Objective Autophagy is a highly conserved intracellular degradation pathway. Many picornaviruses induce autophagy to benefit viral replication, but an understanding of how autophagy occurs remains incomplete. In this ...Objective Autophagy is a highly conserved intracellular degradation pathway. Many picornaviruses induce autophagy to benefit viral replication, but an understanding of how autophagy occurs remains incomplete. In this study, we explored whether coxsackievirus B3(CVB3) infection induced autophagy through endoplasmic reticulum(ER) stress. Methods In CVB3-infected HeLa cells, the specific molecules of ER stress and autophagy were detected using Western blotting, reverse transcription polymerase chain reaction(RT-PCR), and confocal microscopy. Then PKR-like ER protein kinase(PERK) inhibitor, inositol-requiring protein-1(IRE1) inhibitor, or activating transcription factor-6(ATF6) inhibitor worked on CVB3-infected cells, their effect on autophagy was assessed by Western blotting for detecting microtubule-associated protein light chain 3(LC3). Results CVB3 infection induced ER stress, and ER stress sensors PERK/eIF2α, IRE1/XBP1, and ATF6 were activated. CVB3 infection increased the accumulation of green fluorescent protein(GFP)-LC3 punctuation and induced the conversion from LC3-Ⅰ to phosphatidylethanolamine-conjugated LC3-1(LC3-Ⅱ). CVB3 infection still decreased the expression of mammalian target of rapamycin(mTOR) and p-mTOR. Inhibition of PERK, IRE1, or ATF6 significantly decreased the ratio of LC3-Ⅱ to LC3-Ⅰ in CVB3-infected HeLa cells. Conclusion CVB3 infection induced autophagy through ER stress in HeL a cells, and PERK, IRE1, and ATF6 a pathways participated in the regulation of autophagy. Our data suggested that ER stress may inhibit mTOR signaling pathway to induce autophagy during CVB3 infection.展开更多
Zinc is a trace element involved in maintaining cellular structure and function.Although zinc is associated with left ventricular hypertrophy(LVH),there have been few reports on this association.This study aimed to ev...Zinc is a trace element involved in maintaining cellular structure and function.Although zinc is associated with left ventricular hypertrophy(LVH),there have been few reports on this association.This study aimed to evaluate the correlation between Zip14 and expression of endoplasmic reticulum stress(ERS)associated molecules in hypertrophied hearts of rats.Dahl salt-sensitive rats were fed a high salt diet to establish a left ventricular hypertrophy(LVH)rat model.RT-PCR was used to determine Zip14,activating transcription factor(ATF4),ATF6,x-box-binding protein 1(xBP1),C/EBP homologous protein(CHOP),immunoglobulin-binding protein(BiP)mRNA expression.Western blotting was used to evaluate Zip14,BiP,CHOP,GAPDH expression.Zinc levels were measured by Inductively Coupled Plasma Optical Emission Spectroscopy.The results indicated that compared with the Control group,Zip14 mRNA and protein expression in LVH rat hearts were markedly increased(P<0.01).Zinc content in rat heart tissue was significantly increased in the LVH group compared with the Control group(P<0.05).ATF4,ATF6,xBP1 mRNA expressions were increased in LVH rat hearts compared with Control hearts(P<0.001).Compared