Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the m...Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.展开更多
Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1...Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1 a(IRE1 a),double-stranded RNA-dependent protein kinase(PKR)-like ER kinase(PERK)and activating transcription factor 6(ATF6)signaling pathways,is a protective cellular response activated by ER stress.However,UPR activation can also induce cell death upon persistent ER stress.The liver is susceptible to ER stress given its synthetic and other biological functions.Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and the UPR signaling pathways in the pathogenesis of liver diseases,including non-alcoholic fatty liver disease(NAFLD),alcoholic liver disease(ALD),alpha-1 antitrypsin(AAT)deficiency(AATD),cholestatic liver disease,drug-induced liver injury,ischemia/reperfusion(I/R)injury,viral hepatitis and hepatocel-lular carcinoma(HCC).Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of the UPR pathways during the development of the diseases.Moreover,ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.展开更多
Objective:To examine whether exposure of mouse neuronal cells to radiofrequency fields used in mobile communication devices can induce stress in endoplasmic reticulum(ER)and activate unfolded protein response(UPR).Met...Objective:To examine whether exposure of mouse neuronal cells to radiofrequency fields used in mobile communication devices can induce stress in endoplasmic reticulum(ER)and activate unfolded protein response(UPR).Methods:HT22 mouse hippocampus neuronal cells were exposed to continuous wave 900 MHz radiofrequency fields(RF)at 120μW/cm2 power intensity for 4 h/d for 5 consecutive days.The positive control cells were irradiated with 4 Gy of 60Coγ-rays at a dose rate of 0.5 Gy/min(GR).Twenty-four hours after the last exposure,cells were collected,and the expressions of sensor transmembrane proteins were detected using Western blot analysis.Results:The expression levels of Ire1,PERK,p-IRE1 and p-PERK,GRP78 and CHOP proteins were detected.There were no statistically significant differences in the expression levels of IRE1 and PERK proteins in control(CT),sham(SH)-,RF-and GR-exposed cells(P<0.05).The phosphorylated protein levels of p-IRE1 and p-PERK were significantly increased in cells exposed to RF and GR(P<0.05).The expression levels of GRP78 and CHOP were significantly increased in RF-and GR-exposed cells compared to CT and SH-exposed cells(P<0.05).Cells treated with 1μg/ml TM for 24 h showed significantly increased expression levels of GRP78 and CHOP proteins compared to controls(P<0.05).In the presence of 2 mmol/L PBA,TM-induced increased levels of GRP78 and CHOP proteins were reduced(P<0.05).Conclusions:The exposure of non-ionizing 900 MHz RF was able to cause stress in HT22 mouse neuronal cells and activated UPR in ER.Since UPR plays an important role in both cell survival(when UPR is mitigated)and apoptosis/death(under unresolvable stress conditions),further studies are required to determine the fate of the cells exposed to RF.展开更多
In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS...In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.展开更多
【目的】探讨四逆汤对阿霉素诱导的慢性心力衰竭(CHF)大鼠内质网应激的影响。【方法】从90只大鼠中随机选取15只作为正常组,其余大鼠腹腔注射阿霉素构建CHF模型,同时,正常组给予腹腔注射生理盐水。造模结束后,正常组大鼠全部存活,造模...【目的】探讨四逆汤对阿霉素诱导的慢性心力衰竭(CHF)大鼠内质网应激的影响。【方法】从90只大鼠中随机选取15只作为正常组,其余大鼠腹腔注射阿霉素构建CHF模型,同时,正常组给予腹腔注射生理盐水。造模结束后,正常组大鼠全部存活,造模大鼠存活60只。再将60只CHF大鼠随机分为5组,即模型组,四逆汤低、中、高剂量组,曲美他嗪组,每组12只。四逆汤低、中、高剂量组分别给予1.4、4.2、12.6(生药)g·kg^(-1)·d^(-1)灌胃,曲美他嗪组给予曲美他嗪10 mg·kg^(-1)·d^(-1)灌胃,正常组和模型组给予相同体积的生理盐水灌胃。连续给药4周。采用小动物超声测量左心室舒张末期直径(LVEDD)、左心室射血分数(LVEF)和左心室缩短分数(LVFS)变化;采用酶联免疫吸附分析(ELISA)检测血浆脑钠肽(BNP)和血管紧张素Ⅱ(AngⅡ)水平;采用实时荧光定量聚合酶链反应(PCR)技术检测心肌组织葡萄糖调节蛋白78(GRP78)、RNA依赖的蛋白激酶样内质网激酶(PERK)和活化转录因子4(ATF4)mRNA表达。【结果】与正常组比较,模型组大鼠LVEDD显著增大,LVEF、LVFS均显著降低,血浆BNP和AngⅡ含量升高,心肌组织GRP78、PERK及ATF4 m RNA表达量升高(P <0.01);与模型组比较,四逆汤低、中、高剂量组及曲美他嗪组LVEDD降低,LVEF、LVFS均显著增加,血浆BNP和AngⅡ含量减少,心肌组织GRP78、PERK及ATF4 m RNA表达量降低,且呈剂量依赖性,其中,四逆汤高剂量组及曲美他嗪组差异均有统计学意义(P <0.05或P <0.01)。【结论】四逆汤可改善慢性心力衰竭大鼠模型心脏功能,其机制可能与抑制PERK/ATF4信号通路从而减轻内质网应激有关。展开更多
