Previous studies have shown that resveratrol,a bioactive substance found in many plants,can reduce early brain injury after subarachnoid hemorrhage,but how it acts is still unclear.This study explored the mechanism us...Previous studies have shown that resveratrol,a bioactive substance found in many plants,can reduce early brain injury after subarachnoid hemorrhage,but how it acts is still unclear.This study explored the mechanism using the experimental subarachnoid hemorrhage rat model established by injecting autologous blood into the cerebellomedullary cistern.Rat models were treated with an intraperitoneal injection of 60 mg/kg resveratrol 2,6,24 and 46 hours after injury.At 48 hours after injury,their neurological function was assessed using a modified Garcia score.Brain edema was measured by the wet-dry method.Neuronal apoptosis in the prefrontal cortex was detected by terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay.Levels of reactive oxygen species and malondialdehyde in the prefrontal cortex were determined by colorimetry.CHOP,glucose-regulated protein 78,nuclear factor-erythroid2-related factor 2 and heme oxygenase-1 mRNA expression levels in the prefrontal cortex were measured by reverse transcription polymerase chain reaction.Tumor necrosis factor-alpha content in the prefrontal cortex was detected by enzyme linked immunosorbent assay.Immunohistochemical staining was used to detect the number of positive cells of nuclear factor-erythroid 2-related factor 2,heme oxygenase 1,glucose-regulated protein 78,CHOP and glial fibrillary acidic protein.Western blot assay was utilized to analyze the expression levels of nuclear factor-erythroid 2-related factor 2,heme oxygenase 1,glucose-regulated protein 78 and CHOP protein expression levels in the prefrontal cortex.The results showed that resveratrol treatment markedly alleviated neurological deficits and brain edema in experimental subarachnoid hemorrhage rats,and reduced neuronal apoptosis in the prefrontal cortex.Resveratrol reduced the levels of reactive oxygen species and malondialdehyde,and increased the expression of nuclear factor-erythroid 2-related factor 2,heme oxygenase-1 mRNA and protein in the prefrontal cortex.Resveratrol decreased glucose-regulated protein 78,CHOP mRNA and protein expression and tumor necrosis factor-alpha level.It also activated astrocytes.The results suggest that resveratrol exerted neuroprotective effect on subarachnoid hemorrhage by reducing oxidative damage,endoplasmic reticulum stress and neuroinflammation.The study was approved by the Animals Ethics Committee of Shandong University,China on February 22,2016(approval No.LL-201602022).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
BACKGROUND Uridine diphosphate glucuronosyltransferase 1A1(UGT1A1)plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances.However,its contribution to the progression of liver damage re...BACKGROUND Uridine diphosphate glucuronosyltransferase 1A1(UGT1A1)plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances.However,its contribution to the progression of liver damage remains unclear.AIM To determine the role and mechanism of UGT1A1 in liver damage progression.METHODS We investigated the relationship between UGT1A1 expression and liver injury through clinical research.Additionally,the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study.RESULTS Patients with UGT1A1 gene mutations showed varying degrees of liver damage,while patients with acute-onchronic liver failure(ACLF)exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis.This suggests that low UGT1A1 levels may be associated with the progression of liver damage.In mouse models of liver injury induced by carbon tetrachloride(CCl_(4))and concanavalin A(ConA),the hepatic levels of UGT1A1 protein were found to be increased.In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression,the hepatic protein levels of UGT1A1 were decreased,which is consistent with the observations in patients with ACLF.UGT1A1 knockout exacerbated CCl_(4)-and ConA-induced liver injury,hepatocyte apoptosis and necroptosis in mice,intensified hepatocyte endoplasmic reticulum(ER)stress and oxidative stress,and disrupted lipid metabolism.CONCLUSION UGT1A1 is upregulated as a compensatory response during liver injury,and interference with this upregulation process may worsen liver injury.UGT1A1 reduces ER stress,oxidative stress,and lipid metabolism disorder,thereby mitigating hepatocyte apoptosis and necroptosis.展开更多
