Background: Sevoflurane and propofol are effective cardioprotective anaesthetic agents, though the cardioprotection of propofol has not been shown in humans. Their roles and underlying mechanisms in anesthetic postcon...Background: Sevoflurane and propofol are effective cardioprotective anaesthetic agents, though the cardioprotection of propofol has not been shown in humans. Their roles and underlying mechanisms in anesthetic postconditioning are unclear. Mitochondrial permeability transition pore (MPTP) opening is a major cause of ischemia-reperfusion injury. Here we investigated sevoflurane- and propofol-induced postconditioning and their relationship with MPTP. Methods: Isolated perfused rat hearts were exposed to 40 min of ischemia followed by 1 h of reperfusion. During the first 15 min of reperfusion, hearts were treated with either control buffer (CTRL group) or buffer containing 20 μmol/L atractyloside (ATR group), 3% (v/v) sevoflurane (SPC group), 50 μmol/L propofol (PPC group), or the combination of atractyloside with respective anesthetics (SPC+ATR and PPC+ATR groups). Infarct size was determined by dividing the total necrotic area of the left ventricle by the total left ventricular slice area (percent necrotic area). Results: Hearts treated with sevoflurane or propofol showed significantly better recovery of coronary flow, end-diastolic pressures, left ventricular developed pressure and derivatives compared with controls. Sevoflurane resulted in more protective alteration of hemodynamics at most time point of reperfusion than propofol. These improvements were paralleled with the reduction of lactate dehydrogenase release and the decrease of infarct size (SPC vs CTRL: (17.48±2.70)% vs (48.47±6.03)%, P<0.05; PPC vs CTRL: (35.60±2.10)% vs (48.47±6.03)%, P<0.05). SPC group had less infarct size than PPC group (SPC vs PPC: (17.48±2.70)% vs (35.60±2.10)%, P<0.05). Atractyloside coadministration attenuated or completely blocked the cardioprotective effect of postconditioning of sevoflurane and propofol. Conclusion: Postconditioning of sevoflurane and propofol has cardio-protective effect against ischemia-reperfusion injury of heart, which is associated with inhibition of MPTP opening. Compared to propofol, sevofluran展开更多
Background Ischemia/reperfusion injury （IRI） is an inflammatory response that occurs when tissue is reperfused following a prolonged period of ischemia. Several studies have indicated that C-reactive protein （CRP）...Background Ischemia/reperfusion injury （IRI） is an inflammatory response that occurs when tissue is reperfused following a prolonged period of ischemia. Several studies have indicated that C-reactive protein （CRP） might play an important role in inducing IRI. However, the effects of CRP on myocardial IRI and the underlying mechanisms have not been fully elucidated. This study aimed to investigate the association between CRP and myocardial IRI and the underlying mechanisms. Methods We simulated ischemia/reperfusion using oxygen-glucose deprivation/ reoxygenation （OGD/R） in neonatal Sprague-Dawley rat cardiomyocytes; reperfusion injury was induced by three hours of hypoxia with glucose and serum deprivation followed by one hour of reperfusion. Cell viability was tested with MTS assays, and cardiomyocyte damage was evaluated by lactate dehydrogenase （LDH） leakage. Mitochondrial membrane potential was measured using tetramethylrhodamine ethyl ester （TMRE） and mitochondrial permeability transition pore （mPTP） opening was measured using calcein/AM; both TMRE and caocein/AM were visualized with laser scanning confocal microscopy. In addition, we studied the signaling pathways underlying CRP-mediated ischemia/reperfusion injury via Western blot analysis. Results Compared with the simple OGD/R group, after intervention with 10 pg/mL CRP, cell viability decreased markedly （82.36 % ± 6.18% vs. 64.84% ± 4.06%, P = 0.0007）, and the LDH leakage significantly increased （145.3 U/L ± 16.06 U/L vs. 208.2 U/L ± 19.23 U/L, P = 0.0122）. CRP also activated mPTP opening and reduced mitochondrial membrane potential during myocardial ischemia/reperfusion. Pretreatment with 1 pM atorvastatin （Ator） before CRP intervention protected cardiomyocytes from IRI. Mitochondrial KATP channel opener diazoxide and mPTP inhibitor cyclosporin A also offset the effects of CRP in this process. The level of phosphorylated extracellular-signal-regulated kinase （ERK） 1/2 was significantly higher after pre-treatme展开更多