[Objectives] To study the therapeutic effect and mechanism of New Maixian Powder on ulcerative colitis( UC) rats through observing its regulatory effect on the protein kinase R-like endoplasmic reticulum kinase( PERK)...[Objectives] To study the therapeutic effect and mechanism of New Maixian Powder on ulcerative colitis( UC) rats through observing its regulatory effect on the protein kinase R-like endoplasmic reticulum kinase( PERK)/eukaryotic translation initiation factor-2α( e IF-2α)/nuclear transcription factor-kappa B( NF-κB) signaling pathway. [Methods]First,60 SD rats were randomly divided into normal group,model group,mesalazine group,and New Maixian Powder low,medium and high dose groups,10 rats each group. Then,dextran sulfate sodium( DSS) was used to induce UC rats. The mesalazine group was given 0. 42 g/( kg·d) of mesalazine sustained-release granule suspension,New Maixian Powder low,medium and high dose groups were given 1. 5,3,and 6 g/( kg·d) of New Maixian Powder suspension,respectively,and other groups were given an equal volume of physiological saline,continuous intragastric administration for 14 d. Next,the disease activity index( DAI) of UC rats was evaluated; the expression of NF-κB in serum was measured by enzyme-linked immunosorbent assay( ELISA); the expression of PERK and e IF-2α protein and m RNA in colon tissue was detected by Western blot and real-time quantitative polymerase chain reaction( RT q-PCR). [Results] Compared with the normal group,the DAI score and serum NF-κB level in the model group were significantly higher( P < 0. 05),and PERK and e IF-2α protein and m RNA levels in the colon tissue were increased( P < 0. 05); compared with the model group,the DAI score decreased and serum NF-κB level declined in the New Maixian Powder group,and the expression of PERK and e IF-2α protein and m RNA in New Maixian Powder medium dose and high dose groups declined( P < 0. 05). [Conclusions]New Maixian Powder has good therapeutic effect on UC rats,and its mechanism may be connected with the inhibition of the activation of PERK/e IF-2α/NF-κB signaling pathway.展开更多
Both environmental and genetic factors contribute to the development of diabetes mellitus and although monogenic disorders are rare,they offer unique insights into the fundamental biology underlying the disease.Mutati...Both environmental and genetic factors contribute to the development of diabetes mellitus and although monogenic disorders are rare,they offer unique insights into the fundamental biology underlying the disease.Mutations of the insulin gene or genes involved in the response to protein misfolding cause early onset diabetes.These have revealed an important role for endoplasmic reticulum stress in β-cell survival.This form of cellular stress occurs when secretory proteins fail to fold efficiently.Of all the professional secretory cells we possess,β-cells are the most sensitive to endoplasmic reticulum stress because of the large fluctuations in protein synthesis they face daily.Studies of endoplasmic reticulum stress signaling therefore offer the potential to identify new drug targets to treat diabetes.展开更多
基金supported by the Key Science and Technology Research of Henan Province,No.222102310351(to JW)Luoyang 2022 Medical and Health Guiding Science and Technology Plan Project,No.2022057Y(to JY)Henan Medical Science and Technology Research Program Province-Ministry Co-sponsorship,No.SBGJ202002099(to JY)。
文摘Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.