The current letter to the editor pertains to the manuscript entitled'Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury'.Increased levels of uridine diphosphate glucuronos...The current letter to the editor pertains to the manuscript entitled'Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury'.Increased levels of uridine diphosphate glucuronosyltransferase 1A1 during liver injury could mitigate damage by reducing endoplasmic reticulum stress,oxidative stress,and dysregulated lipid metabolism,impeding hepatocyte apoptosis and necroptosis.展开更多
Objective:To study the effects of angiotensin 1-7 (Ang1-7) on endothelial cell injury caused by oxidative stress.Methods: Human umbilical vein endothelial cells (HUVECs) were cultured and divided into blank control gr...Objective:To study the effects of angiotensin 1-7 (Ang1-7) on endothelial cell injury caused by oxidative stress.Methods: Human umbilical vein endothelial cells (HUVECs) were cultured and divided into blank control group, hydrogen peroxide and different Ang1-7 dose groups (1, 2 and 4 μmol/L Ang1-7 groups). The cell proliferation activity, the contents of antioxidant enzymes in cell culture medium, and the contents of endoplasmic reticulum stress molecules in cells were determined.Results: After 6, 12, 18 and 24 h of treatment, CCK-8 proliferation activity values of hydrogen peroxide group were significantly lower than those of blank control group, CCK-8 proliferation activity values of 1, 2 and 4 μmol/L Ang1-7 groups were significantly higher than those of hydrogen peroxide group, and the larger the Ang1-7 dose, the higher the CCK-8 proliferation activity values;after 24 h of treatment, SOD, GSH-Px, HO-1 and CAT contents in cell culture medium of hydrogen peroxide group were significantly lower than those of control group, and GRP78, XBP1 and CHOP contents in cells were significantly higher than those of control group;SOD, GSH-Px, HO-1 and CAT contents in cell culture medium of 1, 2 and 4 μmol/L Ang1-7 groups were significantly higher than those of hydrogen peroxide group, GRP78, XBP1 and CHOP contents in cells were significantly lower than those of hydrogen peroxide group, and the larger the Ang1-7 dose, the more significant the changes of above molecules in cell culture medium and cells.Conclusion: Angiotensin 1-7 has protective effect on the endothelial cell injury caused by oxidative stress.展开更多
The sensorimotor and histological aspects of peripheral neuropathies were already studied by our team in two rat models:the sciatic nerve crush and the Charcot-Marie-Tooth-1A disease.In this study,we sought to highlig...The sensorimotor and histological aspects of peripheral neuropathies were already studied by our team in two rat models:the sciatic nerve crush and the Charcot-Marie-Tooth-1A disease.In this study,we sought to highlight and compare the protein signature of these two pathological situations.Indeed,the identification of protein profiles in diseases can play an important role in the development of pharmacological targets.In fact,Charcot-Marie-Tooth-1A rats develop motor impairments that are more severe in the hind limbs.Therefore,for the first time,protein expression in sciatic nerve of Charcot-Marie-Tooth-1A rats was examined.First,distal sciatic nerves were collected from Charcot-Marie-Tooth-1A and uninjured wild-type rats aged 3 months.After protein extraction,sequential window acquisition of all theoretical fragment ion spectra liquid chromatography and mass spectrometry was employed.445 proteins mapped to Swiss-Prot or trEMBL Uniprot databases were identified and quantified.Of these,153 proteins showed statistically significant differences between Charcot-Marie-Tooth-1A and wild-type groups.The majority of these proteins were overexpressed in Charcot-Marie-Tooth-1A.Hierarchical clustering and functional enrichment using Gene Ontology were used to group these proteins based on their biological effects concerning Charcot-Marie-Tooth-1A pathophysiology.Second,proteomic characterization of wild-type rats subjected to sciatic nerve crush was performed sequential window acquisition of all theoretical fragment ion spectra liquid chromatography and mass spectrometry.One month after injury,distal sciatic nerves were collected and analyzed as described above.Out of 459 identified proteins,92 showed significant differences between sciatic nerve crush and the uninjured