Activating transcription factor 6(ATF6),one of the three sensor proteins in the endoplasmic reticulum(ER),is an important regulator of ER stress-induced apoptosis.ATF6 resides in the ER and,upon activation,is transloc...Activating transcription factor 6(ATF6),one of the three sensor proteins in the endoplasmic reticulum(ER),is an important regulator of ER stress-induced apoptosis.ATF6 resides in the ER and,upon activation,is translocated to the Golgi apparatus,where it is cleaved by site-1 protease(S1P)to generate an amino-terminal cytoplasmic fragment.Although recent studies have made progress in elucidating the regulatory mechanisms of ATF6,its function during early porcine embryonic development under high-temperature(HT)stress remains unclear.In this study,zygotes were divided into four groups:control,HT,HT+ATF6 knockdown,and HT+PF(S1P inhibitor).Results showed that HT exposure induced ER stress,which increased ATF6 protein expression and led to a decrease in the blastocyst rate.Next,ATF6 expression was knocked down in HT embryos under microinjection of ATF6 double-stranded RNA(dsRNA).Results revealed that ATF6 knockdown(ATF6-KD)attenuated the increased expression of CHOP,an ER stress marker,and Ca2+release induced by HT.In addition,ATF6-KD alleviated homeostasis dysregulation among organelles caused by HT-induced ER stress,and further reduced Golgi apparatus and mitochondrial dysfunction in HT embryos.AIFM2 is an important downstream effector of ATF6.Results showed that ATF6-KD reduced the occurrence of AIFM2-mediated embryonic apoptosis at HT.Taken together,our findings suggest that ATF6 is a crucial mediator of apoptosis during early porcine embryonic development,resulting from HT-induced ER stress and disruption of organelle homeostasis.展开更多
Broiler ascites syndrome(AS)is one of the main diseases threatening the health of broilers.It is well documented that myocardial hypertrophy and failure is one of the key mechanisms of broiler ascites syndrome.Therefo...Broiler ascites syndrome(AS)is one of the main diseases threatening the health of broilers.It is well documented that myocardial hypertrophy and failure is one of the key mechanisms of broiler ascites syndrome.Therefore,prevention of cardiac hypertrophy and failure would be one goal to reduce broiler ascites syndrome incidence.Myocardial hyper-trophy and failure are closely related to endoplasmic reticulum stress(ERS)in cardiac myocytes,and the endoplasmic reticulum stress signaling system(ATF6-DR5)is one of the important pathways of myocardial apoptosis.Excessive hyper-trophy will affect the heart muscle's normal contraction and diastole function,and the heart will turn from compen-sated to decompensate thus causing myocardial injury.Myocardial apoptosis is a core component of the pathological changes of this myocardial injury.Nano-selenium is a kind of red elemental selenium nanoparticle.Due to its excellent physical,chemical and biological properties,it has attracted extensive academic attention in recent years.It has been proven to have excellent antioxidant,antibacterial,antitumor,antihypertrophic,and antiapoptotic abilties.Herein,nano-selenium(1μmol/L)can inhibit hydrogen peroxide(H_(2)O_(2))-induced oxidative stress in broiler primary cardiomyocytes,and at the same time reduce cardiomyocyte apoptosis.In vivo,nano-selenium can reduce broiler myocardial injury-related enzyme indicators(AST,CK and LDH),and alleviate myocardial injury.It can also activate the antioxidant enzyme system(SOD,GSH-Px and CAT)and reduce MDA,and make the recovery ofT-AOC ability in the organization.Meanwhile,nano-selenium can down-regulate the genes and proteins expression of ATF-6,GRP-78,CHOP and caspase 12 in the ERS-related signaling pathway,and inhibit that of downstream-related caspase 3,Bax and caspase 9,and increase that of the downstream anti-apoptotic Bcl-2,thereby maintaining the homeostasis of the endoplasmic reticulum and alleviating cardiomyocyte apoptosis.It can be seen that nano-selenium can protect the damaged myocardium in the broiler ascites caused by high-salt drinking by regulating the ATF6-DR5 signaling pathway.This study was performed in chickens and cardiomyocyte cells and attempted to demonstrate that selenium nanoparticles can protect the damaged myocar-dium in broiler ascites.This paper provides a new idea for preventing and treating broiler ascites syndrome.展开更多
