AIM:To investigate the pathophysiological role of C/EBP homologous protein(CHOP)in severe acute pancreatitis and associated lung injury.METHODS:A severe acute pancreatitis model was induced with 6 injections of cerule...AIM:To investigate the pathophysiological role of C/EBP homologous protein(CHOP)in severe acute pancreatitis and associated lung injury.METHODS:A severe acute pancreatitis model was induced with 6 injections of cerulein(Cn,50μg/kg)at 1-h intervals,then intraperitoneal injection of lipopolysaccharide(LPS,7.5 mg/kg)in CHOP-deficient(Chop-/-)mice and wild-type(WT)mice.Animals were sacrificed under anesthesia,3 h or 18 h after LPS injection.Serum amylase,lipase,and cytokines[interleukin(IL)-6 and tumor necrosis factor(TNF)-α],pathological changes,acute lung injury,and apoptosis in the pancreas were evaluated.Serum amylase and lipase activities were detected using a medical automatic chemical analyzer.Enzyme-linked immunosorbent assay kits were used to evaluate TNF-αand IL-6 levels in mouse serum and lung tissue homogenates.Apoptotic cells in sections of pancreatic tissues were determined by terminal deoxynucleotidyl transferase-mediated dUTPbiotin nick-end labeling(TUNEL)analysis.The mouse carotid arteries were cannulated and arterial blood samples were collected for PaO2analysis.The oxygenation index was expressed as PaO2/FiO2.RESULTS:Administration of Cn and LPS for 9 and 24 h induced severe acute pancreatitis in Chop-/-and WT mice.When comparing Chop-/-mice and WT mice,we observed that CHOP-deficient mice had greater increases in serum TNF-α(214.40±19.52 pg/mL vs 150.40±16.70 pg/mL;P=0.037),amylase(4236.40±646.32U/L vs 2535.30±81.83 U/L;P=0.041),lipase(1678.20±170.57 U/L vs 1046.21±35.37 U/L;P=0.008),and IL-6(2054.44±293.81 pg/mL vs 1316.10±108.74pg/mL;P=0.046)than WT mice.The histopathological changes in the pancreases and lungs,decreased PaO2/FiO2ratio,and increased TNF-αand IL-6 levels in the lungs were greater in Chop-/-mice than in WT mice(pancreas:Chop-/-vs WT mice,hemorrhage,P=0.005;edema,P=0.005;inflammatory cells infiltration,P=0.005;total scores,P=0.006;lung:hemorrhage,P=0.017;edema,P=0.017;congestion,P=0.017;neutrophil infiltration,P=0.005,total scores,P=0.001;PaO2/FiO2ratio:393±17.65 vs 453.8,P=0.041;TNF-α:P=0.043;IL-6,P=0.040).Results from TUNEL analysis indicated increased acinar cell apoptosis in mice following the induction of acute pancreatitis.However,Chop-/-mice displayed significantly reduced pancreatic apoptosis compared with the WT mice(201.50±31.43vs 367.00±47.88,P=0.016).CONCLUSION:These results suggest that CHOP can exert protective effects against acute pancreatitis and limit the spread of inflammatory damage to the lungs.展开更多
C/EBP homologous protein, an important transcription factor during endoplasmic reticulum stress, participates in cell apoptosis mediated by endoplasmic reticulum stress. Previous studies have shown that C/EBP homologo...C/EBP homologous protein, an important transcription factor during endoplasmic reticulum stress, participates in cell apoptosis mediated by endoplasmic reticulum stress. Previous studies have shown that C/EBP homologous protein mediates nerve injury during Alzheimer＇s disease, subarachnoid hemorrhage and spinal cord trauma. In this study, we introduced C/EBP homologous protein short hairpin RNA into the brains of ischemia/reperfusion rat models via injection of lentiviral vector through the left lateral ventricle. Silencing C/EBP homologous protein gene expression significantly reduced cerebral infarction volume, decreased water content and tumor necrosis factor-α and interleukin-1β mRNA expression in brain tissues following infarction, diminished the number of TUNEL-positive cells in the infarct region, decreased caspase-3 protein content and increased Bcl-2 protein content. These results suggest that silencing C/EBP homologous protein lessens cell apoptosis and inflammatory reactions, thereby protecting nerves.展开更多