wild-type rats used in the first study.The results suggest that young adult Charcot-Marie-Tooth-1A rats(3 months old)develop compensatory mechanisms at the level of redox balance,protein folding,myelination,and axonogenesis.These mechanisms seem insufficient to hurdle the progress of the disease.Notably,response to oxidative stress appears to be a significant feature of Charcot-Marie-Tooth-1A,potentially playing a role in the pathological process.In contrast to the first experiment,the majority of the proteins that differed from wild-type were downregulated in the sciatic nerve crush group.Functional enrichment suggested that neurogenesis,response to axon injury,and oxidative stress were important biological processes.Protein analysis revealed an imperfect repair at this time point after injury and identified several distinguishable proteins.In conclusion,we suggest that peripheral neuropathies,whether of a genetic or traumatic cause,share some common pathological pathways.This study may provide directions for better characterization of these models and/or identifying new specific therapeutic targets.展开更多
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
Exercise training(ET)has been reported to reduce oxidative stress and endoplasmic reticulum(ER)stress in the heart following myocardial infarction(MI).Thioredoxin 1(Trx1)plays a protective role in the infarcted heart....Exercise training(ET)has been reported to reduce oxidative stress and endoplasmic reticulum(ER)stress in the heart following myocardial infarction(MI).Thioredoxin 1(Trx1)plays a protective role in the infarcted heart.However,whether Trx1 regulates ER stress of the infarcted heart and participates in ET-induced cardiac protective effects are still not well known.In this work,H9c2 cells were treated with hydrogen peroxide(H_(2)O_(2))and recombinant human Trx1 protein(TXN),meanwhile,adult male C57B6L mice were used to establish the MI model,and subjected to a six-week aerobic exercise training(AET)with or without the injection of Trx1 inhibitor,PX-12.Results showed that H_(2)O_(2)significantly increased reactive oxygen species(ROS)level and the expression of TXNIP,CHOP and cleaved caspase12,induced cell apoptosis;TXN intervention reduced ROS level and the expression of CHOP and cleaved caspase12,and inhibited cell apoptosis in H_(2)O_(2)-treated H9c2 cells.Furthermore,AET up-regulated endogenous Trx1 protein expression and down-regulated TXNIP expression,restored ROS level and the expression of ER stress-related proteins,inhibited cell apoptosis as well as improved cardiac fibrosis and heart function in mice after MI.PX-12 partly inhibited the AET-induced beneficial effects in the infarcted heart.This study demonstrates that Trx1 attenuates ER stress-induced cell apoptosis,and AET reduces MI-induced ROS overproduction,ER stress and cell apoptosis partly through up-regulating of Trx1 expression in mice with MI.展开更多
目的 探究盐酸戊乙奎醚(PHC)对脑缺血糖尿病大鼠脑损伤的影响及其与核因子E2相关因子2(Nrf2)/血红素氧化酶1(HO-1)通路的关系。方法 选择SPF级雄性SD大鼠100只,采用链脲佐菌素复制糖尿病模型,在此基础上制作大脑中动脉闭塞模型,随机分...目的 探究盐酸戊乙奎醚(PHC)对脑缺血糖尿病大鼠脑损伤的影响及其与核因子E2相关因子2(Nrf2)/血红素氧化酶1(HO-1)通路的关系。方法 选择SPF级雄性SD大鼠100只,采用链脲佐菌素复制糖尿病模型,在此基础上制作大脑中动脉闭塞模型,随机分为模型组、PHC组、HO-1抑制剂组,另设正常组和糖尿病组,每组20只。TTC染色测定脑梗死面积;称重测脑水肿程度;苏木精-伊红染色、TUNEL染色、髓过氧化物酶免疫组织化学染色观察脑组织损伤情况;试剂盒检测丙二醛、活性氧、总抗氧化能力(T-AOC)水平,Western blot检测Nrf2/HO-1通路及内质网应激相关蛋白表达,包括葡萄糖调节蛋白78(GRP78)、需肌醇酶1(IRE1)、磷酸化IRE1、蛋白激酶R样内质网激酶(PERK)、磷酸化PERK、激活转录因子6(ATF6)。结果 模型组神经功能评分、脑水肿程度、脑梗死面积、丙二醛、活性氧、GRP78、磷酸化IRE1/IRE1、磷酸化PERK/PERK、ATF6表达明显高于正常组和糖尿病组,T-AOC、核蛋白中Nrf2及总蛋白中Nrf2、HO-1表达明显低于正常组和糖尿病组(P<0.05)。PHC组核蛋白中Nrf2及总蛋白中Nrf2、HO-1表达明显高于模型组(0.59±0.07 vs 0.25±0.04,1.52±0.16 vs 0.94±0.11,2.09±0.25 vs 1.27±0.19,P<0.05);HO-1抑制剂组总蛋白中HO-1表达明显低于PHC组(P<0.05)。结论 PHC可能通过Nrf2/HO-1通路调节氧化应激和内质网应激,进而减轻脑缺血糖尿病大鼠脑损伤。展开更多
基金supported by the National Natural Science Foundation of China,No.81873768 and 81671213(both to ZW)the Key Research and Development Foundation of Shandong Province of China,No.2017GSF218091(to ZW)the Fundamental Research Funds of Shandong University of China,No.2015JC008(to ZW)
