We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repet...We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.展开更多
BACKGROUND Dysregulated microRNA(miRNA)is crucial in the progression of diabetic nephropathy(DN).AIM To investigate the potential molecular mechanism of Icariin(ICA)in regulating endoplasmic reticulum(ER)stress-mediat...BACKGROUND Dysregulated microRNA(miRNA)is crucial in the progression of diabetic nephropathy(DN).AIM To investigate the potential molecular mechanism of Icariin(ICA)in regulating endoplasmic reticulum(ER)stress-mediated apoptosis in high glucose(HG)-induced primary rat kidney cells(PRKs),with emphasis on the role of miR-503 and sirtuin 4(SIRT4)in this process.METHODS Single intraperitoneal injection of streptozotocin(65 mg/kg)in Sprague-Dawley rats induce DN in the in vivo hyperglycemic model.Glucose-treated PRKs were used as an in vitro HG model.An immunofluorescence assay identified isolated PRKs.Cell Counting Kit-8 and flow cytometry analyzed the effect of ICA treatment on cell viability and apoptosis,respectively.Real-time quantitative polymerase chain reaction and western blot analyzed the levels of ER stressrelated proteins.Dual luciferase analysis of miR-503 binding to downstream SIRT4 was performed.RESULTS ICA treatment alleviated the upregulated miR-503 expression in vivo(DN)and in vitro(HG).Mechanistically,ICA reduced HG-induced miR-503 overexpression,thereby counteracting its function in downregulating SIRT4 levels.ICA regulated the miR-503/SIRT4 axis and subsequent ER stress to alleviate HG-induced PRKs injury.CONCLUSION ICA reduced HG-mediated inhibition of cell viability,promotion of apoptosis,and ER stress in PRKs.These effects involved regulation of the miR-503/SIRT4 axis.These findings indicate the potential of ICA to treat DN,and implicate miR-503 as a viable target for therapeutic interventions in DN.展开更多
β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unkno...β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.展开更多
BACKGROUND Radiotherapy stands as a promising therapeutic modality for colorectal cancer(CRC);yet,the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission.AIM...BACKGROUND Radiotherapy stands as a promising therapeutic modality for colorectal cancer(CRC);yet,the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission.AIM To elucidate the role played by microRNA-298(miR-298)in CRC radio-resistance.METHODS To establish a radio-resistant CRC cell line,HT-29 cells underwent exposure to 5 gray ionizing radiation that was followed by a 7-d recovery period.The quantification of miR-298 levels within CRC cells was conducted through quantitative RT-PCR,and protein expression determination was realized through Western blotting.Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferation by clonogenic assay.Radio-induced apoptosis was discerned through flow cytometry analysis.RESULTS We observed a marked upregulation of miR-298 in radio-resistant CRC cells.MiR-298 emerged as a key determinant of cell survival following radiation exposure,as its overexpression led to a notable reduction in radiation-induced apoptosis.Intriguingly,miR-298 expression exhibited a strong correlation with CRC cell viability.Further investigation unveiled human dual-specificity tyrosine(Y)-regulated kinase 1A(DYRK1A)as miR-298’s direct target.CONCLUSION Taken together,our findings underline the role played by miR-298 in bolstering radio-resistance in CRC cells by means of DYRK1A downregulation,thereby positioning miR-298 as a promising candidate for mitigating radioresistance in CRC.展开更多