A central mechanism leading to necrosis and apoptosis during cardiac ischemia/reperfusion is believed to be the mitochondrial permeability transition (MPT), due to opening of mitochondrial permeability transition pore...A central mechanism leading to necrosis and apoptosis during cardiac ischemia/reperfusion is believed to be the mitochondrial permeability transition (MPT), due to opening of mitochondrial permeability transition pore (mPTP), a multiprotein complex formed at the contact site between the inner and outer mitochondrial membranes. MPT is important in the processes of cell damage and death. The regulation of the MPT plays a key role in the regulation of cardiac mitochondria injury, appears of a novel target and high interest in various therapeutic indications for cardioprotective.展开更多
Objective:To investigate the protective effect of different cyclosporin A(CsA)doses on myocardial ischemia/reperfusion injury in rat models.Methods:A rat model of myocardial ischemia/reperfusion injury was established...Objective:To investigate the protective effect of different cyclosporin A(CsA)doses on myocardial ischemia/reperfusion injury in rat models.Methods:A rat model of myocardial ischemia/reperfusion injury was established in vivo and the rats were randomly divided into four groups:placebo(PBS;T1),low-dose(CsA dose:1.0 mg/kg:T2),medium-dose(CsA dose:2.5 mg/kg:T3),and high-dose(CsA dose:5.0 mg/kg;T4)groups.Heart function indexes were monitored at different time points,the extent of myocardial infarction was assessed by Evans Blue-TTC staining,and creatine kinase MB mass and cardiac troponin 1 values were measured by biochemical assays.Results:Compared with the T1 and T2 groups,both the creatine kinase MB mass and cardiac troponin 1 were significantly lower in the T3 and T4 groups(P<0.05).The mean arterial pressure(MAP)and left ventricular systolic pressure(LVSP)decreased sequentially in each group,with the extending reperfusion time.Significant decreases in LVSP and MAP were observed in the T3 and T4 groups as compared to the T1 and T2 group(P<0.05)and the T2 group showed a significantly lower LVSP and MAP decline than the T1 group(P<0.05).Compared with the Tl group,the rats from the T2.T3,and T4 groups suffered from a significantly lower extent of myocardial infarction(P<0.05).Also,the a animals in the T3 and T4 groups had a significantly smaller extent of myocardial infarction than those in the T2 group(P<0.05).Conclusions:Various CsA doses exert different degrees of protection against ischemia/reperfusion injury,and this protective effect peaks at approximately 2.5 mg/kg in rat models.展开更多
Calpains are a group of calcium-dependent proteases that are over activated by increased intracellular calcium levels under pathological conditions. A wide range of substrates that regulate necrotic, apoptotic and aut...Calpains are a group of calcium-dependent proteases that are over activated by increased intracellular calcium levels under pathological conditions. A wide range of substrates that regulate necrotic, apoptotic and autophagic pathways are affected by calpain. Calpain plays a very important role in neuronal death and various neurological disorders. This review introduces recent research progress related to the regulatory mechanisms of calpain in neuronal death. Various neuronal programmed death pathways including apoptosis, autophagy and regulated necrosis can be divided into receptor interacting protein-dependent necroptosis, mitochondrial permeability transition-dependent necrosis, pyroptosis and poly （ADP-ribose）polymerase 1-mediated parthanatos. Calpains cleave series of key substrates that may lead to cell death or participate in cell death. Regarding the investigation of calpain-mediated programed cell death, it is necessary to identify specific inhibitors that inhibit calpain mediated neuronal death and nervous system diseases.展开更多
Objective To investigate the protective effects of Shexiang Tongxin Dropping Pill(麝香通心滴丸,STDP)following sodium laurate-induced coronary microembolization(CME)in rats.Methods Forty rats were divided into 4 groups...Objective To investigate the protective effects of Shexiang Tongxin Dropping Pill(麝香通心滴丸,STDP)following sodium laurate-induced coronary microembolization(CME)in rats.Methods Forty rats were divided into 4 groups:the control(sham)group,CME group,low-dose STDP pretreatment group(20 mg·kg^(−1)·d^(−1)),and high-dose STDP pretreatment group(40 mg·kg^(−1)·d^(−1)).The rats were intragastric administrated with STDP 2 weeks before operation.Moreover,the histopathological alterations were observed using optical microscopy and transmission electron microscopy.Antioxidant biomarkers were analyzed by enzyme-linked immunosorbent