Excessive consumption of alcoholic beverages is a serious cause of liver disease worldwide.The metabolism of ethanol generates reactive oxygen species,which play a significant role in the deterio-ration of alcoholic l...Excessive consumption of alcoholic beverages is a serious cause of liver disease worldwide.The metabolism of ethanol generates reactive oxygen species,which play a significant role in the deterio-ration of alcoholic liver disease(ALD).Antioxidant phytochemicals,such as polyphenols,regulate the expression of ALD-associated proteins and peptides,namely,catalase,superoxide dismutase,glutathione,glutathione peroxidase,and glutathione reductase.These plant antioxidants have electrophilic activity and may induce antioxidant enzymes via the Kelch-like ECH-associated protein 1--NF--E2--related factor--2 pathway and antioxidant responsive elements.Furthermore,these antioxidants are reported to alleviate cell injury caused by oxidants or inflammatory cytokines.These phenomena are likely induced via the regulation of mitogen--activating protein kinase(MAPK)pathways by plant antioxidants,similar to preconditioning in ischemia-reperfusion models.Although the relationship between plant antioxidants and ALD has not been adequately investigated,plant antioxidants may be preventive for ALD because of their electrophilic and regulatory activities in the MAPK pathway.展开更多
Activation of extracellular signal-regulated kinase 1/2 has been demonstrated in acute brain ischemia. We hypothesized that activated extracellular signal-regulated kinase 1/2 can protect hippocampal neurons from inju...Activation of extracellular signal-regulated kinase 1/2 has been demonstrated in acute brain ischemia. We hypothesized that activated extracellular signal-regulated kinase 1/2 can protect hippocampal neurons from injury in a diabetic model after cerebral ischemia/reperfusion. In this study, transient whole-brain ischemia was induced by four-vessel occlusion in normal and diabetic rats, and extracellular signal-regulated kinase 1/2 inhibitor (U0126) was administered into diabetic rats 30 minutes before ischemia as a pretreatment. Results showed that the number of surviving neurons in the hippocampal CA1 region was reduced, extracellular signal-regulated kinase 1/2 phosphorylation and KuT0 activity were decreased, and pro-apoptotic Bax expression was upregulated after intervention using U0126. These findings demonstrate that inhibition of extracellular signal-regulated kinase 1/2 activity aggravated neuronal loss in the hippocampus in a diabetic rat after cerebral ischemia/reperfusion, further decreased DNA repairing ability and ac- celerated apoptosis in hippocampal neurons. Extracellular signal-regulated kinase 1/2 activation plays a neuroprotective role in hippocampal neurons in a diabetic rat after cerebral ischemia/ reperfusion.展开更多
Chronic intake of alcohol undoubtedly overwhelms the structural and functional capacity of the liver by initiating complex pathological events characterized by steatosis,steatohepatitis,hepatic fibrosis and cirrhosis....Chronic intake of alcohol undoubtedly overwhelms the structural and functional capacity of the liver by initiating complex pathological events characterized by steatosis,steatohepatitis,hepatic fibrosis and cirrhosis.Subsequently,these initial pathological events are sustained and ushered into a more complex and progressive liver disease,increasing the risk of fibrohepatocarcinogenesis.These coordinated pathological events mainly result from buildup of toxic metabolic derivatives of alcohol including but not limited to acetaldehyde(AA),malondialdehyde(MDA),CYP2E1-generated reactive oxygen species,alcohol-induced gut-derived lipopolysaccharide,AA/MDA protein and DNA adducts.The metabolic derivatives of alcohol together with other comorbidity factors,including hepatitis B and C viral infections,dysregulated iron metabolism,abuse of antibiotics,schistosomiasis,toxic drug metabolites,autoimmune disease and other non-specific factors,have been shown to underlie liver diseases.In view of the multiple etiology of