Summary:Ranolazine,a late sodium current inhibitor,has been demonstrated to be effective on heart failure.18B-glycyrrhetinic acid(18β-GA)has the similar inhibitory effect on late sodium currents.However,its effect on...Summary:Ranolazine,a late sodium current inhibitor,has been demonstrated to be effective on heart failure.18B-glycyrrhetinic acid(18β-GA)has the similar inhibitory effect on late sodium currents.However,its effect on diastolic function is still unknown.This study aimed to determine whether 18β-GA can improve the diastolic function and to explore the underlying mechanisms.Eighty male Sprague Dawley(SD)rats of Langendorff model were randomly divided into the following groups:group A,normal cardiac perfusion group;group B,ischemia-reperfusion group;group C,ischemia-reperfusion with anemoniasulcata toxinⅡ(ATX-Ⅱ);group D,ranolazine group;and group E,18β-GA group with four different concentrations.Furthermore,a pressure-overloaded rat model induced by trans-aortic constriction(TAC)was established.Echocardiography and hemodynamics were used to evaluate diastolic function at 14th day after TAC.Changes of free intracellular calcium(Ca27)concentration was indirectly detected by laser scanning confocal microscope to confirm the inhibition of late sodium currents.With the intervention of ATX-Ⅱon ischemia reperfusion injury group,5 umol/L ranolazine,and 5,10,20,40μmol/L 18β-GA could improve ATX-I-induced cardiac diastolic dysfunction.630 mg/kg glycyrrhizin tablets could improve cardiac diastolic function in the pressure-overloaded rats.18B-GA and ranolazine had similar effects on reducing the free calcium in cardiomyocytes.The study demonstrates that 18B-GA and glycyrrhizin could improve diastolic dysfunction induced by ischemia-reperfusion injury in Langendorff-perfused rat hearts and pressure-overloaded rats.The mechanism may be attributed to the inhibition of enhanced late sodium currents.展开更多
Objective: To investigate the mechanism of Cornus officinalis Total Glycosides (COTG) on myocardial protection, by studying effects of COTG on cardiomyocyte apoptosis induced by hypoxia/reoxygenation and calcium conce...Objective: To investigate the mechanism of Cornus officinalis Total Glycosides (COTG) on myocardial protection, by studying effects of COTG on cardiomyocyte apoptosis induced by hypoxia/reoxygenation and calcium concentration in rats. Methods: The myocardial cells of born 1-3d SD rats were isolated by enzyme digestion, cultured for 3 days. Cells were divided into five groups: Control group, H/R group, Cornus officinalis Total Glycosides low-dose group (LDG), Cornus officinalis Total Glycosides middle-dose group (MDG) and Cornus officinalis Total Glycosides high-dose group (HDG). Three drug groups were pretreated with different doses of Cornus officinalis Total Glycosides before hypoxia/reoxygenation treatment. The apoptotic rate was determined by flow cytometry assay, the intracellular free calcium concentration was examined by flow cytometry, and the ultrastructure of myocardial cells was observed under transmission electron microscope. Results: The results revealed that Cornus officinalis Total Glycosides pretreatment decreased apoptosis rate, but the effect of lower dosage is not significant. Furthermore, Cornus officinalis Total Glycosides can attenuate mitochondrial calcium overload, improve mitochondrial morphology and inhibit cardiomyocyte apoptosis caused by H/R. Conclusion: Cornus officinalis Total Glycosides pretreatment can inhibit cardiomyocyte apoptosis and calcium overload during H/R injury. However, the underlying mechanisms require us to further study.展开更多
Background:Sarcoplasmic reticulum calcium ATPase 2a(SERCA2a)is a key protein that maintains myocardial Ca2+homeostasis.The present study aimed to investigate the mechanism underlying the SERCA2a-SUMOylation(small ubiq...Background:Sarcoplasmic reticulum calcium ATPase 2a(SERCA2a)is a key protein that maintains myocardial Ca2+homeostasis.The present study aimed to investigate the mechanism underlying the SERCA2a-SUMOylation(small ubiquitinlike modifier)process after ischemia/reperfusion injury(I/RI)in vitro and in vivo.Methods:Calcium transient and systolic/diastolic function of cardiomyocytes isolated from Serca2a knockout(KO)and wildtype mice with I/RI were compared.SUMO-relevant protein expression and localization were detected by quantitative real-time PCR(RT-qPCR),Western