with the Control group,CHOP and BiP mRNA and protein expression were markedly increased in LVH rat hearts(P<0.05,P<0.01).Linear regression models showed that Zip14 mRNA expressions were positively correlated with zinc concentration,ATF4 and ATF6 mRNA expressions in Control hearts(P=0.0005,P=0.0052,P=0.0026,respectively)and LVH rat hearts(P<0.0001,P=0.0119,P=0.0033,respectively).In conclusion,upregulation of Zip14 in LVH rat hearts correlated with zinc accumulation and induction of ERS.展开更多
他莫昔芬(tamoxifen,TAM)作为雌激素受体阳性(estrogen receptor,ER+)乳腺癌的一线化疗药物使大多数患者受益,但原发性和继发性耐药问题严重影响临床治疗效果。深入研究ER+乳腺癌TAM耐药机制,改善治疗效果是当前亟待解决的问题。抑癌因...他莫昔芬(tamoxifen,TAM)作为雌激素受体阳性(estrogen receptor,ER+)乳腺癌的一线化疗药物使大多数患者受益,但原发性和继发性耐药问题严重影响临床治疗效果。深入研究ER+乳腺癌TAM耐药机制,改善治疗效果是当前亟待解决的问题。抑癌因子NDRG2(N-myc downstream regulated gene 2,NDRG2)在肿瘤发生发展中发挥重要作用,但是否参与ER+乳腺癌TAM耐药尚不清楚。本研究旨在探明NDRG2在ER+乳腺癌TAM耐药中发挥的作用和机制。通过RT-PCR与免疫印迹分析对比TAM敏感型和耐药型ER+乳腺癌细胞发现,NDRG 2的mRNA转录水平和蛋白质翻译水平在TAM耐药细胞中表达显著下调,且与耐药能力负相关(P<0.001);CCK-8细胞毒性实验和软琼脂克隆形成实验证实,在耐药细胞中过表达NDRG2可显著降低TAM药物半抑制浓度IC 50和软琼脂克隆形成率(P<0.001),逆转耐药表型。分子机制上,X-box结合蛋白1(X-box binding protein 1,XBP1)mRNA剪切实验与内质网相关降解(endoplasmic-reticulum associated degradation,ERAD)报告蛋白的结果显示,过表达NDRG2可增强耐药细胞中剪切型XBP1s mRNA转录与ERAD报告蛋白CD3ε-YFP表达(P<0.001),引发耐药细胞内质网强应激反应;免疫印迹检测结果显示,过表达NDRG2可显著提高耐药细胞中内质网应激感受器肌醇需要激酶1α(inositol requiring enzyme 1,IRE1α)的磷酸化水平及其下游因子,例如内质网EIP辅助因子(endoplasmic reticulum-localized DnaJ 4,ERdj4)、PKR蛋白激酶的细胞抑制剂(cellular Inhibitor of the PKR protein kinase,P58 IPK)、α甘露糖苷酶样应激蛋白(er degradation enhancingαmannosidase likeprotein,EDEM)和蛋白质二硫键异构酶家族A成员5(protein disulfide isomerase family a member 5,PDIA5)的表达水平(P<0.001)。小鼠异种移植瘤研究进一步证实,在耐药细胞中过表达NDRG2可增强TAM治疗效果,显著抑制耐药移植瘤生长(P<0.001)。以上研究结果表明,通过提高耐药细胞中NDRG2表达,增强TAM治疗引发的内质网强烈应激,可逆转ER+乳腺癌细胞耐药性,改善TAM治疗效果。研究结果为解决ER+乳腺癌TAM耐药问题提供了新的思路和有价值的潜在药物靶点。展开更多
Brain ischemic stroke is the leading cause of long-lasting injury,disability,and death in adults.Although the brain represents only about 2%of the total body mass,it consumes almost 20%of the body＇s oxygen.As a resul...Brain ischemic stroke is the leading cause of long-lasting injury,disability,and death in adults.Although the brain represents only about 2%of the total body mass,it consumes almost 20%of the body＇s oxygen.As a result,brain cells are extremely sensitive to hypoxia.Once cerebral ischemia occurs.展开更多
This study aimed to elucidate the molecular mechanisms by which berberine protects against cerebral ischemia/reperfusion(I/R)injury.The oxygen-glucose deprivation/reperfusion(OGD/R)PC12 model was established.Cell coun...This study aimed to elucidate the molecular mechanisms by which berberine protects against cerebral ischemia/reperfusion(I/R)injury.The oxygen-glucose deprivation/reperfusion(OGD/R)PC12 model was established.Cell counting kit-8(CCK-8)was used to detect the toxicity of berberine and the viability of PC12 cells.Hoechst 33258 staining and flow cytometry were used to observe the nuclear morphology,and changes of apoptosis and reactive oxygen species(ROS),respectively.Western blotting and immunofluorescence assay were employed to detect autophagy-related proteins[microtubule-associated protein 1A/1B-light chain 3(LC3),P62/SQSTM-1,Beclin-1]and endoplasmic reticulum(ER)stress-related markers[glucose-regulated