目的研究高血压伴高同型半胱氨酸血症(HHcy)大鼠心肌内质网应激(ERS)时,激活作用转录因子6(ATF6)和C/EBP同源蛋白(CHOP)的表达与左室肥厚的关系及依叶片对其干预效果。方法60只雄性SD大鼠行腹主动脉缩窄术(AAC),术后2周选收缩压(SBP)≥1...目的研究高血压伴高同型半胱氨酸血症(HHcy)大鼠心肌内质网应激(ERS)时,激活作用转录因子6(ATF6)和C/EBP同源蛋白(CHOP)的表达与左室肥厚的关系及依叶片对其干预效果。方法60只雄性SD大鼠行腹主动脉缩窄术(AAC),术后2周选收缩压(SBP)≥140 mm Hg(1 mm Hg=0.133k Pa)大鼠45只随机等分为3组。AAC组普通饲料喂养并双蒸水灌胃;对照组2.5%蛋氨酸饲料喂养并双蒸水灌胃;治疗组2.5%蛋氨酸饲料喂养并依叶片[10 mg/(kg·d)]灌胃。定期测SBP和血同型半胱氨酸(Hcy),查心脏彩超,并用免疫组化和Western blot法观察大鼠心肌ATF6和CHOP的表达。结果术后20周,对照组大鼠SBP,血Hcy,室间隔舒张厚度(IVSD)和左室厚壁舒张厚度(LVPWD),心肌ATF6和CHOP表达均高于AAC组(P<0.05);治疗组大鼠SBP,血Hcy,IVSD和LVPWD,心肌ATF6和CHOP表达均明显低于对照组(P<0.05)。结论高血压伴HHcy大鼠心肌ATF6及CHOP表达较Hcy正常的高血压大鼠明显增高,以凋亡因子CHOP表达更占优势;依叶片有效降压,降低血Hcy,减轻心肌ERS,减缓心肌肥厚的作用。展开更多
Normal spermatogenic processes require the scrotal temperature to be lower than that of the body as excessive heat affects spermatogenesis in the testes,reduces sperm quality and quantity,and even causes infertility.E...Normal spermatogenic processes require the scrotal temperature to be lower than that of the body as excessive heat affects spermatogenesis in the testes,reduces sperm quality and quantity,and even causes infertility.Endoplasmic reticulum stress(ERS)is a crucial factor in many pathologies.Although several studies have linked ERS to heat stress,researchers have not yet determined which ERS signaling pathways contribute to heat-induced testicular damage.Melatonin activates antioxidant enzymes,scavenges free radicals,and protects the testes from inflammation;however,few studies have reported on the influence of melatonin on heat-induced testicular damage.Using a murine model of testicular hyperthermia,we observed that heat stress causes both ERS and apoptosis in the testes,especially in the spermatocytes.These observations were confirmed using the mouse spermatocyte cell line GC2,where the Atf6 and Perk signaling pathways were activated during heat stress.Knockout of the above genes effectively reduced spermatocyte damage caused by heat stress.Pretreatment with melatonin alleviated heat-induced apoptosis by inhibiting the Atf6 and Perk signaling pathways.This mitigation was dependent on the melatonin receptors.In vivo experiments verified that melatonin treatment relieved heat-induced testicular damage.In conclusion,our results demonstrated that ATF6 and PERK are important mediators for heat-induced apoptosis,which can be prevented by melatonin treatment.Thus,our study highlights melatonin as a potential therapeutic agent in mammals for subfertility/infertility induced by testicular hyperthermia.展开更多
基金supported by the National Research Foundation (NRF)of Korea Grant funded by the Korean Government (MSIT) (2020R1A4A1017552,2022R1A2C300769),Republic of Korea。
文摘Activating transcription factor 6(ATF6),one of the three sensor proteins in the endoplasmic reticulum(ER),is an important regulator of ER stress-induced apoptosis.ATF6 resides in the ER and,upon activation,is translocated to the Golgi apparatus,where it is cleaved by site-1 protease(S1P)to generate an amino-terminal cytoplasmic fragment.Although recent studies have made progress in elucidating the regulatory mechanisms of ATF6,its function during early porcine embryonic development under high-temperature(HT)stress remains unclear.In this study,zygotes were divided into four groups:control,HT,HT+ATF6 knockdown,and HT+PF(S1P inhibitor).Results showed that HT exposure induced ER stress,which increased ATF6 protein expression and led to a decrease in the blastocyst rate.Next,ATF6 expression was knocked down in HT embryos under microinjection of ATF6 double-stranded RNA(dsRNA).Results revealed that ATF6 knockdown(ATF6-KD)attenuated the increased expression of CHOP,an ER stress marker,and Ca2+release induced by HT.In addition,ATF6-KD alleviated homeostasis dysregulation among organelles caused by HT-induced ER stress,and further reduced Golgi apparatus and mitochondrial dysfunction in HT embryos.AIFM2 is an important downstream effector of ATF6.Results showed that ATF6-KD reduced the occurrence of AIFM2-mediated embryonic apoptosis at HT.Taken together,our findings suggest that ATF6 is a crucial mediator of apoptosis during early porcine embryonic development,resulting from HT-induced ER stress and disruption of organelle homeostasis.
基金Central Fundamental Research Fund for Universities(No.2662020DKPY013)Thirteenth Five-Year Plan Key R&D Program(No.2016YFD0501208)Innovation and Entrepreneurship Training Program for College Students in Hubei Province(S202110504039).