blotting,and immunofluorescence in vitro and in vivo.Serca2a-SUMOylation,infarct size,and cardiac function of Senp1 or Senp2 overexpressed/suppressed adenovirus infected cardiomyocytes,were detected by immunoprecipitation,triphenyltetrazolium chloride(TTC)-Evans blue staining,and echocardiography respectively.Results:The results showed that the changes of Fura-2 fluorescence intensity and contraction amplitude of cardiomyocytes decreased in the I/RI groups and were further reduced in the Serca2a KO+I/RI groups.Senp1 and Senp2 messenger ribose nucleic acid(mRNA)and protein expression levels in vivo and in cardiomyocytes were highest at 6 h and declined at 12 h after I/RI.However,the highest levels in HL-1 cells were recorded at 12 h.Senp2 expression increased in the cytoplasm,unlike that of Senp1.Inhibition of Senp2 protein reversed the I/RI-induced Serca2a-SUMOylation decline,reduced the infarction area,and improved cardiac function,while inhibition of Senp1 protein could not restore the above indicators.Conclusion:I/RI activated Senp1 and Senp2 protein expression,which promoted Serca2a-deSUMOylation,while inhibition of Senp2 expression reversed Serca2a-SUMOylation and improved cardiac function.展开更多
Background: Acute lung injury (ALI) is a common complication of sepsis that is associated with high mortality, lntracellular Ca^2+ overload plays an important role in the pathophysiology of sepsis-induced ALl, and...Background: Acute lung injury (ALI) is a common complication of sepsis that is associated with high mortality, lntracellular Ca^2+ overload plays an important role in the pathophysiology of sepsis-induced ALl, and cyclic adenosine diphosphate ribose (cADPR) is an important regulator of intracellular Ca^2+ mobilization. The cluster of differentiation 38 (CD38)/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALl is still unknown. This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALl and whether blocking cADPR-mediated calcium overload attenuates ALl. Methods: Septic rat models were established by cecal ligation and puncture (CLP). Rats were divided into the sham group, the CLP group, and the CLP+ 8-bromo-cyclic adenosine diphosphate ribose (8-Br-cADPR) group. Nicotinamide adenine dinucleotide (NAD+), cADPR, CD38, and intracellular Ca^2+ levels in the lung tissues were measured at 6, 12, 24, and 48 h after CLP surgery. Lung histologic injury, tumor necrosis factor (TNF)-a, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activities were measured. Results: NAD+, cADPR, CD38, and intracellular Ca-+ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery. Treatment with 8-Br-cADPR, a specific inhibitor of cADPR, significantly reduced intracellular Ca^2+ levels (P = 0.007), attenuated lung histological injury (P = 0.023), reduced TNF-a and MDA levels (P 〈 0.001 and P = 0.002, respectively) and recovered SOD activity (P = 0.031) in the lungs of septic rats. Conclusions: The CD38/cADPR pathway is activated in the lungs of septic rats, and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALl.展开更多
Objective:To assess any direct effect of extract of Paris polyphylla Simth(EPPS),a Chinese plant,on a cardiomyocyte subject to ischemia-reperfusion injury and to further elucidate its protective effect against myoc...Objective:To assess any direct effect of extract of Paris polyphylla Simth(EPPS),a Chinese plant,on a cardiomyocyte subject to ischemia-reperfusion injury and to further elucidate its protective effect against myocardium ischemia on the cellular level.Methods:Neonatal rat cardiomyocytes were isolated and subjected to an anoxia-reoxia injury simulating the ischemia-reperfusion injury in vivo in the presence or absence of EPPS or diltizem,a positive control.The lactate dehydrogenase(LDH) activities in culture supematants and cell viabilities were analyzed using the enzymatic reaction kinetics monitoring-method and MTT method, respectively.Free intracellular calcium concentrations and activities of Na~+-K~+ ATPase and Ca^(2+) ATPase in cells were also measured with laser confocal microscopy and the inorganic phosphorus-transformation method,respectively.Results:In cardiomyocytes subject to anoxia-reoxia injury,EPPS at 50-400 mg/L showed a concentration-dependent inhibition on LDH leakage and maintenance of cell viability,and the effect was significant at 275 and 400 mg/L(both P0.01).In addition,EPPS at 275 and 400 mg/L significantly inhibited the increase in intracellular free calcium(both P0.01) as well as decreased the activities of Na~+-K~+ ATPase and Ca^(2+) ATPase(P0.01,P0.05).Conclusions:EPPS prevents anoxia-reoxia injury in neonatal rat cardiomyocytes in vitro by preservation of Na~+-K~+ ATPase and Ca^(2+) ATPase activities and inhibition of calcium overload.The direct protective effect on cardiomyocytes may be one of the key mechanisms that underlie the potential therapeutic benefit of EPPS against myocardium ischemia.展开更多
