Background Endoplasmic reticulum （ER） stress-related apoptosis is involved in the pathophysiology of many cardiovascular diseases, and Panax quinquefolium saponin （PQS） is able to inhibit excessive ER stress-relat...Background Endoplasmic reticulum （ER） stress-related apoptosis is involved in the pathophysiology of many cardiovascular diseases, and Panax quinquefolium saponin （PQS） is able to inhibit excessive ER stress-related apoptosis of cardiomyocytes following hypoxia/reoxygenation and myocardial infarction. However, the pathway by which PQS inhibits the ER stress-related apoptosis is not well understood. To further investigate the protective effect of PQS against ER stress-related apoptosis, primary cultured eardiomyocytes were stimulated with thapsigargin （TG）, which is widely used to model cellular ER stress, and it could induce apoptotic cell death in sufficient concentration. Methods Primary cultured cardiomyocytes from neonatal rats were exposed to TG （1 μmol/L） treatment for 24 h, following PQS pre-treatment （160 μg/mL） for 24 h or pre-treatment with small interfering RNA directed against protein kinase-like endoplasmic reticulum kinase （Si-PERK） for 6 h. The viability and apoptosis rate of cardiomyocytes were detected by cell counting kit-8 and flow cytometry respectively. ER stress-related protein expression, such as glucose-regulated protein 78 （GRP78）, calreticulin, PERK, eukaryotic translation initiation factor 2α （elF2c0, activating transcription factor 4 （ATF4）, and C/EBP homologous protein （CHOP） were assayed by western blotting. Results Both PQS pre-treatment and PERK knockdown remarkably inhibited the cardiomyocyte apoptosis induced by TG, increased cell viability, decreased phosphorylation of both PERK and eIF2α, and decreased protein levels of both ATF4 and CHOP. There was no statistically significant difference between PQS pre-treatment and PERK knockdown in the cardioprotective effect. Conclusions Our data indicate that the PERK-eIF2α-ATF4-CHOP pathway of ER stress is involved in the apoptosis induced by TG, and PQS might prevent TG-induced cardiomyocyte apoptosis through a mechanism involving the suppression of this pathway. These findings provide novel data regarding the molecular mechanisms by which PQS inhibits cardiomyocyte apoptosis.展开更多
Efficient functioning of the endoplasmic reticulum(ER) is very important for most cellular activities, such as protein folding and modification. The ER closely interacts with other organelles, including the Golgi body...Efficient functioning of the endoplasmic reticulum(ER) is very important for most cellular activities, such as protein folding and modification. The ER closely interacts with other organelles, including the Golgi body, endosome, membrane, and mitochondria, providing lipids and proteins for the repair of these organelles. ER stress can be induced by various abnormal materials in the cell. ER stress is a compensatory intracellular environment disorder that occurs during areaction. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system, but excessive ER activation can cause cell death. The Pubmed and Web of Science databases were searched for full-text articles, and the terms "endoplasmic reticulum stress/unfolded protein response/gynecologic tumor cell apoptosis" were used as key words. Thirty-five studies of ER stress and unfolded protein response published from 2000 to 2016 were analyzed. Stress triggers apoptosis through a variety of signaling pathways. Increasing evidence has shown that the ER plays an important role in tumor cell diseases. The present review discusses the molecular mechanisms underlying unfolded protein response and its ability to promote survival and proliferation in gynecologic tumor cells.展开更多
This study aimed to investigate the impact of developmental endothelial locus-1(Del-1)on sarcoplasmic reticulum Ca^(2+)ATPase 2(SERCA2)and its potential effects on spinal cord injury(SCI).A total of 48 mice were rando...This study aimed to investigate the impact of developmental endothelial locus-1(Del-1)on sarcoplasmic reticulum Ca^(2+)ATPase 2(SERCA2)and its potential effects on spinal cord injury(SCI).A total of 48 mice were randomly assigned to the sham group,SCI group,and SCI+CE group.Each group was further divided into two subgroups.The Del treatment subgroup received tail-vein injections of Del-1(1μg/d)for a consecutive week,while the other group was injected with an equivalent volume of normal saline.After 1 week of experimentation,the mice were euthanized,and the spinal cord was extracted for further analysis.Initially,the impact of Del-1 on SERCA2 in the spinal cord was assessed using western blotting analysis.Subsequently,the effects of Del-1 on stress,inflammation,and apoptosis in the endoplasmic reticulum(ER)of SCI mice were analyzed through Western blotting analysis and fluorescent TUNEL.Finally,the study utilized Western blotting analysis and fluorescent TUNEL analysis to examine the consequences of Del-1 blocking SERCA2 on ER stress,inflammation,and apoptosis in mice.The results revealed that Del-1 treatment significantly increased the expression of SERCA2 in the spinal cord(P<0.01)and mitigated SCI-induced ER stress,inflammation,and neuronal apoptosis(P<0.01).Blocking SERCA2 expression in the spinal cord of SCI mice promoted ER stress,inflammatory response,and neuronal cell apoptosis(P<0.01).However,Del-1 treatment did not alleviate the effects of blocking SERCA2 on ER stress,inflammatory response,and neuronal cell apoptosis(P>0.05).In conclusion,this study proposed that Del-1 could reduce ER stress,inflammatory response,and nerve cell apoptosis in spinal cord injury by enhancing the expression of SERCA2.展开更多
文摘在Ca2+稳态平衡紊乱、葡萄糖饥饿、错误折叠蛋白质的表达、蛋白质糖基化的抑制或胆固醇合成超载等胁迫条件下,会导致内质网内积累大量的未折叠蛋白质,形成内质网应激(endoplasmic reticulum stress,ERS),对细胞产生根本性的危害。在应激条件下,内质网会产生未折叠蛋白应答(unfolded protein responseUPR),通过改变细胞的转录和翻译过程来缓解内质网应激,维持细胞功能;但是,如果细胞长时间处于UPR条件下,则会诱导细胞凋亡。
基金Acknowledgements This work was supported by International Science and Technology Cooperation Project （2010DFA31690）, National Natural Science Foundation of China （81030063 and 81170140） and China Postdoctoral Science Foundation （2014M562608）. The authors declare no conflict of interests regarding the publication of this paper.