While the Bushen Yizhi Formula can treat Alzheimer’s disease(AD),the yet to be ascertained specific mechanism of action was explored in this work.Methods:Different concentrations of the Bushen Yizhi Formula and amylo...While the Bushen Yizhi Formula can treat Alzheimer’s disease(AD),the yet to be ascertained specific mechanism of action was explored in this work.Methods:Different concentrations of the Bushen Yizhi Formula and amyloid-beta peptide(Aβ)were used to treat rat pheochromocytoma cells(P12)and human neuroblastoma cells(SH-SY5Y).Cell morphological changes were observed to determine the in vitro cell damage.Cell Counting Kit(CCK)-8 assay and flow cytometry were employed to identify cell viability and apoptosis/cell cycle,respectively.Western blotting and immunohistochemistry were employed to measure the expressions of endoplasmic reticulum stress(ERS)-related proteins(GRP78 and CHOP),p-IRE1α,IRE1α,ASK1,p-JNK,JNK,Bax,Bcl-2,XBP-1,and Bim.Fura 2-acetoxymethyl ester(Fura-2/AM)was used to determine the intracellular calcium(Ca^(2+))concentration.Also,an AD model was constructed by injecting Aβinto the CA1 area of the hippocampus in Sprague Dawley rats.AD model rats were gavaged with different concentrations of Bushen Yizhi Formula for 14 consecutive days.The Morris water maze experiment was conducted to test the learning and memory of rats.Hematoxylin&Eosin(H&E)and Terminal-deoxynucleotidyl Transferase(TdT)-mediated dUTP Nick-End Labeling(TUNEL)staining were done to determine histopathological changes in the brain.Results:Bushen Yizhi Formula relieved the Aβ-induced effects including cell injury,decreased viability,increased apoptosis,G0/G1 phase cell cycle arrest,upregulation of GRP78,CHOP,p-IRE1α,p-JNK,Bax,XBP-1 and Bim,as well as down-regulation of Bcl-2.These results were also seen with IRE1αsilencing.While Aβsuppressed the learning and memory abilities of rats,the Bushen Yizhi Formula alleviated these effects of Aβ.Brain nerve cell injury induced by Aβcould also be treated with Bushen Yizhi Formula.Conclusion:Bushen Yizhi Formula could influence ERS through the IRE1αsignaling pathway to achieve its therapeutic effects on AD.展开更多
Selective clearance of organelles,including endoplasmic reticulum(ER)and mitochondria,by autophagy plays an important role in cell health.Here,we describe a developmentally programmed selective ER clearance by autopha...Selective clearance of organelles,including endoplasmic reticulum(ER)and mitochondria,by autophagy plays an important role in cell health.Here,we describe a developmentally programmed selective ER clearance by autophagy.We show that Parkinson's disease-associated PINK1,as well as Atl,Rtnl1,and Trp1 receptors,regulate ER clearance by autophagy.展开更多
BACKGROUND Sirtuin 1(SIRT1)is a nicotinamide adenine dinucleotide(NAD+)-dependent protein deacetylase that is involved in various diseases,including cancers,metabolic diseases,and inflammation-associated diseases.Howe...BACKGROUND Sirtuin 1(SIRT1)is a nicotinamide adenine dinucleotide(NAD+)-dependent protein deacetylase that is involved in various diseases,including cancers,metabolic diseases,and inflammation-associated diseases.However,the role of SIRT1 in ulcerative colitis(UC)is still confusing.AIM To investigate the role of SIRT1 in intestinal epithelial cells(IECs)in UC and further explore the underlying mechanisms.METHODS We developed a coculture model using macrophages and Caco-2 cells.After treatment with the SIRT1 activator SRT1720 or inhibitor nicotinamide(NAM),the expression of occludin and zona occludens 1(ZO-1)was assessed by Western blot analysis.Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis.Dextran sodium sulfate(DSS)-induced colitis mice were exposed to SRT1720 or NAM for 7 d.Transferase-mediated dUTP nick-end labeling(TUNEL)assays were conducted to assess apoptosis in colon tissues.The expression levels of glucose-regulated protein 78(GRP78),CCAAT/enhancerbinding protein homologous protein(CHOP),caspase-12,caspase-9,and caspase-3 in Caco-2 cells and the colon tissues of treated mice were examined by quantitative real-time PCR and Western blot.RESULTS SRT1720 treatment increased the protein levels of occludin and ZO-1 and inhibited Caco-2 apoptosis,whereas NAM administration caused the opposite effects.DSS-induced colitis mice treated with SRT1720 had a lower disease activity index(P<0.01),histological score(P<0.001),inflammatory cytokine levels(P<0.01),and apoptotic cell rate(P<0.01),while exposure to NAM caused the opposite effects.Moreover,SIRT1 activation reduced the expression levels of GRP78,CHOP,cleaved caspase-12,cleaved caspase-9,and cleaved caspase-3 in Caco-2 cells and the colon tissues of treated mice.CONCLUSION SIRT1 activation reduces apoptosis of IECs via the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CHOP and caspase-12.SIRT1 activation may be a potential therapeutic strategy for UC.展开更多