Pancreatitis is an increasingly common and sometimes severe disease that lacks a specific therapy.The pathogenesis of pancreatitis is still not well understood.Calcium(Ca2+)is a versatile carrier of signals regulating...Pancreatitis is an increasingly common and sometimes severe disease that lacks a specific therapy.The pathogenesis of pancreatitis is still not well understood.Calcium(Ca2+)is a versatile carrier of signals regulating many aspects of cellular activity and plays a central role in controlling digestive enzyme secretion in pancreatic acinar cells.Ca2+overload is a key early event and is crucial in the pathogenesis of many diseases.In pancreatic acinar cells,pathological Ca2+signaling(stimulated by bile,alcohol metabolites and othercauses)is a key contributor to the initiation of cell injury due to prolonged and global Ca2+elevation that results in trypsin activation,vacuolization and necrosis,all of which are crucial in the development of pancreatitis.Increased release of Ca2+from stores in the intracellular endoplasmic reticulum and/or increased Ca2+entry through the plasma membrane are causes of such cell damage.Failed mitochondrial adenosine triphosphate(ATP)production reduces re-uptake and extrusion of Ca2+by the sarco/endoplasmic reticulum Ca2+-activated ATPase and plasma membrane Ca2+-ATPase pumps,which contribute to Ca2+overload.Current findings have provided further insight into the roles and mechanisms of abnormal pancreatic acinar Ca2+signals in pancreatitis.The lack of available specific treatments is therefore an objective of ongoing research.Research is currently underway to establish the mechanisms and interactions of Ca2+signals in the pathogenesis of pancreatitis.展开更多
The plasma membrane Ca2+-ATPase(PMCA)is an ATPdriven pump that is critical for the maintenance of low resting[Ca2+]i in all eukaryotic cells.Metabolic stress, either due to inhibition of mitochondrial or glycolytic me...The plasma membrane Ca2+-ATPase(PMCA)is an ATPdriven pump that is critical for the maintenance of low resting[Ca2+]i in all eukaryotic cells.Metabolic stress, either due to inhibition of mitochondrial or glycolytic metabolism,has the capacity to cause ATP depletion and thus inhibit PMCA activity.This has potentially fatal consequences,particularly for non-excitable cells in which the PMCA is the major Ca2+efflux pathway.This is because inhibition of the PMCA inevitably leads to cytosolic Ca2+ overload and the consequent cell death.However,the relationship between metabolic stress,ATP depletion and inhibition of the PMCA is not as simple as one would have originally predicted.There is increasing evidence that metabolic stress can lead to the inhibition of PMCA activity independent of ATP or prior to substantial ATP depletion.In particular,there is evidence that the PMCA has its own glycolytic ATP supply that can fuel the PMCA in the face of impaired mitochondrial function.Moreover, membrane phospholipids,mitochondrial membrane potential,caspase/calpain cleavage and oxidative stress have all been implicated in metabolic stress-induced inhibition of the PMCA.The major focus of this review is to challenge the conventional view of ATP-dependent regulation of the PMCA and bring together some of the alternative or additional mechanisms by which metabolic stress impairs PMCA activity resulting in cytosolic Ca2+ overload and cytotoxicity.展开更多