基金This work was supported by USA National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK)R01 DK093807.
文摘Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1 a(IRE1 a),double-stranded RNA-dependent protein kinase(PKR)-like ER kinase(PERK)and activating transcription factor 6(ATF6)signaling pathways,is a protective cellular response activated by ER stress.However,UPR activation can also induce cell death upon persistent ER stress.The liver is susceptible to ER stress given its synthetic and other biological functions.Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and the UPR signaling pathways in the pathogenesis of liver diseases,including non-alcoholic fatty liver disease(NAFLD),alcoholic liver disease(ALD),alpha-1 antitrypsin(AAT)deficiency(AATD),cholestatic liver disease,drug-induced liver injury,ischemia/reperfusion(I/R)injury,viral hepatitis and hepatocel-lular carcinoma(HCC).Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of the UPR pathways during the development of the diseases.Moreover,ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.
基金This research is supported by funding from the National Natural Science Foundation of China(Grant No.81373025).
文摘Objective:To examine whether exposure of mouse neuronal cells to radiofrequency fields used in mobile communication devices can induce stress in endoplasmic reticulum(ER)and activate unfolded protein response(UPR).Methods:HT22 mouse hippocampus neuronal cells were exposed to continuous wave 900 MHz radiofrequency fields(RF)at 120μW/cm2 power intensity for 4 h/d for 5 consecutive days.The positive control cells were irradiated with 4 Gy of 60Coγ-rays at a dose rate of 0.5 Gy/min(GR).Twenty-four hours after the last exposure,cells were collected,and the expressions of sensor transmembrane proteins were detected using Western blot analysis.Results:The expression levels of Ire1,PERK,p-IRE1 and p-PERK,GRP78 and CHOP proteins were detected.There were no statistically significant differences in the expression levels of IRE1 and PERK proteins in control(CT),sham(SH)-,RF-and GR-exposed cells(P<0.05).The phosphorylated protein levels of p-IRE1 and p-PERK were significantly increased in cells exposed to RF and GR(P<0.05).The expression levels of GRP78 and CHOP were significantly increased in RF-and GR-exposed cells compared to CT and SH-exposed cells(P<0.05).Cells treated with 1μg/ml TM for 24 h showed significantly increased expression levels of GRP78 and CHOP proteins compared to controls(P<0.05).In the presence of 2 mmol/L PBA,TM-induced increased levels of GRP78 and CHOP proteins were reduced(P<0.05).Conclusions:The exposure of non-ionizing 900 MHz RF was able to cause stress in HT22 mouse neuronal cells and activated UPR in ER.Since UPR plays an important role in both cell survival(when UPR is mitigated)and apoptosis/death(under unresolvable stress conditions),further studies are required to determine the fate of the cells exposed to RF.
文摘In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.
