The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs ...The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression.展开更多
AIM: To identify kinases involved in phenotype regulation of vascular endothelial cells(VECs): Proproliferative G-protein signaling 5(RGS5)^(high)(typeⅠ) vs anti-proliferative RGS5^(low)(typeⅡ) VECs.METHODS: Proteom...AIM: To identify kinases involved in phenotype regulation of vascular endothelial cells(VECs): Proproliferative G-protein signaling 5(RGS5)^(high)(typeⅠ) vs anti-proliferative RGS5^(low)(typeⅡ) VECs.METHODS: Proteomic kinase assays were performed to identify the crucial kinase involved in the phenotype regulation of human VECs using typeⅠ VECs, which promotes the proliferation of human vascular smooth muscle cells(VSMCs), and typeⅡ VECs, which suppress the proliferation of human VSMCs. The assays were performed using multiple pairs of typeⅠ and typeⅡ VECs to obtain the least number of candidates. The involvement of the candidate kinases was verified by evaluating the effects of their specific inhibitors on the phenotype regulation of human VECs as well as the expression levels of regulator of RGS5, which is the causative gene for the "typeⅡ to typeⅠ" phenotype conversion of human VECs. RESULTS: p38α mitogen-activated protein kinase(p38α MAPK) was the only kinase that showed distinctive activities between typeⅠ and typeⅡ VECs: p38α MAPK activities were low and high in type-Ⅰand typeⅡ VECs, respectively. We found that an enforced expression of RGS5 indeed lowered p38α MAPK activitiesin typeⅡ VECs. Furthermore, treatments with a p38α MAPK inhibitor nullified the anti-proliferative potential in typeⅡ VECs. Interestingly, MAPK inhibitor treatments enhanced the induction of RGS5 gene. Thus, there is a vicious cycle between "RGS5 induction" and "p38α MAPK inhibition", which can explain the unidirectional process in the stress-induced "typeⅡ to typeⅠ" conversions of human VECs. To understand the upstream signaling of RGS5, which is known as an inhibitory molecule against the G protein-coupled receptor(GPCR)-mediated signaling, we examined the effects of RGS5 overexpression on the signaling events from sphingosine-1-phosphate(S1P) to N-cadherin, because S1 P receptors belong to the GPCR family gene and N-cadherin, one of their downstream effectors, is reportedly involved in the regulation of VEC-VSMC interactions. We found that RGS5 specifically bound with S1P1. Moreover, N-cadherin localization at intercellular junctions in typeⅡ VECs was abolished by "RGS5 overexpression" and "p38α MAPK inhibition".CONCLUSION: p38α MAPK plays crucial roles in "type-Ⅰ vs type-Ⅱ" phenotype regulations of human VECs at the downstream of RGS5.展开更多
Objective： To explore the role that ceramide plays in the activation of mitogen-activated protein kinases （MAPKs） during cerebral ischemia and reperfusion. Methods： Rats were subjected to ischemia by the fourvesse...Objective： To explore the role that ceramide plays in the activation of mitogen-activated protein kinases （MAPKs） during cerebral ischemia and reperfusion. Methods： Rats were subjected to ischemia by the fourvessel occlusion （4-VO） method. The sphingomyelinase inhibitor TPCK was administered to the CA1 subregion of the rat hippocampus before inducing ischemia. Western blot was used to examine the activity of extracellular- signal regulated kinase （ERK） and c-Jun N-terminal protein kinase （JNK） using antibodies against ERK, JNK and diphosphorylated ERK and JNK. Results： At lh reperfusion post-ischemia, JNK reached its peak activity while ERK was undergoing a sharp inactivation （P 〈 0.05）. The level of diphosphorylated JNK was significantly reduced but the sharp inactivation of ERK was visibly reversed （P 〈 0.05） by the sphingomyelinase inhibitor. Conclusion： The ceramide signaling pathway is up-regulated through sphingomyelin hydrolysis in brain ischemia, promoting JNK activation and suppressing ERK activation, culminating in the ischemic lesion.展开更多