Adipose mesenchymal stem cells(ADSCs)have protective effects against glutamate-induced excitotoxicity,but ADSCs are limited in use for treatment of optic nerve injury.Studies have shown that the extracellular vesicles...Adipose mesenchymal stem cells(ADSCs)have protective effects against glutamate-induced excitotoxicity,but ADSCs are limited in use for treatment of optic nerve injury.Studies have shown that the extracellular vesicles(EVs)secreted by ADSCs(ADSC-EVs)not only have the function of ADSCs,but also have unique advantages including non-immunogenicity,low probability of abnormal growth,and easy access to target cells.In the present study,we showed that intravitreal injection of ADSC-EVs substantially reduced glutamate-induced damage to retinal morphology and electroretinography.In addition,R28 cell pretreatment with ADSC-EVs before injury inhibited glutamate-induced overload of intracellular calcium,downregulation ofα-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor(AMPAR)subunit GluA2,and phosphorylation of GluA2 and protein kinase C alpha in vitro.A protein kinase C alpha agonist,12-O-tetradecanoylphorbol 13-acetate,inhibited the neuroprotective effects of ADSC-EVs on glutamate-induced R28 cells.These findings suggest that ADSCEVs ameliorate glutamate-induced excitotoxicity in the retina through inhibiting protein kinase C alpha activation.展开更多
Iron overload can lead to iron deposits in many tissues,particularly in the heart.It has also been shown to be associated with elevated oxidative stress in tissues.Elevated cardiac iron deposits can lead to iron overl...Iron overload can lead to iron deposits in many tissues,particularly in the heart.It has also been shown to be associated with elevated oxidative stress in tissues.Elevated cardiac iron deposits can lead to iron overload cardiomyopathy,a condition which provokes mortality due to heart failure in iron-overloaded patients.Currently,the mechanism of iron uptake into cardiomyocytes is still not clearly understood.Growing evidence suggests L-type Ca2+channels(LTCCs)as a possible pathway for ferrous iron(Fe2+)uptake into cardiomyocytes under iron overload conditions.Nevertheless,controversy still exists since some findings on pharmacological interventions and those using different cell types do not support LTCC’s role as a portal for iron uptake in cardiac cells.Recently,T-type Ca2+channels (TTCC)have been shown to play an important role in the diseased heart.Although TTCC and iron uptake in cardiomyocytes has not been investigated greatly,a recent finding indicated that TTCC could be an important portal in thalassemic hearts.In this review,comprehensive findings collected from previous studies as well as a discussion of the controversy regarding iron uptake mechanisms into cardiomyocytes via calcium channels are presented with the hope that understanding the cellular iron uptake mechanism in cardiomyocytes will lead to improved treatment and prevention strategies,particularly in iron-overloaded patients.展开更多
基金This project was supported by the National Natural Science Foundation of China(No.81600317 and No.81700345)the Open Foundation of Hubei Key Laboratory of Biological Targeted Therapy(No.02.03.2014-10).
文摘Summary:Ranolazine,a late sodium current inhibitor,has been demonstrated to be effective on heart failure.18B-glycyrrhetinic acid(18β-GA)has the similar inhibitory effect on late sodium currents.However,its effect on diastolic function is still unknown.This study aimed to determine whether 18β-GA can improve the diastolic function and to explore the underlying mechanisms.Eighty male Sprague Dawley(SD)rats of Langendorff model were randomly divided into the following groups:group A,normal cardiac perfusion group;group B,ischemia-reperfusion group;group C,ischemia-reperfusion with anemoniasulcata toxinⅡ(ATX-Ⅱ);group D,ranolazine group;and group E,18β-GA group with four different concentrations.Furthermore,a pressure-overloaded rat model induced by trans-aortic constriction(TAC)was established.Echocardiography and hemodynamics were used to evaluate diastolic function at 14th day after TAC.Changes of free intracellular calcium(Ca27)concentration was indirectly detected by laser scanning confocal microscope to confirm the inhibition of late sodium currents.With the intervention of ATX-Ⅱon ischemia reperfusion injury group,5 umol/L ranolazine,and 5,10,20,40μmol/L 18β-GA could improve ATX-I-induced cardiac diastolic dysfunction.630 mg/kg glycyrrhizin tablets could improve cardiac diastolic function in the pressure-overloaded rats.18B-GA and ranolazine had similar effects on reducing the free calcium in cardiomyocytes.The study demonstrates that 18B-GA and glycyrrhizin could improve diastolic dysfunction induced by ischemia-reperfusion injury in Langendorff-perfused rat hearts and pressure-overloaded rats.The mechanism may be attributed to the inhibition of enhanced late sodium currents.