liver diseases,attempts to delineate the mechanism by which each etiological factor causes liver disease has always proved cumbersome if not impossible.In the case of alcoholic liver disease(ALD),it is even more cumbersome and complicated as a result of the many toxic metabolic derivatives of alcohol with their varying liver-specific toxicities.In spite of all these hurdles,researchers and experts in hepatology have strived to expand knowledge and scientific discourse,particularly on ALD and its associated complications through the medium of scientific research,reviews and commentaries.Nonetheless,the molecularmechanisms underpinning ALD,particularly those underlying toxic effects of metabolic derivatives of alcohol on parenchymal and non-parenchymal hepatic cells leading to increased risk of alcohol-induced fibrohepatocarcinogenesis,are still incompletely elucidated.In this review,we examined published scientific findings on how alcohol and its metabolic derivatives mount cellular attack on each hepatic cell and the underlying molecular mechanisms leading to disruption of core hepatic homeostatic functions which probably set the stage for the initiation and progression of ALD to fibro-hepatocarcinogenesis.We also brought to sharp focus,the complex and integrative role of transforming growth factor beta/small mothers against decapentaplegic/plasminogen activator inhibitor-1 and the mitogen activated protein kinase signaling nexus as well as their cross-signaling with toll-like receptormediated gut-dependent signaling pathways implicated in ALD and fibro-hepatocarcinogenesis.Looking into the future,it is hoped that these deliberations may stimulate new research directions on this topic and shape not only therapeutic approaches but also models for studying ALD and fibro-hepatocarcinogenesis.展开更多
Motor function impairment is a common outcome of stroke.Constraint-induced movement therapy(CIMT)involving intensive use of the impaired limb while restraining the unaffected limb is widely used to overcome the effe...Motor function impairment is a common outcome of stroke.Constraint-induced movement therapy(CIMT)involving intensive use of the impaired limb while restraining the unaffected limb is widely used to overcome the effects of'learned non-use'and improve limb function after stroke.However,the underlying mechanism of CIMT remains unclear.In the present study,rats were randomly divided into a middle cerebral artery occlusion(model)group,a CIMT+model(CIMT)group,or a sham group.Restriction of the affected limb by plaster cast was performed in the CIMT and sham groups.Compared with the model group,CIMT significantly improved the forelimb functional performance in rats.By western blot assay,the expression of phosphorylated extracellular regulated protein kinase in the bilateral cortex and hippocampi of cerebral ischemic rats in the CIMT group was significantly lower than that in the model group,and was similar to sham group levels.These data suggest that functional recovery after CIMT may be related to decreased expression of phosphorylated extracellular regulated protein kinase in the bilateral cortex and hippocampi.展开更多
Objective: To analyze the effects of salvianolate on myocardial infarction in a murine in vivo model of ischemia and reperfusion (I/R) injury. Metheds: Myocardial I/R injury model was constructed in mice by 30 min...Objective: To analyze the effects of salvianolate on myocardial infarction in a murine in vivo model of ischemia and reperfusion (I/R) injury. Metheds: Myocardial I/R injury model was constructed in mice by 30 min of coronary occlusion followed by 24 h of reperfusion and pretreated with salvianolate 30 min before I/R (SAL group). The SAL group was compared with SHAM (no I/R and no salvianolate), I/R (no salvianolate), and ischemia preconditioning (IPC) groups. Furthermore, an ERK1/2 inhibitor PD98059 (1 mg/kg), and a phosphatidylinositol-3-kinase (PI3-K) inhibitor, LY294002 (7.5 mg/kg), were administered intraperitoneal injection (i.p) for 30 min prior to salvianolate, followed by I/R surgery in LY and PD groups. By