AIM To investigate the therapeutic effect of hydrogen-rich water(HRW) on inflammatory bowel disease(IBD) and to explore the potential mechanisms involved.METHODS Male mice were randomly divided into the following four...AIM To investigate the therapeutic effect of hydrogen-rich water(HRW) on inflammatory bowel disease(IBD) and to explore the potential mechanisms involved.METHODS Male mice were randomly divided into the following four groups: control group, in which the mice received equivalent volumes of normal saline(NS) intraperitoneally(ip); dextran sulfate sodium(DSS) group, in which the mice received NS ip(5 m L/kg body weight, twice per day at 8 am and 5 pm) for 7 consecutive days after IBD modeling; DSS + HRW group, in which the mice received HRW(in the same volume as the NS treatment) for 7 consecutive days after IBD modeling; and DSS + HRW + Zn PP group, in which the mice received HRW(in the same volume as the NS treatment) and ZnP P [a heme oxygenase-1(HO-1) inhibitor, 25 mg/kg] for 7 consecutive days after IBD modeling. IBD was induced by feeding DSS to the mice, and blood and colon tissues were collected on the 7th d after IBD modeling to determine clinical symptoms, colonic inflammation and the potential mechanisms involved.RESULTS The DSS + HRW group exhibited significantly attenuated weight loss and a lower extent of disease activity index compared with the DSS group on the 7th d(P < 0.05). HRW exerted protective effects against colon shortening and colonic wall thickening in contrast to the DSS group(P < 0.05). The histological study demonstrated milder inflammation in the DSS + HRW group, which was similar to normal inflammatory levels, and the macroscopic and microcosmic damage scores were lower in this group than in the DSS group(P < 0.05). The oxidative stress parameters, including MDA and MPO in the colon, were significantly decreased in the DSS + HRW group compared with the DSS group(P < 0.05). Simultaneously, the protective indicators, superoxide dismutase and glutathione, were markedly increased with the use of HRW. Inflammatory factors were assessed, and the results showed that the DSS + HRW group exhibited significantly reduced levels of TNF-α, IL-6 and IL-1β compared with the DSS group(P < 0.05). In addition, the pivotal proteins involved in endoplasmic reticulum(ER) stress, including p-e IF2α, ATF4, XBP1 s and CHOP, were dramatically reduced after HRW treatment in contrast to the control group(P < 0.05). Furthermore, HRW treatment markedly up-regulated HO-1 expression, and the use of Zn PP obviously reversed the protective role of HRW. In the DSS + HRW + ZnP P group, colon shortening and colonic wall thickening were significantly aggravated, and the macroscopic damage scores were similar to those of the DSS + HRW group(P < 0.05). The histological study also showed more serious colonic damage that was similar to the DSS group.CONCLUSION HRW has a significant therapeutic potential in IBD by inhibiting inflammatory factors, oxidative stress and ER stress and by up-regulating HO-1 expression.展开更多
基金supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund,No.22HHXBSS00047(to PL)the National Natural Science Foundation of China,Nos.82072166(to PL),82071394(to XG)+4 种基金Science and Technology Planning Project of Tianjin,No.20YFZCSY00030(to PL)Science and Technology Project of Tianjin Municipal Health Commission,No.TJWJ2021QN005(to XG)Tianjin Key Medical Discipline(Specialty)Construction Project,No.TJYXZDXK-006ATianjin Municipal Education Commission Scientific Research Program Project,No.2020KJ164(to JZ)China Postdoctoral Science Foundation,No.2022M712392(to ZY).
文摘We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.