文摘Previous studies have shown that resveratrol,a bioactive substance found in many plants,can reduce early brain injury after subarachnoid hemorrhage,but how it acts is still unclear.This study explored the mechanism using the experimental subarachnoid hemorrhage rat model established by injecting autologous blood into the cerebellomedullary cistern.Rat models were treated with an intraperitoneal injection of 60 mg/kg resveratrol 2,6,24 and 46 hours after injury.At 48 hours after injury,their neurological function was assessed using a modified Garcia score.Brain edema was measured by the wet-dry method.Neuronal apoptosis in the prefrontal cortex was detected by terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay.Levels of reactive oxygen species and malondialdehyde in the prefrontal cortex were determined by colorimetry.CHOP,glucose-regulated protein 78,nuclear factor-erythroid2-related factor 2 and heme oxygenase-1 mRNA expression levels in the prefrontal cortex were measured by reverse transcription polymerase chain reaction.Tumor necrosis factor-alpha content in the prefrontal cortex was detected by enzyme linked immunosorbent assay.Immunohistochemical staining was used to detect the number of positive cells of nuclear factor-erythroid 2-related factor 2,heme oxygenase 1,glucose-regulated protein 78,CHOP and glial fibrillary acidic protein.Western blot assay was utilized to analyze the expression levels of nuclear factor-erythroid 2-related factor 2,heme oxygenase 1,glucose-regulated protein 78 and CHOP protein expression levels in the prefrontal cortex.The results showed that resveratrol treatment markedly alleviated neurological deficits and brain edema in experimental subarachnoid hemorrhage rats,and reduced neuronal apoptosis in the prefrontal cortex.Resveratrol reduced the levels of reactive oxygen species and malondialdehyde,and increased the expression of nuclear factor-erythroid 2-related factor 2,heme oxygenase-1 mRNA and protein in the prefrontal cortex.Resveratrol decreased glucose-regulated protein 78,CHOP mRNA and protein expression and tumor necrosis factor-alpha level.It also activated astrocytes.The results suggest that resveratrol exerted neuroprotective effect on subarachnoid hemorrhage by reducing oxidative damage,endoplasmic reticulum stress and neuroinflammation.The study was approved by the Animals Ethics Committee of Shandong University,China on February 22,2016(approval No.LL-201602022).
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.
基金the Science and Technology Research Foundations of Guizhou Province,No.QKHJC-ZK(2022)YB642Zunyi Science and Technology Plan Project,No.ZSKHHZ(2022)344,No.ZSKHHZ(2022)360,and No.ZYK160+2 种基金Hubei Province Central Leading Local Science and Technology Development Special Project,No.2022BCE030Changzhou Science and Technology Projects,No.CE20225054Bijie City Science and Planning Bureau,No.BKH(2022)8.
文摘BACKGROUND Uridine diphosphate glucuronosyltransferase 1A1(UGT1A1)plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances.However,its contribution to the progression of liver damage remains unclear.AIM To determine the role and mechanism of UGT1A1 in liver damage progression.METHODS We investigated the relationship between UGT1A1 expression and liver injury through clinical research.Additionally,the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study.RESULTS Patients with UGT1A1 gene mutations showed varying degrees of liver damage,while patients with acute-onchronic liver failure(ACLF)exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis.This suggests that low UGT1A1 levels may be associated with the progression of liver damage.In mouse models of liver injury induced by carbon tetrachloride(CCl_(4))and concanavalin A(ConA),the hepatic levels of UGT1A1 protein were found to be increased.In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression,the hepatic protein levels of UGT1A1 were decreased,which is consistent with the observations in patients with ACLF.UGT1A1 knockout exacerbated CCl_(4)-and ConA-induced liver injury,hepatocyte apoptosis and necroptosis in mice,intensified hepatocyte endoplasmic reticulum(ER)stress and oxidative stress,and disrupted lipid metabolism.CONCLUSION UGT1A1 is upregulated as a compensatory response during liver injury,and interference with this upregulation process may worsen liver injury.UGT1A1 reduces ER stress,oxidative stress,and lipid metabolism disorder,thereby mitigating hepatocyte apoptosis and necroptosis.
文摘The current letter to the editor pertains to the manuscript entitled'Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury'.Increased levels of uridine diphosphate glucuronosyltransferase 1A1 during liver injury could mitigate damage by reducing endoplasmic reticulum stress,oxidative stress,and dysregulated lipid metabolism,impeding hepatocyte apoptosis and necroptosis.