文摘Background Endoplasmic reticulum （ER） stress-related apoptosis is involved in the pathophysiology of many cardiovascular diseases, and Panax quinquefolium saponin （PQS） is able to inhibit excessive ER stress-related apoptosis of cardiomyocytes following hypoxia/reoxygenation and myocardial infarction. However, the pathway by which PQS inhibits the ER stress-related apoptosis is not well understood. To further investigate the protective effect of PQS against ER stress-related apoptosis, primary cultured eardiomyocytes were stimulated with thapsigargin （TG）, which is widely used to model cellular ER stress, and it could induce apoptotic cell death in sufficient concentration. Methods Primary cultured cardiomyocytes from neonatal rats were exposed to TG （1 μmol/L） treatment for 24 h, following PQS pre-treatment （160 μg/mL） for 24 h or pre-treatment with small interfering RNA directed against protein kinase-like endoplasmic reticulum kinase （Si-PERK） for 6 h. The viability and apoptosis rate of cardiomyocytes were detected by cell counting kit-8 and flow cytometry respectively. ER stress-related protein expression, such as glucose-regulated protein 78 （GRP78）, calreticulin, PERK, eukaryotic translation initiation factor 2α （elF2c0, activating transcription factor 4 （ATF4）, and C/EBP homologous protein （CHOP） were assayed by western blotting. Results Both PQS pre-treatment and PERK knockdown remarkably inhibited the cardiomyocyte apoptosis induced by TG, increased cell viability, decreased phosphorylation of both PERK and eIF2α, and decreased protein levels of both ATF4 and CHOP. There was no statistically significant difference between PQS pre-treatment and PERK knockdown in the cardioprotective effect. Conclusions Our data indicate that the PERK-eIF2α-ATF4-CHOP pathway of ER stress is involved in the apoptosis induced by TG, and PQS might prevent TG-induced cardiomyocyte apoptosis through a mechanism involving the suppression of this pathway. These findings provide novel data regarding the molecular mechanisms by which PQS inhibits cardiomyocyte apoptosis.
文摘Efficient functioning of the endoplasmic reticulum(ER) is very important for most cellular activities, such as protein folding and modification. The ER closely interacts with other organelles, including the Golgi body, endosome, membrane, and mitochondria, providing lipids and proteins for the repair of these organelles. ER stress can be induced by various abnormal materials in the cell. ER stress is a compensatory intracellular environment disorder that occurs during areaction. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system, but excessive ER activation can cause cell death. The Pubmed and Web of Science databases were searched for full-text articles, and the terms "endoplasmic reticulum stress/unfolded protein response/gynecologic tumor cell apoptosis" were used as key words. Thirty-five studies of ER stress and unfolded protein response published from 2000 to 2016 were analyzed. Stress triggers apoptosis through a variety of signaling pathways. Increasing evidence has shown that the ER plays an important role in tumor cell diseases. The present review discusses the molecular mechanisms underlying unfolded protein response and its ability to promote survival and proliferation in gynecologic tumor cells.
基金National Key Research and Development Plan of China(Grant No.2016YFC1101503)。
文摘This study aimed to investigate the impact of developmental endothelial locus-1(Del-1)on sarcoplasmic reticulum Ca^(2+)ATPase 2(SERCA2)and its potential effects on spinal cord injury(SCI).A total of 48 mice were randomly assigned to the sham group,SCI group,and SCI+CE group.Each group was further divided into two subgroups.The Del treatment subgroup received tail-vein injections of Del-1(1μg/d)for a consecutive week,while the other group was injected with an equivalent volume of normal saline.After 1 week of experimentation,the mice were euthanized,and the spinal cord was extracted for further analysis.Initially,the impact of Del-1 on SERCA2 in the spinal cord was assessed using western blotting analysis.Subsequently,the effects of Del-1 on stress,inflammation,and apoptosis in the endoplasmic reticulum(ER)of SCI mice were analyzed through Western blotting analysis and fluorescent TUNEL.Finally,the study utilized Western blotting analysis and fluorescent TUNEL analysis to examine the consequences of Del-1 blocking SERCA2 on ER stress,inflammation,and apoptosis in mice.The results revealed that Del-1 treatment significantly increased the expression of SERCA2 in the spinal cord(P<0.01)and mitigated SCI-induced ER stress,inflammation,and neuronal apoptosis(P<0.01).Blocking SERCA2 expression in the spinal cord of SCI mice promoted ER stress,inflammatory response,and neuronal cell apoptosis(P<0.01).However,Del-1 treatment did not alleviate the effects of blocking SERCA2 on ER stress,inflammatory response,and neuronal cell apoptosis(P>0.05).In conclusion,this study proposed that Del-1 could reduce ER stress,inflammatory response,and nerve cell apoptosis in spinal cord injury by enhancing the expression of SERCA2.