文摘目的:评估外周血microRNA(miR)-21、血浆聚腺苷二磷酸核糖聚合酶1[poly(ADP-ribose)polymerase-1,PARP-1]在过敏性鼻炎(allergic rhinitis,AR)和过敏性鼻炎-哮喘综合征(combined allergic rhinitis and asthma syndrome,CARAS)中的诊断价值。方法:收集44例CARAS患者、31例AR患者和42例健康对照的外周血,采用RT-qPCR法检测外周血中miR-21的表达水平,采用ELISA法检测血浆中PARP-1蛋白水平。应用Pearson进行相关性分析。受试者工作特征(receiveroperatingcharacteris-tic,ROC)曲线判断miR-21和PARP-1的诊断灵敏度与特异度。结果:CARAS组患者外周血miR-21的表达较健康对照组升高。AR组患者血浆PARP-1的水平较CARAS组和健康对照组升高。Pearson相关性分析结果显示,外周血miR-21的表达水平在AR患者中与嗜酸性粒细胞计数相关,在CARAS患者中与鼻呼出气一氧化氮(fractionalnasalnitricoxide,FnNO)水平相关;血浆PARP-1在AR患者中与1秒钟用力呼气量占预计值百分比(forced expiratory volume in onesecond percent predicted,FEV1%pred)相关,在CARAS患者中与FEV1%pred及1秒钟用力呼气量(forced expiratory volume in one second,FEV1)/用力肺活量(forced vital capacity,FVC)(FEV1/FVC)相关。ROC曲线分析显示,外周血miR-21作为CARAS的诊断标志物时,灵敏度为51.35%,特异度为80.95%。血浆PARP-1作为AR的诊断标志物时,灵敏度为90.32%,特异度为54.76%。血浆PARP-1作为AR进展为CARAS的诊断标志物时,灵敏度为45.45%,特异度为90.32%。结论:AR和CARAS患者外周血miR-21、PARP-1存在差异表达,外周血miR-21可作为CARAS的诊断标志物,PARP-1可作为AR的诊断标志物及AR进展为CARAS的生物标志物。这对寻求AR和CARAS的诊治靶点有十分重要的价值。
基金The First Affiliated Hospital of Guangzhou University of Chinese Medicine Innovation and Strengthening Fund,No.2019QN14.
文摘BACKGROUND Dysregulated microRNA(miRNA)is crucial in the progression of diabetic nephropathy(DN).AIM To investigate the potential molecular mechanism of Icariin(ICA)in regulating endoplasmic reticulum(ER)stress-mediated apoptosis in high glucose(HG)-induced primary rat kidney cells(PRKs),with emphasis on the role of miR-503 and sirtuin 4(SIRT4)in this process.METHODS Single intraperitoneal injection of streptozotocin(65 mg/kg)in Sprague-Dawley rats induce DN in the in vivo hyperglycemic model.Glucose-treated PRKs were used as an in vitro HG model.An immunofluorescence assay identified isolated PRKs.Cell Counting Kit-8 and flow cytometry analyzed the effect of ICA treatment on cell viability and apoptosis,respectively.Real-time quantitative polymerase chain reaction and western blot analyzed the levels of ER stressrelated proteins.Dual luciferase analysis of miR-503 binding to downstream SIRT4 was performed.RESULTS ICA treatment alleviated the upregulated miR-503 expression in vivo(DN)and in vitro(HG).Mechanistically,ICA reduced HG-induced miR-503 overexpression,thereby counteracting its function in downregulating SIRT4 levels.ICA regulated the miR-503/SIRT4 axis and subsequent ER stress to alleviate HG-induced PRKs injury.CONCLUSION ICA reduced HG-mediated inhibition of cell viability,promotion of apoptosis,and ER stress in PRKs.These effects involved regulation of the miR-503/SIRT4 axis.These findings indicate the potential of ICA to treat DN,and implicate miR-503 as a viable target for therapeutic interventions in DN.
基金supported by the National Natural Science Foundation of China,Nos.82104158(to XT),31800887(to LY),31972902(to LY),82001422(to YL)China Postdoctoral Science Foundation,No.2020M683750(to LY)partially by Young Talent Fund of University Association for Science and Technology in Shaanxi Province of China,No.20200307(to LY).
文摘β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.
基金This study was reviewed and approved by the Experimental Animal Ethics Committee of the First Affiliated Hospital of Guangxi Medical University(Approval No.2023-E386-01).