assay.Mitochondrial functions including the mitochondrial permeability transition pore(mPTP)mtDNA copy number were determined and proteins of AKT/GSK3βwere analyzed by Western blot.Results The rats in the CME group showed a significant increase in the fibrinogen-like protein 2 expression level and mitochondrial dysfunction and a decrease in the expression level of antioxidant biomarkers(superoxide dismutase and catalase,P<0.01 for all).In contrast,the rats in the low-and high-dose STDP pretreatment groups showed a significant decrease in coronary microthrombi(P<0.05);moreover,STDP restored the antioxidant-related protein activities and mitochondrial function,inhibited mPTP opening,decreased AKT-Ser473 phosphorylation,and increased GSK3β-Ser9 phosphorylation(P<0.05 or P<0.01).Conclusion STDP may be useful for treatment of CME,possibly via regulation of mPTP opening and AKT/GSK3βphosphorylation.展开更多
The mitochondrion serves many functions in the central nervous system （CNS） and other organs beyond the well-recognized role of adenosine triphosphate （ATP） production. This includes calcium-dependent cell signali...The mitochondrion serves many functions in the central nervous system （CNS） and other organs beyond the well-recognized role of adenosine triphosphate （ATP） production. This includes calcium-dependent cell signaling, regulation of gene expression, synthesis and release of cytotoxic reactive oxygen species, and the release of cytochrome c and other apoptotic cell death factors. Traumatic injury to the CNS results in a rapid and, in some cases, sustained loss of mitochondrial function. One consequence of compromised mitochondrial function is induction of the mitochondrial permeability transition （mPT） state due to formation of the cyclosporine A sensitive permeability transition pore （mPTP）. In this mini-review, we summarize evidence supporting the involvement of the mPTP as a mediator of mitochondrial and cellular demise following CNS traumatic injury and discuss the beneficial effects and limitations of the current ex- perimental strategies targeting the mPTP.展开更多
Objective:To assess acute toxicity,the in vitro and in vivo effects of methanol and ethyl acetate extracts(JME and JEE)of Jatonik polyherbal mixture on some mitochondria-related parameters and their effect on the acti...Objective:To assess acute toxicity,the in vitro and in vivo effects of methanol and ethyl acetate extracts(JME and JEE)of Jatonik polyherbal mixture on some mitochondria-related parameters and their effect on the activity of some liver enzymes.Methods:Acute toxicity of JME and JEE was determined using Lorke’s method.In vitro and in vivo opening of the mitochondrial membrane permeability transition pore(MMPT pore)was spectrophotometrically assayed.Production of malondialdehyde(MDA)as an index of lipid peroxidation and the activity of mitochondrial ATPase was evaluated in vitro and in vivo and the effect of JME and JEE on the activity of liver enzymes such as alkaline phosphatase(ALP),aspartate and alanine aminotransferase(AST and ALT)and gamma-glutamyl transferase(GGT)was also investigated.Results:JME had an LD_(50) of 3808 mg/kg b.w whereas JEE had an LD_(50) greater than 5000 mg/kg b.w.of rats.After the rats have been fed with both extracts,a photomicrograph of a piece of liver tissue showed no apparent symptoms of toxicity.From the in vitro and in vivo studies,both extracts prompted intact mitochondria to open their MMPT pores.When compared to the control,lipid peroxide product release and ATPase activity were significantly increased(P<0.05)in vitro and in vivo.The activities of AST,ALT,and GGT were all reduced at 50 mg/kg when treated with JME,but the activity of AST was considerably enhanced when treated with JEE(P<0.05).The results revealed that both JME and JEE of the Jatonik polyherbal mixture had low toxicity,profound MMPTpore induction,and enhanced ATPase activity,but an increased MDA production.Conclusion:Jatonik extracts may be a promising target for drug development in diseases where there is dysregulation of apoptosis,however,further studies are needed to better clarify the molecular mechanism involved in these phenomena.展开更多
基金Project supported by the National Natural Science Foundation ofChina (No. 30772090)the Natural Science Foundation of ZhejiangProvince (No. Y204141)+2 种基金the Foundation from Science and Technology Department of Zhejiang Province (No. 2007R10034)theFoundation from Personnel Department of Zhejiang Province (NoJ20050046)the Foundation from Health Department of ZhejiangProvince (No. 2007QN007), China