文摘Broiler ascites syndrome(AS)is one of the main diseases threatening the health of broilers.It is well documented that myocardial hypertrophy and failure is one of the key mechanisms of broiler ascites syndrome.Therefore,prevention of cardiac hypertrophy and failure would be one goal to reduce broiler ascites syndrome incidence.Myocardial hyper-trophy and failure are closely related to endoplasmic reticulum stress(ERS)in cardiac myocytes,and the endoplasmic reticulum stress signaling system(ATF6-DR5)is one of the important pathways of myocardial apoptosis.Excessive hyper-trophy will affect the heart muscle's normal contraction and diastole function,and the heart will turn from compen-sated to decompensate thus causing myocardial injury.Myocardial apoptosis is a core component of the pathological changes of this myocardial injury.Nano-selenium is a kind of red elemental selenium nanoparticle.Due to its excellent physical,chemical and biological properties,it has attracted extensive academic attention in recent years.It has been proven to have excellent antioxidant,antibacterial,antitumor,antihypertrophic,and antiapoptotic abilties.Herein,nano-selenium(1μmol/L)can inhibit hydrogen peroxide(H_(2)O_(2))-induced oxidative stress in broiler primary cardiomyocytes,and at the same time reduce cardiomyocyte apoptosis.In vivo,nano-selenium can reduce broiler myocardial injury-related enzyme indicators(AST,CK and LDH),and alleviate myocardial injury.It can also activate the antioxidant enzyme system(SOD,GSH-Px and CAT)and reduce MDA,and make the recovery ofT-AOC ability in the organization.Meanwhile,nano-selenium can down-regulate the genes and proteins expression of ATF-6,GRP-78,CHOP and caspase 12 in the ERS-related signaling pathway,and inhibit that of downstream-related caspase 3,Bax and caspase 9,and increase that of the downstream anti-apoptotic Bcl-2,thereby maintaining the homeostasis of the endoplasmic reticulum and alleviating cardiomyocyte apoptosis.It can be seen that nano-selenium can protect the damaged myocardium in the broiler ascites caused by high-salt drinking by regulating the ATF6-DR5 signaling pathway.This study was performed in chickens and cardiomyocyte cells and attempted to demonstrate that selenium nanoparticles can protect the damaged myocar-dium in broiler ascites.This paper provides a new idea for preventing and treating broiler ascites syndrome.
文摘目的研究高血压伴高同型半胱氨酸血症(HHcy)大鼠心肌内质网应激(ERS)时,激活作用转录因子6(ATF6)和C/EBP同源蛋白(CHOP)的表达与左室肥厚的关系及依叶片对其干预效果。方法60只雄性SD大鼠行腹主动脉缩窄术(AAC),术后2周选收缩压(SBP)≥140 mm Hg(1 mm Hg=0.133k Pa)大鼠45只随机等分为3组。AAC组普通饲料喂养并双蒸水灌胃;对照组2.5%蛋氨酸饲料喂养并双蒸水灌胃;治疗组2.5%蛋氨酸饲料喂养并依叶片[10 mg/(kg·d)]灌胃。定期测SBP和血同型半胱氨酸(Hcy),查心脏彩超,并用免疫组化和Western blot法观察大鼠心肌ATF6和CHOP的表达。结果术后20周,对照组大鼠SBP,血Hcy,室间隔舒张厚度(IVSD)和左室厚壁舒张厚度(LVPWD),心肌ATF6和CHOP表达均高于AAC组(P<0.05);治疗组大鼠SBP,血Hcy,IVSD和LVPWD,心肌ATF6和CHOP表达均明显低于对照组(P<0.05)。结论高血压伴HHcy大鼠心肌ATF6及CHOP表达较Hcy正常的高血压大鼠明显增高,以凋亡因子CHOP表达更占优势;依叶片有效降压,降低血Hcy,减轻心肌ERS,减缓心肌肥厚的作用。
基金supported by the National Natural Science Foundation of China(32072815)General Project of the Key R&D Plan of Shaanxi Province(2019NY-091)+1 种基金Program of Shaanxi Province Science and Technology Innovation Team(2019TD-036)Fundamental Research Funds for the Central Universities(2452020157)。
文摘Normal spermatogenic processes require the scrotal temperature to be lower than that of the body as excessive heat affects spermatogenesis in the testes,reduces sperm quality and quantity,and even causes infertility.Endoplasmic reticulum stress(ERS)is a crucial factor in many pathologies.Although several studies have linked ERS to heat stress,researchers have not yet determined which ERS signaling pathways contribute to heat-induced testicular damage.Melatonin activates antioxidant enzymes,scavenges free radicals,and protects the testes from inflammation;however,few studies have reported on the influence of melatonin on heat-induced testicular damage.Using a murine model of testicular hyperthermia,we observed that heat stress causes both ERS and apoptosis in the testes,especially in the spermatocytes.These observations were confirmed using the mouse spermatocyte cell line GC2,where the Atf6 and Perk signaling pathways were activated during heat stress.Knockout of the above genes effectively reduced spermatocyte damage caused by heat stress.Pretreatment with melatonin alleviated heat-induced apoptosis by inhibiting the Atf6 and Perk signaling pathways.This mitigation was dependent on the melatonin receptors.In vivo experiments verified that melatonin treatment relieved heat-induced testicular damage.In conclusion,our results demonstrated that ATF6 and PERK are important mediators for heat-induced apoptosis,which can be prevented by melatonin treatment.Thus,our study highlights melatonin as a potential therapeutic agent in mammals for subfertility/infertility induced by testicular hyperthermia.