Objective: This study was designed to explore whether inhibition of the extracellular-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K) signaling pathways can inhibit the growth of xenografts of endometr...Objective: This study was designed to explore whether inhibition of the extracellular-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K) signaling pathways can inhibit the growth of xenografts of endometrial cancer cell lines with different estrogen receptors (ER) profiles in vivo and to provide preliminary laboratory basis for the probability of endometrial adenocarcinoma treatment with blockage of the two pathways, especially to endometrial cancer with low ER status. Methods: Human endometrial cancer Ishikawa bearing ER and HEC-1Awith low ER status cells were subcutaneously injected into BALB/c nude mice to establish endometrial cancer xenograft tumor models. The effects of PI3K/Akt inhibitor LY294002, MAPK/ERK1/2 inhibitor PD-98059 and their combinations on the growth of the xenograft tumors and apoptotic state of Ishikawa and HEC-1Acells were tested in vivo using the inhibitory rate, the terminal deoxynucleotidyl transferase-mediated nick-end labeling assay, H/E-stain. Western blot analysis was used to detect the alterations of activated ERK (P-ERK) and AKT (P-AKT) during this process. Results: LY294002, a PI3K/Akt pathway inhibitor, induced significant suppression in the growth of both Ishikawa and HEC-1Acell xenograft tumors, concomitant with increased apoptosis in xenografts as evidenced by TUNEL. A similar effect was also observed when the MAPK/ERK1/2 signaling pathway was inhibited by PD98059. Concurrent inhibition of the PI3K/Akt and MAPK/ERK1/2 pathways showed enhanced anti-tumor effects in vivo as indicated by increased apoptosis. At the same time, the levels of P-ERK and P-AKT in both xenograft tumors decreased, and their levels in combination group was the lowest. Conclusions: PD98059, LY294002 and their combinations showed remarkable inhibitory effects on xenograft tumors of endometrial carcinoma cell lines with different expression status of ER in vivo through blockage of PI3K/Akt and MAPK/ERK1/2 signaling pathways. This suggests that targeting these pathways may be an effective therapeutic strategy against endometrial carcinomas, especially for ER-negative cancers which show poor response to endocrinal therapy.展开更多
目的:探讨染料木黄酮(Genistein,Gen)与5氟尿嘧啶(5-fluorouracil,5-FU)诱导人肝癌M H C C97-L细胞周期阻滞与细胞外调节蛋白激酶(extracellular regulated protein kinasesERK)1/2信号通路的关系.方法:MTS法检测细胞增殖;流式细胞术检...目的:探讨染料木黄酮(Genistein,Gen)与5氟尿嘧啶(5-fluorouracil,5-FU)诱导人肝癌M H C C97-L细胞周期阻滞与细胞外调节蛋白激酶(extracellular regulated protein kinasesERK)1/2信号通路的关系.方法:MTS法检测细胞增殖;流式细胞术检测细胞周期;Western blot检测总ERK1/2和磷酸化ERK1/2蛋白表达.结果:Gen与5-FU单用及联用均能抑制肝癌MHCC97-L细胞增殖;Gen诱导细胞S期阻滞少量抑制ERK1/2磷酸化,ERK1/2抑制剂可促进Gen对MHCC97-L细胞的生长抑制作用,而对S期阻滞无明显影响;5-FU单用和二者联用组均阻滞S期细胞,并显著激活ERK1/2磷酸化ERK1/2抑制剂可促进两组药物对MHCC97-L细胞的生长抑制和诱导S期阻滞作用.结论:Gen与5-FU单用及联用均可通过阻滞细胞周期来发挥抗肝癌细胞增殖的作用;抑制ERK1/2通路可抵抗Gen诱导的肝癌细胞S期阻滞,而促进5-FU单用和二者联用组诱导肝癌细胞S期阻滞.展开更多
Extracellular signal-regulated protein kinase 5 （ERK5）, also known as big mitogen-activated protein kinase 1 （MAPK1）, is an important member of ERK family, which is a subfamily of the large MAPK family. ERK5 is ex...Extracellular signal-regulated protein kinase 5 （ERK5）, also known as big mitogen-activated protein kinase 1 （MAPK1）, is an important member of ERK family, which is a subfamily of the large MAPK family. ERK5 is expressed in many tissues, including the dorsal root ganglion （DRG） neurons and the spinal cord. In this review, we focus on elaborating ERK5-associated pathway in pathological pain, in which the ERK5/CREB （cyclic adenosine monophos- phate （cAMP）-response element-binding protein） pathway plays a crucial role in the transduction of pain signal and contributes to pain hypersensitivity. ERK5 activation in the spinal dorsal horn occurs mainly in microglia. The activation of ERK5 can be mediated by N-methyI-D-aspartate （NMDA） receptors. We also elaborate the relationship between ERK5 activation and nerve growth factor-tyrosine kinase A （NGF-TrkA）, and the connection between ERK5 activation and brain-derived neurotrophic factor （BDNF） in pathological pain in detail.展开更多
基金supported by the National Natural Science Foundation of China,No.81202620the Domestic Visiting Scholar Program for Young Talent Teachers in University of Shandong Province
文摘The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression.