protein 78(GRP78),C/EBP homologous protein(CHOP),Bcl-2-associated X(Bax)and cleaved caspase-3].The GFP-RFP-LC3 adenovirus was used to assay the change of autophagic flux.Our results showed that berberine could increase the viability of PC12 cells,decrease the concentrations of ROS after OGD/R treatment,and suppress OGD/R-induced ER stress and autophagy.Moreover,the results revealed the involvement of the mammalian target of rapamycin(mTOR)pathway in the induction of autophagy,and berberine could activate the phosphorylation of mTOR and thus mitigate autophagy.In conclusion,our study suggested that berberine may protect against OGD/R-induced apoptosis by regulating ER stress and autophagy,and it holds promises in the treatment of cerebral I/R injury.展开更多
Objective： The aim of this study was to explore the mechanisms by which the flavonoid casticin enhances tumor necrosis factor-related apoptosis-inducing ligand （TRAIL）-induced apoptosis in colon cancer cells. Meth...Objective： The aim of this study was to explore the mechanisms by which the flavonoid casticin enhances tumor necrosis factor-related apoptosis-inducing ligand （TRAIL）-induced apoptosis in colon cancer cells. Methods： Human colon cancer HT-29 cells were treated with TRAIL or casticin. Cytotoxicity was examined by MTT assay, and apoptosis determined by morphological observation and flow cytometric analysis. Death receptor 5 （DRS）, DR4, and endoplasmic reticulum （ER） stress response markers, including glucose regulating protein 78 （GRP78）, activating transcription factor 4 （ATF4） and CHOP （CCAAT/enhancer binding protein homologous protein）, were examined with western blot. Small interfering RNA （siRNA） transfection was employed to knock down CHOP. Results： HT-29 cells were resistance to TRAIL-induced apoptosis, but casticin, at subtoxic concentrations, potentiated HT-29 cells to TRAIL-induced apoptosis. Casticin up-regulated the expression of DR5 time-and dose-dependent manners, but had no effect on the expression of DR4. Also, casticin increased the levels of ER stress response markers （GRP78, ATF4 and CHOP） in a similar way to DR5. Knockdown of CHOP by specific siRNA, or salubrinal, an ER stress inhibitor, abolished the up-regulation of DR5 and enhancement of TRAIL-induced apoptosis by casticin. Conclusion： Casticin enhances TRAIL-induced apoptosis of colon cancer cells by ER stress-mediated up-regulation of DR5.展开更多
目的探讨香砂六君子汤对脾虚高脂血症大鼠内质网应激蛋白激酶R样内质网激酶(protein kinase R-like ER kinase,PERK)信号通路的影响。方法SD大鼠随机分为4组,即正常对照组、脾虚高脂组、香砂六君子汤组和辛伐他汀组,后3组采用饮食不节...目的探讨香砂六君子汤对脾虚高脂血症大鼠内质网应激蛋白激酶R样内质网激酶(protein kinase R-like ER kinase,PERK)信号通路的影响。方法SD大鼠随机分为4组,即正常对照组、脾虚高脂组、香砂六君子汤组和辛伐他汀组,后3组采用饮食不节加力竭游泳的复合方法造模15 d后,正常组喂饲基础饲料,其余3组喂饲高脂饲料。12周后,分别给予相对剂量药物和生理盐水。4周后,检测各组大鼠血脂含量、D-木糖排泄率,油红O染色观察肝脏脂质沉积情况,实时荧光定量PCR及Western blot法检测大鼠肝脏葡萄糖调节蛋白78(glucose regulated protein 78 kD,GRP78)、PERK和活化转录因子4(the activating transcription factor 6,ATF4)基因及蛋白表达。结果与正常对照组比较,脾虚高脂组大鼠血清脂质异常,表现为总胆固醇(cholesterol,TC)、甘油三酯(triglyceride,TG)、低密度脂蛋白胆固醇酯(low density lipoprotein-cholesterol,LDL-C)明显升高,高密度脂蛋白胆固醇酯(high density lipoprotein-cholesterol,HDL-C)明显降低,尿D-木糖排泄率明显降低;肝脏脂质沉积显著,可见明显脂滴;肝脏GRP78、PERK和ATF4 mRNA水平及蛋白表达水平显著升高。与脾虚高脂组比较,香砂六君子汤组和辛伐他汀组大鼠血清TC、TG、LDL-C明显降低,HDL-C明显升高,尿D-木糖排泄率明显升高;其肝脏脂质沉积情况有明显改善,脂滴不同程度减轻;肝脏GRP78、PERK和ATF4 mRNA水平及蛋白表达水平明显降低。结论香砂六君子汤可能通过调控内网应激PERK信号通路来纠正脾虚脂质紊乱的状态。展开更多