文摘Objective: To investigate the mechanism of Cornus officinalis Total Glycosides (COTG) on myocardial protection, by studying effects of COTG on cardiomyocyte apoptosis induced by hypoxia/reoxygenation and calcium concentration in rats. Methods: The myocardial cells of born 1-3d SD rats were isolated by enzyme digestion, cultured for 3 days. Cells were divided into five groups: Control group, H/R group, Cornus officinalis Total Glycosides low-dose group (LDG), Cornus officinalis Total Glycosides middle-dose group (MDG) and Cornus officinalis Total Glycosides high-dose group (HDG). Three drug groups were pretreated with different doses of Cornus officinalis Total Glycosides before hypoxia/reoxygenation treatment. The apoptotic rate was determined by flow cytometry assay, the intracellular free calcium concentration was examined by flow cytometry, and the ultrastructure of myocardial cells was observed under transmission electron microscope. Results: The results revealed that Cornus officinalis Total Glycosides pretreatment decreased apoptosis rate, but the effect of lower dosage is not significant. Furthermore, Cornus officinalis Total Glycosides can attenuate mitochondrial calcium overload, improve mitochondrial morphology and inhibit cardiomyocyte apoptosis caused by H/R. Conclusion: Cornus officinalis Total Glycosides pretreatment can inhibit cardiomyocyte apoptosis and calcium overload during H/R injury. However, the underlying mechanisms require us to further study.
基金supported by grants from the Natural Science Foundation of Jiangsu Province(No.BK20190988)the Scientific Research Project of Jiangsu Health Committee(No.H2018005)+1 种基金the Key Research and Development Program of Xuzhou(No.KC20097)the Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX21_2671).
文摘Background:Sarcoplasmic reticulum calcium ATPase 2a(SERCA2a)is a key protein that maintains myocardial Ca2+homeostasis.The present study aimed to investigate the mechanism underlying the SERCA2a-SUMOylation(small ubiquitinlike modifier)process after ischemia/reperfusion injury(I/RI)in vitro and in vivo.Methods:Calcium transient and systolic/diastolic function of cardiomyocytes isolated from Serca2a knockout(KO)and wildtype mice with I/RI were compared.SUMO-relevant protein expression and localization were detected by quantitative real-time PCR(RT-qPCR),Western blotting,and immunofluorescence in vitro and in vivo.Serca2a-SUMOylation,infarct size,and cardiac function of Senp1 or Senp2 overexpressed/suppressed adenovirus infected cardiomyocytes,were detected by immunoprecipitation,triphenyltetrazolium chloride(TTC)-Evans blue staining,and echocardiography respectively.Results:The results showed that the changes of Fura-2 fluorescence intensity and contraction amplitude of cardiomyocytes decreased in the I/RI groups and were further reduced in the Serca2a KO+I/RI groups.Senp1 and Senp2 messenger ribose nucleic acid(mRNA)and protein expression levels in vivo and in cardiomyocytes were highest at 6 h and declined at 12 h after I/RI.However,the highest levels in HL-1 cells were recorded at 12 h.Senp2 expression increased in the cytoplasm,unlike that of Senp1.Inhibition of Senp2 protein reversed the I/RI-induced Serca2a-SUMOylation decline,reduced the infarction area,and improved cardiac function,while inhibition of Senp1 protein could not restore the above indicators.Conclusion:I/RI activated Senp1 and Senp2 protein expression,which promoted Serca2a-deSUMOylation,while inhibition of Senp2 expression reversed Serca2a-SUMOylation and improved cardiac function.
文摘Background: Acute lung injury (ALI) is a common complication of sepsis that is associated with high mortality, lntracellular Ca^2+ overload plays an important role in the pathophysiology of sepsis-induced ALl, and cyclic adenosine diphosphate ribose (cADPR) is an important regulator of intracellular Ca^2+ mobilization. The cluster of differentiation 38 (CD38)/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALl is still unknown. This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALl and whether blocking cADPR-mediated calcium overload attenuates ALl. Methods: Septic rat models were established by cecal ligation and puncture (CLP). Rats were divided into the sham group, the CLP group, and the CLP+ 8-bromo-cyclic adenosine diphosphate ribose (8-Br-cADPR) group. Nicotinamide adenine dinucleotide (NAD+), cADPR, CD38, and intracellular Ca^2+ levels in the lung tissues were measured at 6, 12, 24, and 48 h after CLP surgery. Lung histologic injury, tumor necrosis factor (TNF)-a, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activities were measured. Results: NAD+, cADPR, CD38, and intracellular Ca-+ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery. Treatment with 8-Br-cADPR, a specific inhibitor of cADPR, significantly reduced intracellular Ca^2+ levels (P = 0.007), attenuated lung histological injury (P = 0.023), reduced TNF-a and MDA levels (P 〈 0.001 and P = 0.002, respectively) and recovered SOD activity (P = 0.031) in the lungs of septic rats. Conclusions: The CD38/cADPR pathway is activated in the lungs of septic rats, and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALl.