文摘BACKGROUND Radiotherapy stands as a promising therapeutic modality for colorectal cancer(CRC);yet,the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission.AIM To elucidate the role played by microRNA-298(miR-298)in CRC radio-resistance.METHODS To establish a radio-resistant CRC cell line,HT-29 cells underwent exposure to 5 gray ionizing radiation that was followed by a 7-d recovery period.The quantification of miR-298 levels within CRC cells was conducted through quantitative RT-PCR,and protein expression determination was realized through Western blotting.Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferation by clonogenic assay.Radio-induced apoptosis was discerned through flow cytometry analysis.RESULTS We observed a marked upregulation of miR-298 in radio-resistant CRC cells.MiR-298 emerged as a key determinant of cell survival following radiation exposure,as its overexpression led to a notable reduction in radiation-induced apoptosis.Intriguingly,miR-298 expression exhibited a strong correlation with CRC cell viability.Further investigation unveiled human dual-specificity tyrosine(Y)-regulated kinase 1A(DYRK1A)as miR-298’s direct target.CONCLUSION Taken together,our findings underline the role played by miR-298 in bolstering radio-resistance in CRC cells by means of DYRK1A downregulation,thereby positioning miR-298 as a promising candidate for mitigating radioresistance in CRC.
基金supported by the National Natural Science Foundation of China[81904266,82004309].
文摘While the Bushen Yizhi Formula can treat Alzheimer’s disease(AD),the yet to be ascertained specific mechanism of action was explored in this work.Methods:Different concentrations of the Bushen Yizhi Formula and amyloid-beta peptide(Aβ)were used to treat rat pheochromocytoma cells(P12)and human neuroblastoma cells(SH-SY5Y).Cell morphological changes were observed to determine the in vitro cell damage.Cell Counting Kit(CCK)-8 assay and flow cytometry were employed to identify cell viability and apoptosis/cell cycle,respectively.Western blotting and immunohistochemistry were employed to measure the expressions of endoplasmic reticulum stress(ERS)-related proteins(GRP78 and CHOP),p-IRE1α,IRE1α,ASK1,p-JNK,JNK,Bax,Bcl-2,XBP-1,and Bim.Fura 2-acetoxymethyl ester(Fura-2/AM)was used to determine the intracellular calcium(Ca^(2+))concentration.Also,an AD model was constructed by injecting Aβinto the CA1 area of the hippocampus in Sprague Dawley rats.AD model rats were gavaged with different concentrations of Bushen Yizhi Formula for 14 consecutive days.The Morris water maze experiment was conducted to test the learning and memory of rats.Hematoxylin&Eosin(H&E)and Terminal-deoxynucleotidyl Transferase(TdT)-mediated dUTP Nick-End Labeling(TUNEL)staining were done to determine histopathological changes in the brain.Results:Bushen Yizhi Formula relieved the Aβ-induced effects including cell injury,decreased viability,increased apoptosis,G0/G1 phase cell cycle arrest,upregulation of GRP78,CHOP,p-IRE1α,p-JNK,Bax,XBP-1 and Bim,as well as down-regulation of Bcl-2.These results were also seen with IRE1αsilencing.While Aβsuppressed the learning and memory abilities of rats,the Bushen Yizhi Formula alleviated these effects of Aβ.Brain nerve cell injury induced by Aβcould also be treated with Bushen Yizhi Formula.Conclusion:Bushen Yizhi Formula could influence ERS through the IRE1αsignaling pathway to achieve its therapeutic effects on AD.
文摘Selective clearance of organelles,including endoplasmic reticulum(ER)and mitochondria,by autophagy plays an important role in cell health.Here,we describe a developmentally programmed selective ER clearance by autophagy.We show that Parkinson's disease-associated PINK1,as well as Atl,Rtnl1,and Trp1 receptors,regulate ER clearance by autophagy.