Endoplasmic reticulum stress is closely involved in the early stage of diabetic retinopathy. In the present study, a streptozotocin-induced diabetic animal model was given an intraperitoneal injection of tauroursodeox...Endoplasmic reticulum stress is closely involved in the early stage of diabetic retinopathy. In the present study, a streptozotocin-induced diabetic animal model was given an intraperitoneal injection of tauroursodeoxycholic acid. Results from immunofluorescent co-localization experiments showed that both caspase-12 protein and c-Jun N-terminal kinase 1 phosphorylation levels significantly in- creased, which was associated with retinal ganglion cell death in diabetic retinas. The C/ERB ho- mologous protein pathway directly contributed to glial reactivity, and was subsequently responsible for neuronal loss and vascular abnormalities in diabetic retinopathy. Our experimental findings in- dicate that endoplasmic reticulum stress plays an important role in diabetes-induced retinal neu- ronal loss and vascular abnormalities, and that inhibiting the activation of the endoplasmic reticulum stress pathway provides effective protection against diabetic retinopathy.展开更多
Endoplasmic reticulum(ER)stress,as an emerging hallmark feature of cancer,has a considerable impact on cell proliferation,metastasis,invasion,and chemotherapy resistance.Ovarian cancer(OvCa)is one of the leading cause...Endoplasmic reticulum(ER)stress,as an emerging hallmark feature of cancer,has a considerable impact on cell proliferation,metastasis,invasion,and chemotherapy resistance.Ovarian cancer(OvCa)is one of the leading causes of cancer-related mortality across the world due to the late stage of disease at diagnosis.Studies have explored the influence of ER stress on OvCa in recent years,while the predictive role of ER stress-related genes in OvCa prognosis remains unexplored.Here,we enrolled 552 cases of ER stress-related genes involved in OvCa from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)cohorts for the screening of prognosis-related genes.The least absolute shrinkage and selection operator(LASSO)regression was applied to establish an ER stress-related risk signature based on the TCGA cohort.A seven-gene signature revealed a favorable predictive efficacy for the TCGA,International Cancer Genome Consortium(ICGC),and another GEO cohort(P<0.001,P<0.001,and P=0.04,respectively).Moreover,functional annotation indicated that this signature was enriched in cellular response and senescence,cytokines interaction,as well as multiple immune-associated terms.The immune infiltration profiles further delineated an immunologic unresponsive status in the high-risk group.In conclusion,ER stress-related genes are vital factors predicting the prognosis of OvCa,and possess great application potential in the clinic.展开更多
基金supported by the China Mega-project for Infectious Disease [2018ZX10102001,2018ZX10711001,2018ZX10734401,and 2018ZX10734404]the SKLID Development Grant [2011SKLID104]