基金Supported by the Major Scientific and Technological Specialized Project for"Significant New Formulation of New Drugs(No. 2009ZX09301,2009ZX09303-003)"
文摘Objective:To assess any direct effect of extract of Paris polyphylla Simth(EPPS),a Chinese plant,on a cardiomyocyte subject to ischemia-reperfusion injury and to further elucidate its protective effect against myocardium ischemia on the cellular level.Methods:Neonatal rat cardiomyocytes were isolated and subjected to an anoxia-reoxia injury simulating the ischemia-reperfusion injury in vivo in the presence or absence of EPPS or diltizem,a positive control.The lactate dehydrogenase(LDH) activities in culture supematants and cell viabilities were analyzed using the enzymatic reaction kinetics monitoring-method and MTT method, respectively.Free intracellular calcium concentrations and activities of Na~+-K~+ ATPase and Ca^(2+) ATPase in cells were also measured with laser confocal microscopy and the inorganic phosphorus-transformation method,respectively.Results:In cardiomyocytes subject to anoxia-reoxia injury,EPPS at 50-400 mg/L showed a concentration-dependent inhibition on LDH leakage and maintenance of cell viability,and the effect was significant at 275 and 400 mg/L(both P0.01).In addition,EPPS at 275 and 400 mg/L significantly inhibited the increase in intracellular free calcium(both P0.01) as well as decreased the activities of Na~+-K~+ ATPase and Ca^(2+) ATPase(P0.01,P0.05).Conclusions:EPPS prevents anoxia-reoxia injury in neonatal rat cardiomyocytes in vitro by preservation of Na~+-K~+ ATPase and Ca^(2+) ATPase activities and inhibition of calcium overload.The direct protective effect on cardiomyocytes may be one of the key mechanisms that underlie the potential therapeutic benefit of EPPS against myocardium ischemia.
基金This work is supported by grants from National Natural Science Foundation of China (No. 81102079) and China Postdoctoral Science Foundation (No. 201003776). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors report no conflict of interest. The authors are responsible for the content and writing of the paper.
基金Supported by grants from the National Natural Science Foundation of China No.30171167,No.30901945the Specialized Research Fund for the Doctoral Program of Higher Education No.20130201130009
文摘Pancreatitis is an increasingly common and sometimes severe disease that lacks a specific therapy.The pathogenesis of pancreatitis is still not well understood.Calcium(Ca2+)is a versatile carrier of signals regulating many aspects of cellular activity and plays a central role in controlling digestive enzyme secretion in pancreatic acinar cells.Ca2+overload is a key early event and is crucial in the pathogenesis of many diseases.In pancreatic acinar cells,pathological Ca2+signaling(stimulated by bile,alcohol metabolites and othercauses)is a key contributor to the initiation of cell injury due to prolonged and global Ca2+elevation that results in trypsin activation,vacuolization and necrosis,all of which are crucial in the development of pancreatitis.Increased release of Ca2+from stores in the intracellular endoplasmic reticulum and/or increased Ca2+entry through the plasma membrane are causes of such cell damage.Failed mitochondrial adenosine triphosphate(ATP)production reduces re-uptake and extrusion of Ca2+by the sarco/endoplasmic reticulum Ca2+-activated ATPase and plasma membrane Ca2+-ATPase pumps,which contribute to Ca2+overload.Current findings have provided further insight into the roles and mechanisms of abnormal pancreatic acinar Ca2+signals in pancreatitis.The lack of available specific treatments is therefore an objective of ongoing research.Research is currently underway to establish the mechanisms and interactions of Ca2+signals in the pathogenesis of pancreatitis.