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
Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cereb...Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.展开更多
Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate（ATP） depletion and subsequent i...Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate（ATP） depletion and subsequent induced endoplasmic reticulum（ER） stress are proposed to be the underlying mechanisms of ischemic retinal cell death. Recently, we found that a naphthalene derivative can inhibit ATPase activity of valosin-containing protein, universally expressed within various types of cells, including retinal neural cells, with strong cytoprotective activity. Based on the chemical structure, we developed novel valosin-containing protein modulators, Kyoto University Substances（KUSs）, that not only inhibit intracellular ATP depletion, but also ameliorate ER stress. Suppressing ER stress by KUSs is associated with neural cell survival in animal models of several neurodegenerative diseases, such as glaucoma and retinal degeneration. Given that a major pathology of ischemic retinal diseases, other than intracellular ATP depletion, is ER stress-induced cell death, KUSs may provide a novel strategy for cell protection in ischemic conditions. Hence, we investigated the efficacy of KUS121 in a rat model of retinal ischemic injury. Intravitreal injections of KUS121, which is clinically preferable route of drug administration in retinal diseases, significantly suppressed inner retinal thinning and retinal cell death, and maintained visual functions. Valosin-containing protein modulation by KUS is a promising novel therapeutic strategy for ischemic retinal diseases.展开更多
The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neuro...The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neurons.In this study,we established rat models of optic nerve-crush injury and injected valproate into the vitreous cavity immediately after modeling.We evaluated changes in the ultrastructure morphology of the endoplasmic reticulum of retinal ganglion cells over time via transmission electron microscope.Immunohistochemistry and western blot assay revealed that valproate upregulated the expression of the endoplasmic reticulum stress marker glucose-regulated protein 78 and downregulated the expression of transcription factor C/EBP homologous protein,phosphorylated eukaryotic translation initiation factor 2α,and caspase-12 in the endoplasmic reticulum of retinal ganglion cells.These findings suggest that valproate reduces apoptosis of retinal ganglion cells in the rat after optic nerve-crush injury by attenuating phosphorylated eukaryotic translation initiation factor 2α-C/EBP homologous protein signaling and caspase-12 activation during endoplasmic reticulum stress.These findings represent a newly discovered mechanism that regulates how valproate protects neurons.展开更多
目的探讨慢性HBV感染者外周血白细胞内质网应激相关基因糖调节蛋白78（GRP78）、CCAAT增强子结合蛋白同源蛋白（CHOP）和X盒结合蛋白l（XBP1）m RNA水平及其与临床指标的相关性。方法采用实时荧光定量PCR技术检测40例正常人（NC）、43...目的探讨慢性HBV感染者外周血白细胞内质网应激相关基因糖调节蛋白78（GRP78）、CCAAT增强子结合蛋白同源蛋白（CHOP）和X盒结合蛋白l（XBP1）m RNA水平及其与临床指标的相关性。方法采用实时荧光定量PCR技术检测40例正常人（NC）、43例慢性无症状HBV携带者（ASC）、47例慢性乙型肝炎（CHB）、41例乙型肝炎肝硬化（LC）和35例乙型肝炎相关肝细胞癌（HCC）患者外周血白细胞GRP78、CHOP和XBP1 m RNA水平,分析其与病毒学和生化学指标的相关性。结果 ASC、CHB、LC和HCC患者外周血白细胞GRP78 m RNA水平和XBP1 m RNA水平分别为（0.58±0.53）和（0.76±0.57）、（0.59±0.67）和（0.50±0.64）、（1.07±1.09）和（1.44±1.00）和（1.17±1.69）和（0.90±1.33）,均显著高于健康人[分别为（0.01±0.61）和（0.01±0.97）,P〈0.01和P〈0.05];在HBs Ag〈1500IU/ml、1500-20000IU/ml和〉20000IU/ml组患者,GRP78 m RNA水平分别为（0.48±0.59）、（0.76±0.56）和（0.74±0.56）,三组间差异有统计学意义（P〈0.05）;HBV DNA水平为1×10^3-10^5copies/ml组XBP1 m RNA水平为（0.86±1.13）,显著低于HBV DNA〉1×105copies/ml组[（1.44±1.31）,P〈0.05];在不同转氨酶水平间、HBe Ag阳性与阴性组间和胆红素正常与升高组间,以上三种基因m RNA水平差异均无统计学意义（P〉0.05）。结论内质网应激可能与慢性HBV感染后的疾病进展相关。展开更多
基金Supported by A research grant from the National Science Council of Taiwan,No.NSC97-2320-B-002-020-MY3