文摘Objective Autophagy is a highly conserved intracellular degradation pathway. Many picornaviruses induce autophagy to benefit viral replication, but an understanding of how autophagy occurs remains incomplete. In this study, we explored whether coxsackievirus B3(CVB3) infection induced autophagy through endoplasmic reticulum(ER) stress. Methods In CVB3-infected HeLa cells, the specific molecules of ER stress and autophagy were detected using Western blotting, reverse transcription polymerase chain reaction(RT-PCR), and confocal microscopy. Then PKR-like ER protein kinase(PERK) inhibitor, inositol-requiring protein-1(IRE1) inhibitor, or activating transcription factor-6(ATF6) inhibitor worked on CVB3-infected cells, their effect on autophagy was assessed by Western blotting for detecting microtubule-associated protein light chain 3(LC3). Results CVB3 infection induced ER stress, and ER stress sensors PERK/eIF2α, IRE1/XBP1, and ATF6 were activated. CVB3 infection increased the accumulation of green fluorescent protein(GFP)-LC3 punctuation and induced the conversion from LC3-Ⅰ to phosphatidylethanolamine-conjugated LC3-1(LC3-Ⅱ). CVB3 infection still decreased the expression of mammalian target of rapamycin(mTOR) and p-mTOR. Inhibition of PERK, IRE1, or ATF6 significantly decreased the ratio of LC3-Ⅱ to LC3-Ⅰ in CVB3-infected HeLa cells. Conclusion CVB3 infection induced autophagy through ER stress in HeL a cells, and PERK, IRE1, and ATF6 a pathways participated in the regulation of autophagy. Our data suggested that ER stress may inhibit mTOR signaling pathway to induce autophagy during CVB3 infection.
基金supported by the key projects of Tianjin Natural Science Foundation(Grant No.17JCZDJC34800).
文摘Zinc is a trace element involved in maintaining cellular structure and function.Although zinc is associated with left ventricular hypertrophy(LVH),there have been few reports on this association.This study aimed to evaluate the correlation between Zip14 and expression of endoplasmic reticulum stress(ERS)associated molecules in hypertrophied hearts of rats.Dahl salt-sensitive rats were fed a high salt diet to establish a left ventricular hypertrophy(LVH)rat model.RT-PCR was used to determine Zip14,activating transcription factor(ATF4),ATF6,x-box-binding protein 1(xBP1),C/EBP homologous protein(CHOP),immunoglobulin-binding protein(BiP)mRNA expression.Western blotting was used to evaluate Zip14,BiP,CHOP,GAPDH expression.Zinc levels were measured by Inductively Coupled Plasma Optical Emission Spectroscopy.The results indicated that compared with the Control group,Zip14 mRNA and protein expression in LVH rat hearts were markedly increased(P<0.01).Zinc content in rat heart tissue was significantly increased in the LVH group compared with the Control group(P<0.05).ATF4,ATF6,xBP1 mRNA expressions were increased in LVH rat hearts compared with Control hearts(P<0.001).Compared with the Control group,CHOP and BiP mRNA and protein expression were markedly increased in LVH rat hearts(P<0.05,P<0.01).Linear regression models showed that Zip14 mRNA expressions were positively correlated with zinc concentration,ATF4 and ATF6 mRNA expressions in Control hearts(P=0.0005,P=0.0052,P=0.0026,respectively)and LVH rat hearts(P<0.0001,P=0.0119,P=0.0033,respectively).In conclusion,upregulation of Zip14 in LVH rat hearts correlated with zinc accumulation and induction of ERS.