using a double staining method, the ratio of the infarct size (IS) to left ventricle (LV) and of risk region (RR) to LV were compared among the groups. Correlations between IS and RR were analyzed. Western-blot was used to detect the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation changes. Results: There were no significant differences between RR to LV ratio among the SHAM, I/R, IPC and SAL groups (P〉0.05). The SAL and IPC groups had IS of 26.1% ± 1.4% and 22.3% ±2.9% of RR, respectively, both of which were significantly smaller than the I/R group (38.5% ± 2.9% of RR, P〈0.05, P〈0.01, respectively). Moreover, the phosphorylation of ERK1/2 was increased in SAL group (P〈0.05), while AKT had no significant change. LY294002 further reduced IS, whereas the protective role of salvianolate could be attenuated by PD98059, which increased the IS. Additionally, the IS was not linearly related to the RR (r=0.23, 0.45, 0.62, 0.17, and 0.52 in the SHAM, I/R, SAL, LY and PD groups, respectively). Conclusion: Salvianolate could reduce myocardial I/R injury in mice in vivo, which involves an ERK1/2 pathway, but not a PI3-K signaling pathway.展开更多
We have reported that norcantharidin (NCTD) induces human melanoma A375-S2cell apoptosis and that the activation of caspase and the mitochondrial pathway are involved in theapoptotic process. This study aimed at inves...We have reported that norcantharidin (NCTD) induces human melanoma A375-S2cell apoptosis and that the activation of caspase and the mitochondrial pathway are involved in theapoptotic process. This study aimed at investigating the roles of mitogen-activated protein kinase(MAPK) and protein kinase C (PKC) in A375-S2 cell apoptosis induced by NCTD. We assessed theeffects of NCTD on cell growth inhibition using the 3-(4,5-dimethylthiazol-2-yl)-2 ,5-dipheyltetrazolium bromide ( MTT) assay, DNA fragmentation ( DNA agarose gel electrophoresis ) ,and MAPK protein levels (Western blot analysis) in A375-S2 cells. Photomicroscopic data were alsocollected. The NCTD inhibitory effect on A375-S2 cells was partially reversed by MAPK and PKCinhibitors. The expression of phosphorylated JNK and p38 also increased after the treatment withNCTD, and inhibitors of c-Jun NH2 - terminal kinase (JNK) and p38 ( SP600125 and SB203580,respectively) had significant inhibitory effects on the upregulation of phosphorylated JNK and p38expression. Simultaneously, the PKC inhibitor staurosporine blocked the upregulation ofphosphorylated JNK and phosphorylated p_(38), but had little effect on extracellularsignal-regulated kinase (ERK) expression. These results suggest that the activation of JNK andp_(38) MAPK promotes the process of NCTD-induced A375-S2 cell apoptosis and that PKC plays animportant regulation role in the activation of MAPKs.展开更多
基金Supported by JSPS KAKENHI Grant Number 25450196grants-in-aid from The Ministry of Agriculture,Forestry and Fisheries of Japan
文摘Excessive consumption of alcoholic beverages is a serious cause of liver disease worldwide.The metabolism of ethanol generates reactive oxygen species,which play a significant role in the deterio-ration of alcoholic liver disease(ALD).Antioxidant phytochemicals,such as polyphenols,regulate the expression of ALD-associated proteins and peptides,namely,catalase,superoxide dismutase,glutathione,glutathione peroxidase,and glutathione reductase.These plant antioxidants have electrophilic activity and may induce antioxidant enzymes via the Kelch-like ECH-associated protein 1--NF--E2--related factor--2 pathway and antioxidant responsive elements.Furthermore,these antioxidants are reported to alleviate cell injury caused by oxidants or inflammatory cytokines.These phenomena are likely induced via the regulation of mitogen--activating protein kinase(MAPK)pathways by plant antioxidants,similar to preconditioning in ischemia-reperfusion models.Although the relationship between plant antioxidants and ALD has not been adequately investigated,plant antioxidants may be preventive for ALD because of their electrophilic and regulatory activities in the MAPK pathway.