文摘Background: Sevoflurane and propofol are effective cardioprotective anaesthetic agents, though the cardioprotection of propofol has not been shown in humans. Their roles and underlying mechanisms in anesthetic postconditioning are unclear. Mitochondrial permeability transition pore (MPTP) opening is a major cause of ischemia-reperfusion injury. Here we investigated sevoflurane- and propofol-induced postconditioning and their relationship with MPTP. Methods: Isolated perfused rat hearts were exposed to 40 min of ischemia followed by 1 h of reperfusion. During the first 15 min of reperfusion, hearts were treated with either control buffer (CTRL group) or buffer containing 20 μmol/L atractyloside (ATR group), 3% (v/v) sevoflurane (SPC group), 50 μmol/L propofol (PPC group), or the combination of atractyloside with respective anesthetics (SPC+ATR and PPC+ATR groups). Infarct size was determined by dividing the total necrotic area of the left ventricle by the total left ventricular slice area (percent necrotic area). Results: Hearts treated with sevoflurane or propofol showed significantly better recovery of coronary flow, end-diastolic pressures, left ventricular developed pressure and derivatives compared with controls. Sevoflurane resulted in more protective alteration of hemodynamics at most time point of reperfusion than propofol. These improvements were paralleled with the reduction of lactate dehydrogenase release and the decrease of infarct size (SPC vs CTRL: (17.48±2.70)% vs (48.47±6.03)%, P<0.05; PPC vs CTRL: (35.60±2.10)% vs (48.47±6.03)%, P<0.05). SPC group had less infarct size than PPC group (SPC vs PPC: (17.48±2.70)% vs (35.60±2.10)%, P<0.05). Atractyloside coadministration attenuated or completely blocked the cardioprotective effect of postconditioning of sevoflurane and propofol. Conclusion: Postconditioning of sevoflurane and propofol has cardio-protective effect against ischemia-reperfusion injury of heart, which is associated with inhibition of MPTP opening. Compared to propofol, sevofluran
文摘Background Ischemia/reperfusion injury （IRI） is an inflammatory response that occurs when tissue is reperfused following a prolonged period of ischemia. Several studies have indicated that C-reactive protein （CRP） might play an important role in inducing IRI. However, the effects of CRP on myocardial IRI and the underlying mechanisms have not been fully elucidated. This study aimed to investigate the association between CRP and myocardial IRI and the underlying mechanisms. Methods We simulated ischemia/reperfusion using oxygen-glucose deprivation/ reoxygenation （OGD/R） in neonatal Sprague-Dawley rat cardiomyocytes; reperfusion injury was induced by three hours of hypoxia with glucose and serum deprivation followed by one hour of reperfusion. Cell viability was tested with MTS assays, and cardiomyocyte damage was evaluated by lactate dehydrogenase （LDH） leakage. Mitochondrial membrane potential was measured using tetramethylrhodamine ethyl ester （TMRE） and mitochondrial permeability transition pore （mPTP） opening was measured using calcein/AM; both TMRE and caocein/AM were visualized with laser scanning confocal microscopy. In addition, we studied the signaling pathways underlying CRP-mediated ischemia/reperfusion injury via Western blot analysis. Results Compared with the simple OGD/R group, after intervention with 10 pg/mL CRP, cell viability decreased markedly （82.36 % ± 6.18% vs. 64.84% ± 4.06%, P = 0.0007）, and the LDH leakage significantly increased （145.3 U/L ± 16.06 U/L vs. 208.2 U/L ± 19.23 U/L, P = 0.0122）. CRP also activated mPTP opening and reduced mitochondrial membrane potential during myocardial ischemia/reperfusion. Pretreatment with 1 pM atorvastatin （Ator） before CRP intervention protected cardiomyocytes from IRI. Mitochondrial KATP channel opener diazoxide and mPTP inhibitor cyclosporin A also offset the effects of CRP in this process. The level of phosphorylated extracellular-signal-regulated kinase （ERK） 1/2 was significantly higher after pre-treatme
文摘A central mechanism leading to necrosis and apoptosis during cardiac ischemia/reperfusion is believed to be the mitochondrial permeability transition (MPT), due to opening of mitochondrial permeability transition pore (mPTP), a multiprotein complex formed at the contact site between the inner and outer mitochondrial membranes. MPT is important in the processes of cell damage and death. The regulation of the MPT plays a key role in the regulation of cardiac mitochondria injury, appears of a novel target and high interest in various therapeutic indications for cardioprotective.