文摘AIM:To investigate the pathophysiological role of C/EBP homologous protein(CHOP)in severe acute pancreatitis and associated lung injury.METHODS:A severe acute pancreatitis model was induced with 6 injections of cerulein(Cn,50μg/kg)at 1-h intervals,then intraperitoneal injection of lipopolysaccharide(LPS,7.5 mg/kg)in CHOP-deficient(Chop-/-)mice and wild-type(WT)mice.Animals were sacrificed under anesthesia,3 h or 18 h after LPS injection.Serum amylase,lipase,and cytokines[interleukin(IL)-6 and tumor necrosis factor(TNF)-α],pathological changes,acute lung injury,and apoptosis in the pancreas were evaluated.Serum amylase and lipase activities were detected using a medical automatic chemical analyzer.Enzyme-linked immunosorbent assay kits were used to evaluate TNF-αand IL-6 levels in mouse serum and lung tissue homogenates.Apoptotic cells in sections of pancreatic tissues were determined by terminal deoxynucleotidyl transferase-mediated dUTPbiotin nick-end labeling(TUNEL)analysis.The mouse carotid arteries were cannulated and arterial blood samples were collected for PaO2analysis.The oxygenation index was expressed as PaO2/FiO2.RESULTS:Administration of Cn and LPS for 9 and 24 h induced severe acute pancreatitis in Chop-/-and WT mice.When comparing Chop-/-mice and WT mice,we observed that CHOP-deficient mice had greater increases in serum TNF-α(214.40±19.52 pg/mL vs 150.40±16.70 pg/mL;P=0.037),amylase(4236.40±646.32U/L vs 2535.30±81.83 U/L;P=0.041),lipase(1678.20±170.57 U/L vs 1046.21±35.37 U/L;P=0.008),and IL-6(2054.44±293.81 pg/mL vs 1316.10±108.74pg/mL;P=0.046)than WT mice.The histopathological changes in the pancreases and lungs,decreased PaO2/FiO2ratio,and increased TNF-αand IL-6 levels in the lungs were greater in Chop-/-mice than in WT mice(pancreas:Chop-/-vs WT mice,hemorrhage,P=0.005;edema,P=0.005;inflammatory cells infiltration,P=0.005;total scores,P=0.006;lung:hemorrhage,P=0.017;edema,P=0.017;congestion,P=0.017;neutrophil infiltration,P=0.005,total scores,P=0.001;PaO2/FiO2ratio:393±17.65 vs 453.8,P=0.041;TNF-α:P=0.043;IL-6,P=0.040).Results from TUNEL analysis indicated increased acinar cell apoptosis in mice following the induction of acute pancreatitis.However,Chop-/-mice displayed significantly reduced pancreatic apoptosis compared with the WT mice(201.50±31.43vs 367.00±47.88,P=0.016).CONCLUSION:These results suggest that CHOP can exert protective effects against acute pancreatitis and limit the spread of inflammatory damage to the lungs.
文摘C/EBP homologous protein, an important transcription factor during endoplasmic reticulum stress, participates in cell apoptosis mediated by endoplasmic reticulum stress. Previous studies have shown that C/EBP homologous protein mediates nerve injury during Alzheimer＇s disease, subarachnoid hemorrhage and spinal cord trauma. In this study, we introduced C/EBP homologous protein short hairpin RNA into the brains of ischemia/reperfusion rat models via injection of lentiviral vector through the left lateral ventricle. Silencing C/EBP homologous protein gene expression significantly reduced cerebral infarction volume, decreased water content and tumor necrosis factor-α and interleukin-1β mRNA expression in brain tissues following infarction, diminished the number of TUNEL-positive cells in the infarct region, decreased caspase-3 protein content and increased Bcl-2 protein content. These results suggest that silencing C/EBP homologous protein lessens cell apoptosis and inflammatory reactions, thereby protecting nerves.
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.
基金supported by the National Natural Science Foundation of China,Nos.82260245(to YX),81660207(to YX),81960253(to YL),82160268(to YL),U1812403(to ZG)Science and Technology Projects of Guizhou Province,Nos.[2019]1440(to YX),[2020]1Z067(to WH)+1 种基金Cultivation Foundation of Guizhou Medical University,No.[20NSP069](to YX)Excellent Young Talents Plan of Guizhou Medical University,No.(2022)101(to WH)。
文摘Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.