文摘【目的】探讨四逆汤对阿霉素诱导的慢性心力衰竭(CHF)大鼠内质网应激的影响。【方法】从90只大鼠中随机选取15只作为正常组,其余大鼠腹腔注射阿霉素构建CHF模型,同时,正常组给予腹腔注射生理盐水。造模结束后,正常组大鼠全部存活,造模大鼠存活60只。再将60只CHF大鼠随机分为5组,即模型组,四逆汤低、中、高剂量组,曲美他嗪组,每组12只。四逆汤低、中、高剂量组分别给予1.4、4.2、12.6(生药)g·kg^(-1)·d^(-1)灌胃,曲美他嗪组给予曲美他嗪10 mg·kg^(-1)·d^(-1)灌胃,正常组和模型组给予相同体积的生理盐水灌胃。连续给药4周。采用小动物超声测量左心室舒张末期直径(LVEDD)、左心室射血分数(LVEF)和左心室缩短分数(LVFS)变化;采用酶联免疫吸附分析(ELISA)检测血浆脑钠肽(BNP)和血管紧张素Ⅱ(AngⅡ)水平;采用实时荧光定量聚合酶链反应(PCR)技术检测心肌组织葡萄糖调节蛋白78(GRP78)、RNA依赖的蛋白激酶样内质网激酶(PERK)和活化转录因子4(ATF4)mRNA表达。【结果】与正常组比较,模型组大鼠LVEDD显著增大,LVEF、LVFS均显著降低,血浆BNP和AngⅡ含量升高,心肌组织GRP78、PERK及ATF4 m RNA表达量升高(P <0.01);与模型组比较,四逆汤低、中、高剂量组及曲美他嗪组LVEDD降低,LVEF、LVFS均显著增加,血浆BNP和AngⅡ含量减少,心肌组织GRP78、PERK及ATF4 m RNA表达量降低,且呈剂量依赖性,其中,四逆汤高剂量组及曲美他嗪组差异均有统计学意义(P <0.05或P <0.01)。【结论】四逆汤可改善慢性心力衰竭大鼠模型心脏功能,其机制可能与抑制PERK/ATF4信号通路从而减轻内质网应激有关。
基金Supported by Science and Technology Program of Zhejiang Province(2016C33085)
文摘[Objectives] To study the therapeutic effect and mechanism of New Maixian Powder on ulcerative colitis( UC) rats through observing its regulatory effect on the protein kinase R-like endoplasmic reticulum kinase( PERK)/eukaryotic translation initiation factor-2α( e IF-2α)/nuclear transcription factor-kappa B( NF-κB) signaling pathway. [Methods]First,60 SD rats were randomly divided into normal group,model group,mesalazine group,and New Maixian Powder low,medium and high dose groups,10 rats each group. Then,dextran sulfate sodium( DSS) was used to induce UC rats. The mesalazine group was given 0. 42 g/( kg·d) of mesalazine sustained-release granule suspension,New Maixian Powder low,medium and high dose groups were given 1. 5,3,and 6 g/( kg·d) of New Maixian Powder suspension,respectively,and other groups were given an equal volume of physiological saline,continuous intragastric administration for 14 d. Next,the disease activity index( DAI) of UC rats was evaluated; the expression of NF-κB in serum was measured by enzyme-linked immunosorbent assay( ELISA); the expression of PERK and e IF-2α protein and m RNA in colon tissue was detected by Western blot and real-time quantitative polymerase chain reaction( RT q-PCR). [Results] Compared with the normal group,the DAI score and serum NF-κB level in the model group were significantly higher( P < 0. 05),and PERK and e IF-2α protein and m RNA levels in the colon tissue were increased( P < 0. 05); compared with the model group,the DAI score decreased and serum NF-κB level declined in the New Maixian Powder group,and the expression of PERK and e IF-2α protein and m RNA in New Maixian Powder medium dose and high dose groups declined( P < 0. 05). [Conclusions]New Maixian Powder has good therapeutic effect on UC rats,and its mechanism may be connected with the inhibition of the activation of PERK/e IF-2α/NF-κB signaling pathway.
基金Supported by a PhD studentship form Diabetes UK (for Thomas SE)
文摘Both environmental and genetic factors contribute to the development of diabetes mellitus and although monogenic disorders are rare,they offer unique insights into the fundamental biology underlying the disease.Mutations of the insulin gene or genes involved in the response to protein misfolding cause early onset diabetes.These have revealed an important role for endoplasmic reticulum stress in β-cell survival.This form of cellular stress occurs when secretory proteins fail to fold efficiently.Of all the professional secretory cells we possess,β-cells are the most sensitive to endoplasmic reticulum stress because of the large fluctuations in protein synthesis they face daily.Studies of endoplasmic reticulum stress signaling therefore offer the potential to identify new drug targets to treat diabetes.