基金supported by the Hebei Province Natural Science Program,No.H2012401007a grant from the foundation Key Project of Hebei Province Education Ministry,No.ZD2010106
文摘Activation of extracellular signal-regulated kinase 1/2 has been demonstrated in acute brain ischemia. We hypothesized that activated extracellular signal-regulated kinase 1/2 can protect hippocampal neurons from injury in a diabetic model after cerebral ischemia/reperfusion. In this study, transient whole-brain ischemia was induced by four-vessel occlusion in normal and diabetic rats, and extracellular signal-regulated kinase 1/2 inhibitor (U0126) was administered into diabetic rats 30 minutes before ischemia as a pretreatment. Results showed that the number of surviving neurons in the hippocampal CA1 region was reduced, extracellular signal-regulated kinase 1/2 phosphorylation and KuT0 activity were decreased, and pro-apoptotic Bax expression was upregulated after intervention using U0126. These findings demonstrate that inhibition of extracellular signal-regulated kinase 1/2 activity aggravated neuronal loss in the hippocampus in a diabetic rat after cerebral ischemia/reperfusion, further decreased DNA repairing ability and ac- celerated apoptosis in hippocampal neurons. Extracellular signal-regulated kinase 1/2 activation plays a neuroprotective role in hippocampal neurons in a diabetic rat after cerebral ischemia/ reperfusion.
基金Supported by National Natural Science Foundation of China,No.81374012 and No.81573652
文摘Chronic intake of alcohol undoubtedly overwhelms the structural and functional capacity of the liver by initiating complex pathological events characterized by steatosis,steatohepatitis,hepatic fibrosis and cirrhosis.Subsequently,these initial pathological events are sustained and ushered into a more complex and progressive liver disease,increasing the risk of fibrohepatocarcinogenesis.These coordinated pathological events mainly result from buildup of toxic metabolic derivatives of alcohol including but not limited to acetaldehyde(AA),malondialdehyde(MDA),CYP2E1-generated reactive oxygen species,alcohol-induced gut-derived lipopolysaccharide,AA/MDA protein and DNA adducts.The metabolic derivatives of alcohol together with other comorbidity factors,including hepatitis B and C viral infections,dysregulated iron metabolism,abuse of antibiotics,schistosomiasis,toxic drug metabolites,autoimmune disease and other non-specific factors,have been shown to underlie liver diseases.In view of the multiple etiology of liver diseases,attempts to delineate the mechanism by which each etiological factor causes liver disease has always proved cumbersome if not impossible.In the case of alcoholic liver disease(ALD),it is even more cumbersome and complicated as a result of the many toxic metabolic derivatives of alcohol with their varying liver-specific toxicities.In spite of all these hurdles,researchers and experts in hepatology have strived to expand knowledge and scientific discourse,particularly on ALD and its associated complications through the medium of scientific research,reviews and commentaries.Nonetheless,the molecularmechanisms underpinning ALD,particularly those underlying toxic effects of metabolic derivatives of alcohol on parenchymal and non-parenchymal hepatic cells leading to increased risk of alcohol-induced fibrohepatocarcinogenesis,are still incompletely elucidated.In this review,we examined published scientific findings on how alcohol and its metabolic derivatives mount cellular attack on each hepatic cell and the underlying molecular mechanisms leading to disruption of core hepatic homeostatic functions which probably set the stage for the initiation and progression of ALD to fibro-hepatocarcinogenesis.We also brought to sharp focus,the complex and integrative role of transforming growth factor beta/small mothers against decapentaplegic/plasminogen activator inhibitor-1 and the mitogen activated protein kinase signaling nexus as well as their cross-signaling with toll-like receptormediated gut-dependent signaling pathways implicated in ALD and fibro-hepatocarcinogenesis.Looking into the future,it is hoped that these deliberations may stimulate new research directions on this topic and shape not only therapeutic approaches but also models for studying ALD and fibro-hepatocarcinogenesis.
基金supported by grants from the National Natural Science Foundation of China,No.81372119a grant from the Science and Technology Commission of Shanghai Municipality,No.12ZR1404000
文摘Motor function impairment is a common outcome of stroke.Constraint-induced movement therapy(CIMT)involving intensive use of the impaired limb while restraining the unaffected limb is widely used to overcome the effects of'learned non-use'and improve limb function after stroke.However,the underlying mechanism of CIMT remains unclear.In the present study,rats were randomly divided into a middle cerebral artery occlusion(model)group,a CIMT+model(CIMT)group,or a sham group.Restriction of the affected limb by plaster cast was performed in the CIMT and sham groups.Compared with the model group,CIMT significantly improved the forelimb functional performance in rats.By western blot assay,the expression of phosphorylated extracellular regulated protein kinase in the bilateral cortex and hippocampi of cerebral ischemic rats in the CIMT group was significantly lower than that in the model group,and was similar to sham group levels.These data suggest that functional recovery after CIMT may be related to decreased expression of phosphorylated extracellular regulated protein kinase in the bilateral cortex and hippocampi.