文摘他莫昔芬(tamoxifen,TAM)作为雌激素受体阳性(estrogen receptor,ER+)乳腺癌的一线化疗药物使大多数患者受益,但原发性和继发性耐药问题严重影响临床治疗效果。深入研究ER+乳腺癌TAM耐药机制,改善治疗效果是当前亟待解决的问题。抑癌因子NDRG2(N-myc downstream regulated gene 2,NDRG2)在肿瘤发生发展中发挥重要作用,但是否参与ER+乳腺癌TAM耐药尚不清楚。本研究旨在探明NDRG2在ER+乳腺癌TAM耐药中发挥的作用和机制。通过RT-PCR与免疫印迹分析对比TAM敏感型和耐药型ER+乳腺癌细胞发现,NDRG 2的mRNA转录水平和蛋白质翻译水平在TAM耐药细胞中表达显著下调,且与耐药能力负相关(P<0.001);CCK-8细胞毒性实验和软琼脂克隆形成实验证实,在耐药细胞中过表达NDRG2可显著降低TAM药物半抑制浓度IC 50和软琼脂克隆形成率(P<0.001),逆转耐药表型。分子机制上,X-box结合蛋白1(X-box binding protein 1,XBP1)mRNA剪切实验与内质网相关降解(endoplasmic-reticulum associated degradation,ERAD)报告蛋白的结果显示,过表达NDRG2可增强耐药细胞中剪切型XBP1s mRNA转录与ERAD报告蛋白CD3ε-YFP表达(P<0.001),引发耐药细胞内质网强应激反应;免疫印迹检测结果显示,过表达NDRG2可显著提高耐药细胞中内质网应激感受器肌醇需要激酶1α(inositol requiring enzyme 1,IRE1α)的磷酸化水平及其下游因子,例如内质网EIP辅助因子(endoplasmic reticulum-localized DnaJ 4,ERdj4)、PKR蛋白激酶的细胞抑制剂(cellular Inhibitor of the PKR protein kinase,P58 IPK)、α甘露糖苷酶样应激蛋白(er degradation enhancingαmannosidase likeprotein,EDEM)和蛋白质二硫键异构酶家族A成员5(protein disulfide isomerase family a member 5,PDIA5)的表达水平(P<0.001)。小鼠异种移植瘤研究进一步证实,在耐药细胞中过表达NDRG2可增强TAM治疗效果,显著抑制耐药移植瘤生长(P<0.001)。以上研究结果表明,通过提高耐药细胞中NDRG2表达,增强TAM治疗引发的内质网强烈应激,可逆转ER+乳腺癌细胞耐药性,改善TAM治疗效果。研究结果为解决ER+乳腺癌TAM耐药问题提供了新的思路和有价值的潜在药物靶点。
文摘Brain ischemic stroke is the leading cause of long-lasting injury,disability,and death in adults.Although the brain represents only about 2%of the total body mass,it consumes almost 20%of the body＇s oxygen.As a result,brain cells are extremely sensitive to hypoxia.Once cerebral ischemia occurs.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81360199)Science and Technology Department of Guizhou Province(Guizhou Specific Grant[2019]4008)+2 种基金Science and Technology Plan Project of Guizhou Province(Basic Science and Technology Cooperation[2020]1Z060)Science and Technology Fund Project of Guizhou Health and Health Commission(No.gzwjkj2019-1-039)Science and Technology Fund Project of Southwest Guizhou Autonomous Prefecture(2019-1-10).
文摘This study aimed to elucidate the molecular mechanisms by which berberine protects against cerebral ischemia/reperfusion(I/R)injury.The oxygen-glucose deprivation/reperfusion(OGD/R)PC12 model was established.Cell counting kit-8(CCK-8)was used to detect the toxicity of berberine and the viability of PC12 cells.Hoechst 33258 staining and flow cytometry were used to observe the nuclear morphology,and changes of apoptosis and reactive oxygen species(ROS),respectively.Western blotting and immunofluorescence assay were employed to detect autophagy-related proteins[microtubule-associated protein 1A/1B-light chain 3(LC3),P62/SQSTM-1,Beclin-1]and endoplasmic reticulum(ER)stress-related markers[glucose-regulated protein 78(GRP78),C/EBP homologous protein(CHOP),Bcl-2-associated X(Bax)and cleaved caspase-3].The GFP-RFP-LC3 adenovirus was used to assay the change of autophagic flux.Our results showed that berberine could increase the viability of PC12 cells,decrease the concentrations of ROS after OGD/R treatment,and suppress OGD/R-induced ER stress and autophagy.Moreover,the results revealed the involvement of the mammalian target of rapamycin(mTOR)pathway in the induction of autophagy,and berberine could activate the phosphorylation of mTOR and thus mitigate autophagy.In conclusion,our study suggested that berberine may protect against OGD/R-induced apoptosis by regulating ER stress and autophagy,and it holds promises in the treatment of cerebral I/R injury.