基金financially supported by Key Science and Technology Project of Haikou City,with grant number 2011-0142
文摘Objective:To investigate the protective effect of different cyclosporin A(CsA)doses on myocardial ischemia/reperfusion injury in rat models.Methods:A rat model of myocardial ischemia/reperfusion injury was established in vivo and the rats were randomly divided into four groups:placebo(PBS;T1),low-dose(CsA dose:1.0 mg/kg:T2),medium-dose(CsA dose:2.5 mg/kg:T3),and high-dose(CsA dose:5.0 mg/kg;T4)groups.Heart function indexes were monitored at different time points,the extent of myocardial infarction was assessed by Evans Blue-TTC staining,and creatine kinase MB mass and cardiac troponin 1 values were measured by biochemical assays.Results:Compared with the T1 and T2 groups,both the creatine kinase MB mass and cardiac troponin 1 were significantly lower in the T3 and T4 groups(P<0.05).The mean arterial pressure(MAP)and left ventricular systolic pressure(LVSP)decreased sequentially in each group,with the extending reperfusion time.Significant decreases in LVSP and MAP were observed in the T3 and T4 groups as compared to the T1 and T2 group(P<0.05)and the T2 group showed a significantly lower LVSP and MAP decline than the T1 group(P<0.05).Compared with the Tl group,the rats from the T2.T3,and T4 groups suffered from a significantly lower extent of myocardial infarction(P<0.05).Also,the a animals in the T3 and T4 groups had a significantly smaller extent of myocardial infarction than those in the T2 group(P<0.05).Conclusions:Various CsA doses exert different degrees of protection against ischemia/reperfusion injury,and this protective effect peaks at approximately 2.5 mg/kg in rat models.
基金supported by the National Natural Science Foundation of China,No.81571939&81772134the Wu Jie-Ping Medical Foundation of the Minister of Health of China,No.320.6750.14118+1 种基金the Natural Science Foundation of Hunan Province of China,No.2015JJ2187the Teacher Research Foundation of Central South University of China,No.2014JSJJ026
文摘Calpains are a group of calcium-dependent proteases that are over activated by increased intracellular calcium levels under pathological conditions. A wide range of substrates that regulate necrotic, apoptotic and autophagic pathways are affected by calpain. Calpain plays a very important role in neuronal death and various neurological disorders. This review introduces recent research progress related to the regulatory mechanisms of calpain in neuronal death. Various neuronal programmed death pathways including apoptosis, autophagy and regulated necrosis can be divided into receptor interacting protein-dependent necroptosis, mitochondrial permeability transition-dependent necrosis, pyroptosis and poly （ADP-ribose）polymerase 1-mediated parthanatos. Calpains cleave series of key substrates that may lead to cell death or participate in cell death. Regarding the investigation of calpain-mediated programed cell death, it is necessary to identify specific inhibitors that inhibit calpain mediated neuronal death and nervous system diseases.
