differences were determined among different interventional groups.Hematoxylin-eosin staining also showed reduced brain tissue injuries.Compared with the SB20358 group,the cells were regularly arranged,the structures were complete,and the number of viable neurons was higher in the SB20358 ＋ electroacupuncture group.Terminal deoxynucleotidyl transferase（Td T）-mediated d UTP nick-end labeling assay showed a decreased apoptotic index in each group,with a significant decrease in the SB20358 ＋ electroacupuncture group.Immunohistochemistry revealed reduced phosphorylated p38 expression at 3 days in the electroacupuncture group and SB20358 ＋ electroacupuncture group compared with the ischemia/reperfusion group.There was no significant difference in phosphorylated p38 expression between the ischemia/reperfusion group and SB20358 group.These findings confirmed that the electroacupuncture effects on mitigating cerebral ischemia/reperfusion injury are possibly associated with the p38 MAPK signaling pathway.A time period of 3 days could promote the repair of ischemic cerebral nerves.
文摘Mitogen-activated protein kinases(MAPKs)are a family of proteins that constitute signaling pathways involved in processes that control gene expression,cell division, cell survival,apoptosis,metabolism,differentiation and motility.The MAPK pathways can be divided into conventional and atypical MAPK pathways.The first group converts a signal into a cellular response through a relay of three consecutive phosphorylation events exerted by MAPK kinase kinases,MAPK kinase,and MAPK.Atypical MAPK pathways are not organized into this three-tiered cascade.MAPK that belongs to both conventional and atypical MAPK pathways can phosphorylate both non-protein kinase substrates and other protein kinases.The latter are referred to as MAPK-activated protein kinases.This review focuses on one such MAPK-activated protein kinase,MAPK-activated protein kinase 5(MK5)or p38-regulated/activated protein kinase(PRAK).This protein is highly conserved throughout the animal kingdom and seems to be the target of both conventional and atypical MAPK pathways.Recent findings on the regulation of the activity and subcellular localization,bona fide interaction partners and physiological roles of MK5/PRAK are discussed.
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 in part by grants from the Young Scientists Awards Foundation of Shandong Province of China,No.BS2013YY049the China Postdoctoral Science Foundation,No.2012M511036
文摘Rutin has anti-inflammatory, antioxidant, anti-viral, anti-tumor and immune regulatory effects. However, the neuroprotective effects of rutin in spinal cord injury are unknown. The p38 mitogen activated protein kinase （p38 MAPK） pathway is the most important member of the MAPK family that controls inflammation. We assumed that the mechanism of rutin in the repair of spinal cord injury is associated with the inhibition of p38 MAPK pathway. Allen’s method was used to establish a rat model of spinal cord injury. The rat model was intraperitoneally injected with rutin （30 mg/kg） for 3 days. After treatment with rutin, Basso, Beattie and Bresnahan locomotor function scores increased. Water content, tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 levels, p38 MAPK protein expression and caspase-3 and -9 activities in T8–9 spinal cord decreased. Oxidative stress related markers superoxide dismutase and glutathione peroxidase levels increased in peripheral blood. Rutin exerts neuroprotective effect through anti-oxidation, anti-inflammation, anti-apoptosis and inhibition of p38 MAPK pathway.