基金Supported by A Grant-in-Aid from the Ministry of HealthLabour and Welfare of Japan+2 种基金No.KHD1017by that from JSTPRESTO
文摘AIM: To identify kinases involved in phenotype regulation of vascular endothelial cells(VECs): Proproliferative G-protein signaling 5(RGS5)^(high)(typeⅠ) vs anti-proliferative RGS5^(low)(typeⅡ) VECs.METHODS: Proteomic kinase assays were performed to identify the crucial kinase involved in the phenotype regulation of human VECs using typeⅠ VECs, which promotes the proliferation of human vascular smooth muscle cells(VSMCs), and typeⅡ VECs, which suppress the proliferation of human VSMCs. The assays were performed using multiple pairs of typeⅠ and typeⅡ VECs to obtain the least number of candidates. The involvement of the candidate kinases was verified by evaluating the effects of their specific inhibitors on the phenotype regulation of human VECs as well as the expression levels of regulator of RGS5, which is the causative gene for the "typeⅡ to typeⅠ" phenotype conversion of human VECs. RESULTS: p38α mitogen-activated protein kinase(p38α MAPK) was the only kinase that showed distinctive activities between typeⅠ and typeⅡ VECs: p38α MAPK activities were low and high in type-Ⅰand typeⅡ VECs, respectively. We found that an enforced expression of RGS5 indeed lowered p38α MAPK activitiesin typeⅡ VECs. Furthermore, treatments with a p38α MAPK inhibitor nullified the anti-proliferative potential in typeⅡ VECs. Interestingly, MAPK inhibitor treatments enhanced the induction of RGS5 gene. Thus, there is a vicious cycle between "RGS5 induction" and "p38α MAPK inhibition", which can explain the unidirectional process in the stress-induced "typeⅡ to typeⅠ" conversions of human VECs. To understand the upstream signaling of RGS5, which is known as an inhibitory molecule against the G protein-coupled receptor(GPCR)-mediated signaling, we examined the effects of RGS5 overexpression on the signaling events from sphingosine-1-phosphate(S1P) to N-cadherin, because S1 P receptors belong to the GPCR family gene and N-cadherin, one of their downstream effectors, is reportedly involved in the regulation of VEC-VSMC interactions. We found that RGS5 specifically bound with S1P1. Moreover, N-cadherin localization at intercellular junctions in typeⅡ VECs was abolished by "RGS5 overexpression" and "p38α MAPK inhibition".CONCLUSION: p38α MAPK plays crucial roles in "type-Ⅰ vs type-Ⅱ" phenotype regulations of human VECs at the downstream of RGS5.
基金supported by grants from the National Natural Science Foundation of China (No.30871200)the Practice and Innovation Training Program for Students in Colleges and Universities of Jiangsu Province (NO.20090370)
文摘Objective： To explore the role that ceramide plays in the activation of mitogen-activated protein kinases （MAPKs） during cerebral ischemia and reperfusion. Methods： Rats were subjected to ischemia by the fourvessel occlusion （4-VO） method. The sphingomyelinase inhibitor TPCK was administered to the CA1 subregion of the rat hippocampus before inducing ischemia. Western blot was used to examine the activity of extracellular- signal regulated kinase （ERK） and c-Jun N-terminal protein kinase （JNK） using antibodies against ERK, JNK and diphosphorylated ERK and JNK. Results： At lh reperfusion post-ischemia, JNK reached its peak activity while ERK was undergoing a sharp inactivation （P 〈 0.05）. The level of diphosphorylated JNK was significantly reduced but the sharp inactivation of ERK was visibly reversed （P 〈 0.05） by the sphingomyelinase inhibitor. Conclusion： The ceramide signaling pathway is up-regulated through sphingomyelin hydrolysis in brain ischemia, promoting JNK activation and suppressing ERK activation, culminating in the ischemic lesion.