基金Supported by the Zhejiang Provincial Administration of Traditional Chinese Medicine(No.2018ZB082)Beijing Lisheng Cardiovascular Health Foundation of China(No.LSG1501132)Zhejiang Natural Science Foundation(No.Y15H020003)。
文摘Objective To investigate the protective effects of Shexiang Tongxin Dropping Pill(麝香通心滴丸,STDP)following sodium laurate-induced coronary microembolization(CME)in rats.Methods Forty rats were divided into 4 groups:the control(sham)group,CME group,low-dose STDP pretreatment group(20 mg·kg^(−1)·d^(−1)),and high-dose STDP pretreatment group(40 mg·kg^(−1)·d^(−1)).The rats were intragastric administrated with STDP 2 weeks before operation.Moreover,the histopathological alterations were observed using optical microscopy and transmission electron microscopy.Antioxidant biomarkers were analyzed by enzyme-linked immunosorbent assay.Mitochondrial functions including the mitochondrial permeability transition pore(mPTP)mtDNA copy number were determined and proteins of AKT/GSK3βwere analyzed by Western blot.Results The rats in the CME group showed a significant increase in the fibrinogen-like protein 2 expression level and mitochondrial dysfunction and a decrease in the expression level of antioxidant biomarkers(superoxide dismutase and catalase,P<0.01 for all).In contrast,the rats in the low-and high-dose STDP pretreatment groups showed a significant decrease in coronary microthrombi(P<0.05);moreover,STDP restored the antioxidant-related protein activities and mitochondrial function,inhibited mPTP opening,decreased AKT-Ser473 phosphorylation,and increased GSK3β-Ser9 phosphorylation(P<0.05 or P<0.01).Conclusion STDP may be useful for treatment of CME,possibly via regulation of mPTP opening and AKT/GSK3βphosphorylation.
基金supported by a grant from the Kentucky Spinal Cord and Head Injury Research Trust
文摘The mitochondrion serves many functions in the central nervous system （CNS） and other organs beyond the well-recognized role of adenosine triphosphate （ATP） production. This includes calcium-dependent cell signaling, regulation of gene expression, synthesis and release of cytotoxic reactive oxygen species, and the release of cytochrome c and other apoptotic cell death factors. Traumatic injury to the CNS results in a rapid and, in some cases, sustained loss of mitochondrial function. One consequence of compromised mitochondrial function is induction of the mitochondrial permeability transition （mPT） state due to formation of the cyclosporine A sensitive permeability transition pore （mPTP）. In this mini-review, we summarize evidence supporting the involvement of the mPTP as a mediator of mitochondrial and cellular demise following CNS traumatic injury and discuss the beneficial effects and limitations of the current ex- perimental strategies targeting the mPTP.
文摘Objective:To assess acute toxicity,the in vitro and in vivo effects of methanol and ethyl acetate extracts(JME and JEE)of Jatonik polyherbal mixture on some mitochondria-related parameters and their effect on the activity of some liver enzymes.Methods:Acute toxicity of JME and JEE was determined using Lorke’s method.In vitro and in vivo opening of the mitochondrial membrane permeability transition pore(MMPT pore)was spectrophotometrically assayed.Production of malondialdehyde(MDA)as an index of lipid peroxidation and the activity of mitochondrial ATPase was evaluated in vitro and in vivo and the effect of JME and JEE on the activity of liver enzymes such as alkaline phosphatase(ALP),aspartate and alanine aminotransferase(AST and ALT)and gamma-glutamyl transferase(GGT)was also investigated.Results:JME had an LD_(50) of 3808 mg/kg b.w whereas JEE had an LD_(50) greater than 5000 mg/kg b.w.of rats.After the rats have been fed with both extracts,a photomicrograph of a piece of liver tissue showed no apparent symptoms of toxicity.From the in vitro and in vivo studies,both extracts prompted intact mitochondria to open their MMPT pores.When compared to the control,lipid peroxide product release and ATPase activity were significantly increased(P<0.05)in vitro and in vivo.The activities of AST,ALT,and GGT were all reduced at 50 mg/kg when treated with JME,but the activity of AST was considerably enhanced when treated with JEE(P<0.05).The results revealed that both JME and JEE of the Jatonik polyherbal mixture had low toxicity,profound MMPTpore induction,and enhanced ATPase activity,but an increased MDA production.Conclusion:Jatonik extracts may be a promising target for drug development in diseases where there is dysregulation of apoptosis,however,further studies are needed to better clarify the molecular mechanism involved in these phenomena.