基金Supported by National Natural Science Foundation of China(No.81473471 and No.81573708)Foundation of Guangdong Hospital of Chinese Medicine(No.YK2013B2N11,No.YN2014ZH01,and No.YN2014ZHR203)
文摘Objective: To analyze the effects of salvianolate on myocardial infarction in a murine in vivo model of ischemia and reperfusion (I/R) injury. Metheds: Myocardial I/R injury model was constructed in mice by 30 min of coronary occlusion followed by 24 h of reperfusion and pretreated with salvianolate 30 min before I/R (SAL group). The SAL group was compared with SHAM (no I/R and no salvianolate), I/R (no salvianolate), and ischemia preconditioning (IPC) groups. Furthermore, an ERK1/2 inhibitor PD98059 (1 mg/kg), and a phosphatidylinositol-3-kinase (PI3-K) inhibitor, LY294002 (7.5 mg/kg), were administered intraperitoneal injection (i.p) for 30 min prior to salvianolate, followed by I/R surgery in LY and PD groups. By using a double staining method, the ratio of the infarct size (IS) to left ventricle (LV) and of risk region (RR) to LV were compared among the groups. Correlations between IS and RR were analyzed. Western-blot was used to detect the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation changes. Results: There were no significant differences between RR to LV ratio among the SHAM, I/R, IPC and SAL groups (P〉0.05). The SAL and IPC groups had IS of 26.1% ± 1.4% and 22.3% ±2.9% of RR, respectively, both of which were significantly smaller than the I/R group (38.5% ± 2.9% of RR, P〈0.05, P〈0.01, respectively). Moreover, the phosphorylation of ERK1/2 was increased in SAL group (P〈0.05), while AKT had no significant change. LY294002 further reduced IS, whereas the protective role of salvianolate could be attenuated by PD98059, which increased the IS. Additionally, the IS was not linearly related to the RR (r=0.23, 0.45, 0.62, 0.17, and 0.52 in the SHAM, I/R, SAL, LY and PD groups, respectively). Conclusion: Salvianolate could reduce myocardial I/R injury in mice in vivo, which involves an ERK1/2 pathway, but not a PI3-K signaling pathway.
文摘We have reported that norcantharidin (NCTD) induces human melanoma A375-S2cell apoptosis and that the activation of caspase and the mitochondrial pathway are involved in theapoptotic process. This study aimed at investigating the roles of mitogen-activated protein kinase(MAPK) and protein kinase C (PKC) in A375-S2 cell apoptosis induced by NCTD. We assessed theeffects of NCTD on cell growth inhibition using the 3-(4,5-dimethylthiazol-2-yl)-2 ,5-dipheyltetrazolium bromide ( MTT) assay, DNA fragmentation ( DNA agarose gel electrophoresis ) ,and MAPK protein levels (Western blot analysis) in A375-S2 cells. Photomicroscopic data were alsocollected. The NCTD inhibitory effect on A375-S2 cells was partially reversed by MAPK and PKCinhibitors. The expression of phosphorylated JNK and p38 also increased after the treatment withNCTD, and inhibitors of c-Jun NH2 - terminal kinase (JNK) and p38 ( SP600125 and SB203580,respectively) had significant inhibitory effects on the upregulation of phosphorylated JNK and p38expression. Simultaneously, the PKC inhibitor staurosporine blocked the upregulation ofphosphorylated JNK and phosphorylated p_(38), but had little effect on extracellularsignal-regulated kinase (ERK) expression. These results suggest that the activation of JNK andp_(38) MAPK promotes the process of NCTD-induced A375-S2 cell apoptosis and that PKC plays animportant regulation role in the activation of MAPKs.