文摘Objective： The aim of this study was to explore the mechanisms by which the flavonoid casticin enhances tumor necrosis factor-related apoptosis-inducing ligand （TRAIL）-induced apoptosis in colon cancer cells. Methods： Human colon cancer HT-29 cells were treated with TRAIL or casticin. Cytotoxicity was examined by MTT assay, and apoptosis determined by morphological observation and flow cytometric analysis. Death receptor 5 （DRS）, DR4, and endoplasmic reticulum （ER） stress response markers, including glucose regulating protein 78 （GRP78）, activating transcription factor 4 （ATF4） and CHOP （CCAAT/enhancer binding protein homologous protein）, were examined with western blot. Small interfering RNA （siRNA） transfection was employed to knock down CHOP. Results： HT-29 cells were resistance to TRAIL-induced apoptosis, but casticin, at subtoxic concentrations, potentiated HT-29 cells to TRAIL-induced apoptosis. Casticin up-regulated the expression of DR5 time-and dose-dependent manners, but had no effect on the expression of DR4. Also, casticin increased the levels of ER stress response markers （GRP78, ATF4 and CHOP） in a similar way to DR5. Knockdown of CHOP by specific siRNA, or salubrinal, an ER stress inhibitor, abolished the up-regulation of DR5 and enhancement of TRAIL-induced apoptosis by casticin. Conclusion： Casticin enhances TRAIL-induced apoptosis of colon cancer cells by ER stress-mediated up-regulation of DR5.
基金supported by the National Natural Science Foundation of China,No.81170877the National Basic Research Program of China,No.2007CB512203
文摘Endoplasmic reticulum stress is closely involved in the early stage of diabetic retinopathy. In the present study, a streptozotocin-induced diabetic animal model was given an intraperitoneal injection of tauroursodeoxycholic acid. Results from immunofluorescent co-localization experiments showed that both caspase-12 protein and c-Jun N-terminal kinase 1 phosphorylation levels significantly in- creased, which was associated with retinal ganglion cell death in diabetic retinas. The C/ERB ho- mologous protein pathway directly contributed to glial reactivity, and was subsequently responsible for neuronal loss and vascular abnormalities in diabetic retinopathy. Our experimental findings in- dicate that endoplasmic reticulum stress plays an important role in diabetes-induced retinal neu- ronal loss and vascular abnormalities, and that inhibiting the activation of the endoplasmic reticulum stress pathway provides effective protection against diabetic retinopathy.
基金This work was supported by the Shanghai Shenkang Hospital Development Center’s Shenkang Promotion of Clin‑ical Skills and Clinical Innovation in Municipal Hospitals Three-Year Action Plan(No.2020‒2023)the Major Clinical Research Project(No.SHDC2020CR1048B)the Pilot Construction Project of High-Level Universities in Shanghai(No.DGF501017-06),China。
文摘Endoplasmic reticulum(ER)stress,as an emerging hallmark feature of cancer,has a considerable impact on cell proliferation,metastasis,invasion,and chemotherapy resistance.Ovarian cancer(OvCa)is one of the leading causes of cancer-related mortality across the world due to the late stage of disease at diagnosis.Studies have explored the influence of ER stress on OvCa in recent years,while the predictive role of ER stress-related genes in OvCa prognosis remains unexplored.Here,we enrolled 552 cases of ER stress-related genes involved in OvCa from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)cohorts for the screening of prognosis-related genes.The least absolute shrinkage and selection operator(LASSO)regression was applied to establish an ER stress-related risk signature based on the TCGA cohort.A seven-gene signature revealed a favorable predictive efficacy for the TCGA,International Cancer Genome Consortium(ICGC),and another GEO cohort(P<0.001,P<0.001,and P=0.04,respectively).Moreover,functional annotation indicated that this signature was enriched in cellular response and senescence,cytokines interaction,as well as multiple immune-associated terms.The immune infiltration profiles further delineated an immunologic unresponsive status in the high-risk group.In conclusion,ER stress-related genes are vital factors predicting the prognosis of OvCa,and possess great application potential in the clinic.