基金Supported by the National Nature Science Foundation of China,No.81600414the Natural Science Foundation of Zhejiang Province,No.LQ16H030001Zhejiang TCM Science and Technology Project,No.2016ZA123 and No.2018ZA013
文摘BACKGROUND Sirtuin 1(SIRT1)is a nicotinamide adenine dinucleotide(NAD+)-dependent protein deacetylase that is involved in various diseases,including cancers,metabolic diseases,and inflammation-associated diseases.However,the role of SIRT1 in ulcerative colitis(UC)is still confusing.AIM To investigate the role of SIRT1 in intestinal epithelial cells(IECs)in UC and further explore the underlying mechanisms.METHODS We developed a coculture model using macrophages and Caco-2 cells.After treatment with the SIRT1 activator SRT1720 or inhibitor nicotinamide(NAM),the expression of occludin and zona occludens 1(ZO-1)was assessed by Western blot analysis.Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis.Dextran sodium sulfate(DSS)-induced colitis mice were exposed to SRT1720 or NAM for 7 d.Transferase-mediated dUTP nick-end labeling(TUNEL)assays were conducted to assess apoptosis in colon tissues.The expression levels of glucose-regulated protein 78(GRP78),CCAAT/enhancerbinding protein homologous protein(CHOP),caspase-12,caspase-9,and caspase-3 in Caco-2 cells and the colon tissues of treated mice were examined by quantitative real-time PCR and Western blot.RESULTS SRT1720 treatment increased the protein levels of occludin and ZO-1 and inhibited Caco-2 apoptosis,whereas NAM administration caused the opposite effects.DSS-induced colitis mice treated with SRT1720 had a lower disease activity index(P<0.01),histological score(P<0.001),inflammatory cytokine levels(P<0.01),and apoptotic cell rate(P<0.01),while exposure to NAM caused the opposite effects.Moreover,SIRT1 activation reduced the expression levels of GRP78,CHOP,cleaved caspase-12,cleaved caspase-9,and cleaved caspase-3 in Caco-2 cells and the colon tissues of treated mice.CONCLUSION SIRT1 activation reduces apoptosis of IECs via the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CHOP and caspase-12.SIRT1 activation may be a potential therapeutic strategy for UC.
基金Supported by the Project of Innovative Research Team for Key Science and Technology in Shaanxi Province,No.2013KCJ-23the Fundamental Research Funds for the Central Universities,No.1191320114the National Natural Science Foundation of China,No.81601672
文摘AIM To investigate the therapeutic effect of hydrogen-rich water(HRW) on inflammatory bowel disease(IBD) and to explore the potential mechanisms involved.METHODS Male mice were randomly divided into the following four groups: control group, in which the mice received equivalent volumes of normal saline(NS) intraperitoneally(ip); dextran sulfate sodium(DSS) group, in which the mice received NS ip(5 m L/kg body weight, twice per day at 8 am and 5 pm) for 7 consecutive days after IBD modeling; DSS + HRW group, in which the mice received HRW(in the same volume as the NS treatment) for 7 consecutive days after IBD modeling; and DSS + HRW + Zn PP group, in which the mice received HRW(in the same volume as the NS treatment) and ZnP P [a heme oxygenase-1(HO-1) inhibitor, 25 mg/kg] for 7 consecutive days after IBD modeling. IBD was induced by feeding DSS to the mice, and blood and colon tissues were collected on the 7th d after IBD modeling to determine clinical symptoms, colonic inflammation and the potential mechanisms involved.RESULTS The DSS + HRW group exhibited significantly attenuated weight loss and a lower extent of disease activity index compared with the DSS group on the 7th d(P < 0.05). HRW exerted protective effects against colon shortening and colonic wall thickening in contrast to the DSS group(P < 0.05). The histological study demonstrated milder inflammation in the DSS + HRW group, which was similar to normal inflammatory levels, and the macroscopic and microcosmic damage scores were lower in this group than in the DSS group(P < 0.05). The oxidative stress parameters, including MDA and MPO in the colon, were significantly decreased in the DSS + HRW group compared with the DSS group(P < 0.05). Simultaneously, the protective indicators, superoxide dismutase and glutathione, were markedly increased with the use of HRW. Inflammatory factors were assessed, and the results showed that the DSS + HRW group exhibited significantly reduced levels of TNF-α, IL-6 and IL-1β compared with the DSS group(P < 0.05). In addition, the pivotal proteins involved in endoplasmic reticulum(ER) stress, including p-e IF2α, ATF4, XBP1 s and CHOP, were dramatically reduced after HRW treatment in contrast to the control group(P < 0.05). Furthermore, HRW treatment markedly up-regulated HO-1 expression, and the use of Zn PP obviously reversed the protective role of HRW. In the DSS + HRW + ZnP P group, colon shortening and colonic wall thickening were significantly aggravated, and the macroscopic damage scores were similar to those of the DSS + HRW group(P < 0.05). The histological study also showed more serious colonic damage that was similar to the DSS group.CONCLUSION HRW has a significant therapeutic potential in IBD by inhibiting inflammatory factors, oxidative stress and ER stress and by up-regulating HO-1 expression.