基金Supported by A New Investigator Award from the BBSRC
文摘The plasma membrane Ca2+-ATPase(PMCA)is an ATPdriven pump that is critical for the maintenance of low resting[Ca2+]i in all eukaryotic cells.Metabolic stress, either due to inhibition of mitochondrial or glycolytic metabolism,has the capacity to cause ATP depletion and thus inhibit PMCA activity.This has potentially fatal consequences,particularly for non-excitable cells in which the PMCA is the major Ca2+efflux pathway.This is because inhibition of the PMCA inevitably leads to cytosolic Ca2+ overload and the consequent cell death.However,the relationship between metabolic stress,ATP depletion and inhibition of the PMCA is not as simple as one would have originally predicted.There is increasing evidence that metabolic stress can lead to the inhibition of PMCA activity independent of ATP or prior to substantial ATP depletion.In particular,there is evidence that the PMCA has its own glycolytic ATP supply that can fuel the PMCA in the face of impaired mitochondrial function.Moreover, membrane phospholipids,mitochondrial membrane potential,caspase/calpain cleavage and oxidative stress have all been implicated in metabolic stress-induced inhibition of the PMCA.The major focus of this review is to challenge the conventional view of ATP-dependent regulation of the PMCA and bring together some of the alternative or additional mechanisms by which metabolic stress impairs PMCA activity resulting in cytosolic Ca2+ overload and cytotoxicity.
基金supported by the National Key R&D Program of China,No.2016YFC1201800(to JFH)the Key Research and Development Program of Hunan Province,Nos.2018SK2090(to JFH),2022SK2079(to JFH)+2 种基金the Natural Science Foundation of Hu nan Province,No.2021JJ30891(to DC)the Human Resource Bank Program of Hunan Province,No.2020TP3003(to JFH)the School-Enterprise Joint Program of Central South University,No.2021XQLH092(to TQD)。
文摘Adipose mesenchymal stem cells(ADSCs)have protective effects against glutamate-induced excitotoxicity,but ADSCs are limited in use for treatment of optic nerve injury.Studies have shown that the extracellular vesicles(EVs)secreted by ADSCs(ADSC-EVs)not only have the function of ADSCs,but also have unique advantages including non-immunogenicity,low probability of abnormal growth,and easy access to target cells.In the present study,we showed that intravitreal injection of ADSC-EVs substantially reduced glutamate-induced damage to retinal morphology and electroretinography.In addition,R28 cell pretreatment with ADSC-EVs before injury inhibited glutamate-induced overload of intracellular calcium,downregulation ofα-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor(AMPAR)subunit GluA2,and phosphorylation of GluA2 and protein kinase C alpha in vitro.A protein kinase C alpha agonist,12-O-tetradecanoylphorbol 13-acetate,inhibited the neuroprotective effects of ADSC-EVs on glutamate-induced R28 cells.These findings suggest that ADSCEVs ameliorate glutamate-induced excitotoxicity in the retina through inhibiting protein kinase C alpha activation.
基金Supported by Thailand Research Fund grants RTA5280006 (Chattipakorn N)BRG5480003(Chattipakorn S)+1 种基金the National Research Council of Thailand(Chattipakorn N)the Thai-land Research Fund Royal Golden Jubilee project(Kumfu S and Chattipakorn N)
文摘Iron overload can lead to iron deposits in many tissues,particularly in the heart.It has also been shown to be associated with elevated oxidative stress in tissues.Elevated cardiac iron deposits can lead to iron overload cardiomyopathy,a condition which provokes mortality due to heart failure in iron-overloaded patients.Currently,the mechanism of iron uptake into cardiomyocytes is still not clearly understood.Growing evidence suggests L-type Ca2+channels(LTCCs)as a possible pathway for ferrous iron(Fe2+)uptake into cardiomyocytes under iron overload conditions.Nevertheless,controversy still exists since some findings on pharmacological interventions and those using different cell types do not support LTCC’s role as a portal for iron uptake in cardiac cells.Recently,T-type Ca2+channels (TTCC)have been shown to play an important role in the diseased heart.Although TTCC and iron uptake in cardiomyocytes has not been investigated greatly,a recent finding indicated that TTCC could be an important portal in thalassemic hearts.In this review,comprehensive findings collected from previous studies as well as a discussion of the controversy regarding iron uptake mechanisms into cardiomyocytes via calcium channels are presented with the hope that understanding the cellular iron uptake mechanism in cardiomyocytes will lead to improved treatment and prevention strategies,particularly in iron-overloaded patients.