基金supported in part by research grants from the Astellas Foundation for Research on Metabolic Disorders,the Japan Foundation for Applied Enzymology,the Uehara Memorial Foundation,Mochida Memorial Foundation for Medical and Pharmaceutical Research,YOKOYAMA Foundation for Clinical Pharmacology(YRY1308)Japan Intractable Diseases Research Foundation,Japan Research Foundation for Clinical Pharmacology,ONO Medical Research Foundation,Takeda Science Foundation,Japan National Society for the Prevention of Blindness,a Grant-in-Aid for Young Scientists(24791850,to IHO+2 种基金15K20255,to HM)the Ministry of Education,Culture,Sports,Science,and Technology of Japan(to IHO)the Ministry of Health,Labour and Welfare of Japan(to IHO)
文摘Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate（ATP） depletion and subsequent induced endoplasmic reticulum（ER） stress are proposed to be the underlying mechanisms of ischemic retinal cell death. Recently, we found that a naphthalene derivative can inhibit ATPase activity of valosin-containing protein, universally expressed within various types of cells, including retinal neural cells, with strong cytoprotective activity. Based on the chemical structure, we developed novel valosin-containing protein modulators, Kyoto University Substances（KUSs）, that not only inhibit intracellular ATP depletion, but also ameliorate ER stress. Suppressing ER stress by KUSs is associated with neural cell survival in animal models of several neurodegenerative diseases, such as glaucoma and retinal degeneration. Given that a major pathology of ischemic retinal diseases, other than intracellular ATP depletion, is ER stress-induced cell death, KUSs may provide a novel strategy for cell protection in ischemic conditions. Hence, we investigated the efficacy of KUS121 in a rat model of retinal ischemic injury. Intravitreal injections of KUS121, which is clinically preferable route of drug administration in retinal diseases, significantly suppressed inner retinal thinning and retinal cell death, and maintained visual functions. Valosin-containing protein modulation by KUS is a promising novel therapeutic strategy for ischemic retinal diseases.
基金supported by the National Natural Science Foundation of China,Nos.30772368(to DH),81371034(to XH)the Key Project of Natural Science Foundation of Shaanxi Province,No.2017JZ025(to DH).
文摘The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neurons.In this study,we established rat models of optic nerve-crush injury and injected valproate into the vitreous cavity immediately after modeling.We evaluated changes in the ultrastructure morphology of the endoplasmic reticulum of retinal ganglion cells over time via transmission electron microscope.Immunohistochemistry and western blot assay revealed that valproate upregulated the expression of the endoplasmic reticulum stress marker glucose-regulated protein 78 and downregulated the expression of transcription factor C/EBP homologous protein,phosphorylated eukaryotic translation initiation factor 2α,and caspase-12 in the endoplasmic reticulum of retinal ganglion cells.These findings suggest that valproate reduces apoptosis of retinal ganglion cells in the rat after optic nerve-crush injury by attenuating phosphorylated eukaryotic translation initiation factor 2α-C/EBP homologous protein signaling and caspase-12 activation during endoplasmic reticulum stress.These findings represent a newly discovered mechanism that regulates how valproate protects neurons.
文摘目的探讨慢性HBV感染者外周血白细胞内质网应激相关基因糖调节蛋白78（GRP78）、CCAAT增强子结合蛋白同源蛋白（CHOP）和X盒结合蛋白l（XBP1）m RNA水平及其与临床指标的相关性。方法采用实时荧光定量PCR技术检测40例正常人（NC）、43例慢性无症状HBV携带者（ASC）、47例慢性乙型肝炎（CHB）、41例乙型肝炎肝硬化（LC）和35例乙型肝炎相关肝细胞癌（HCC）患者外周血白细胞GRP78、CHOP和XBP1 m RNA水平,分析其与病毒学和生化学指标的相关性。结果 ASC、CHB、LC和HCC患者外周血白细胞GRP78 m RNA水平和XBP1 m RNA水平分别为（0.58±0.53）和（0.76±0.57）、（0.59±0.67）和（0.50±0.64）、（1.07±1.09）和（1.44±1.00）和（1.17±1.69）和（0.90±1.33）,均显著高于健康人[分别为（0.01±0.61）和（0.01±0.97）,P〈0.01和P〈0.05];在HBs Ag〈1500IU/ml、1500-20000IU/ml和〉20000IU/ml组患者,GRP78 m RNA水平分别为（0.48±0.59）、（0.76±0.56）和（0.74±0.56）,三组间差异有统计学意义（P〈0.05）;HBV DNA水平为1×10^3-10^5copies/ml组XBP1 m RNA水平为（0.86±1.13）,显著低于HBV DNA〉1×105copies/ml组[（1.44±1.31）,P〈0.05];在不同转氨酶水平间、HBe Ag阳性与阴性组间和胆红素正常与升高组间,以上三种基因m RNA水平差异均无统计学意义（P〉0.05）。结论内质网应激可能与慢性HBV感染后的疾病进展相关。