文摘Objective: This study was designed to explore whether inhibition of the extracellular-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K) signaling pathways can inhibit the growth of xenografts of endometrial cancer cell lines with different estrogen receptors (ER) profiles in vivo and to provide preliminary laboratory basis for the probability of endometrial adenocarcinoma treatment with blockage of the two pathways, especially to endometrial cancer with low ER status. Methods: Human endometrial cancer Ishikawa bearing ER and HEC-1Awith low ER status cells were subcutaneously injected into BALB/c nude mice to establish endometrial cancer xenograft tumor models. The effects of PI3K/Akt inhibitor LY294002, MAPK/ERK1/2 inhibitor PD-98059 and their combinations on the growth of the xenograft tumors and apoptotic state of Ishikawa and HEC-1Acells were tested in vivo using the inhibitory rate, the terminal deoxynucleotidyl transferase-mediated nick-end labeling assay, H/E-stain. Western blot analysis was used to detect the alterations of activated ERK (P-ERK) and AKT (P-AKT) during this process. Results: LY294002, a PI3K/Akt pathway inhibitor, induced significant suppression in the growth of both Ishikawa and HEC-1Acell xenograft tumors, concomitant with increased apoptosis in xenografts as evidenced by TUNEL. A similar effect was also observed when the MAPK/ERK1/2 signaling pathway was inhibited by PD98059. Concurrent inhibition of the PI3K/Akt and MAPK/ERK1/2 pathways showed enhanced anti-tumor effects in vivo as indicated by increased apoptosis. At the same time, the levels of P-ERK and P-AKT in both xenograft tumors decreased, and their levels in combination group was the lowest. Conclusions: PD98059, LY294002 and their combinations showed remarkable inhibitory effects on xenograft tumors of endometrial carcinoma cell lines with different expression status of ER in vivo through blockage of PI3K/Akt and MAPK/ERK1/2 signaling pathways. This suggests that targeting these pathways may be an effective therapeutic strategy against endometrial carcinomas, especially for ER-negative cancers which show poor response to endocrinal therapy.
文摘目的:探讨染料木黄酮(Genistein,Gen)与5氟尿嘧啶(5-fluorouracil,5-FU)诱导人肝癌M H C C97-L细胞周期阻滞与细胞外调节蛋白激酶(extracellular regulated protein kinasesERK)1/2信号通路的关系.方法:MTS法检测细胞增殖;流式细胞术检测细胞周期;Western blot检测总ERK1/2和磷酸化ERK1/2蛋白表达.结果:Gen与5-FU单用及联用均能抑制肝癌MHCC97-L细胞增殖;Gen诱导细胞S期阻滞少量抑制ERK1/2磷酸化,ERK1/2抑制剂可促进Gen对MHCC97-L细胞的生长抑制作用,而对S期阻滞无明显影响;5-FU单用和二者联用组均阻滞S期细胞,并显著激活ERK1/2磷酸化ERK1/2抑制剂可促进两组药物对MHCC97-L细胞的生长抑制和诱导S期阻滞作用.结论:Gen与5-FU单用及联用均可通过阻滞细胞周期来发挥抗肝癌细胞增殖的作用;抑制ERK1/2通路可抵抗Gen诱导的肝癌细胞S期阻滞,而促进5-FU单用和二者联用组诱导肝癌细胞S期阻滞.
基金supported by the Medical and Healthcare Project of Zhejiang Province(No.2015119381),China
文摘Extracellular signal-regulated protein kinase 5 （ERK5）, also known as big mitogen-activated protein kinase 1 （MAPK1）, is an important member of ERK family, which is a subfamily of the large MAPK family. ERK5 is expressed in many tissues, including the dorsal root ganglion （DRG） neurons and the spinal cord. In this review, we focus on elaborating ERK5-associated pathway in pathological pain, in which the ERK5/CREB （cyclic adenosine monophos- phate （cAMP）-response element-binding protein） pathway plays a crucial role in the transduction of pain signal and contributes to pain hypersensitivity. ERK5 activation in the spinal dorsal horn occurs mainly in microglia. The activation of ERK5 can be mediated by N-methyI-D-aspartate （NMDA） receptors. We also elaborate the relationship between ERK5 activation and nerve growth factor-tyrosine kinase A （NGF-TrkA）, and the connection between ERK5 activation and brain-derived neurotrophic factor （BDNF） in pathological pain in detail.