文摘Objective:To study the effects of angiotensin 1-7 (Ang1-7) on endothelial cell injury caused by oxidative stress.Methods: Human umbilical vein endothelial cells (HUVECs) were cultured and divided into blank control group, hydrogen peroxide and different Ang1-7 dose groups (1, 2 and 4 μmol/L Ang1-7 groups). The cell proliferation activity, the contents of antioxidant enzymes in cell culture medium, and the contents of endoplasmic reticulum stress molecules in cells were determined.Results: After 6, 12, 18 and 24 h of treatment, CCK-8 proliferation activity values of hydrogen peroxide group were significantly lower than those of blank control group, CCK-8 proliferation activity values of 1, 2 and 4 μmol/L Ang1-7 groups were significantly higher than those of hydrogen peroxide group, and the larger the Ang1-7 dose, the higher the CCK-8 proliferation activity values;after 24 h of treatment, SOD, GSH-Px, HO-1 and CAT contents in cell culture medium of hydrogen peroxide group were significantly lower than those of control group, and GRP78, XBP1 and CHOP contents in cells were significantly higher than those of control group;SOD, GSH-Px, HO-1 and CAT contents in cell culture medium of 1, 2 and 4 μmol/L Ang1-7 groups were significantly higher than those of hydrogen peroxide group, GRP78, XBP1 and CHOP contents in cells were significantly lower than those of hydrogen peroxide group, and the larger the Ang1-7 dose, the more significant the changes of above molecules in cell culture medium and cells.Conclusion: Angiotensin 1-7 has protective effect on the endothelial cell injury caused by oxidative stress.
基金supported by a doctoral fellowship from the European Union(European Regional Development Fund).
文摘The sensorimotor and histological aspects of peripheral neuropathies were already studied by our team in two rat models:the sciatic nerve crush and the Charcot-Marie-Tooth-1A disease.In this study,we sought to highlight and compare the protein signature of these two pathological situations.Indeed,the identification of protein profiles in diseases can play an important role in the development of pharmacological targets.In fact,Charcot-Marie-Tooth-1A rats develop motor impairments that are more severe in the hind limbs.Therefore,for the first time,protein expression in sciatic nerve of Charcot-Marie-Tooth-1A rats was examined.First,distal sciatic nerves were collected from Charcot-Marie-Tooth-1A and uninjured wild-type rats aged 3 months.After protein extraction,sequential window acquisition of all theoretical fragment ion spectra liquid chromatography and mass spectrometry was employed.445 proteins mapped to Swiss-Prot or trEMBL Uniprot databases were identified and quantified.Of these,153 proteins showed statistically significant differences between Charcot-Marie-Tooth-1A and wild-type groups.The majority of these proteins were overexpressed in Charcot-Marie-Tooth-1A.Hierarchical clustering and functional enrichment using Gene Ontology were used to group these proteins based on their biological effects concerning Charcot-Marie-Tooth-1A pathophysiology.Second,proteomic characterization of wild-type rats subjected to sciatic nerve crush was performed sequential window acquisition of all theoretical fragment ion spectra liquid chromatography and mass spectrometry.One month after injury,distal sciatic nerves were collected and analyzed as described above.Out of 459 identified proteins,92 showed significant differences between sciatic nerve crush and the uninjured wild-type rats used in the first study.The results suggest that young adult Charcot-Marie-Tooth-1A rats(3 months old)develop compensatory mechanisms at the level of redox balance,protein folding,myelination,and axonogenesis.These mechanisms seem insufficient to hurdle the progress of the disease.Notably,response to oxidative stress appears to be a significant feature of Charcot-Marie-Tooth-1A,potentially playing a role in the pathological process.In contrast to the first experiment,the majority of the proteins that differed from wild-type were downregulated in the sciatic nerve crush group.Functional enrichment suggested that neurogenesis,response to axon injury,and oxidative stress were important biological processes.Protein analysis revealed an imperfect repair at this time point after injury and identified several distinguishable proteins.In conclusion,we suggest that peripheral neuropathies,whether of a genetic or traumatic cause,share some common pathological pathways.This study may provide directions for better characterization of these models and/or identifying new specific therapeutic targets.
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supported by National Natural Science Foundation of China(Grant No.31701039,31671240)the Fundamental Research Funds for the Central Universities,Shaanxi Normal University(Grant Number GK201803096).
文摘Exercise training(ET)has been reported to reduce oxidative stress and endoplasmic reticulum(ER)stress in the heart following myocardial infarction(MI).Thioredoxin 1(Trx1)plays a protective role in the infarcted heart.However,whether Trx1 regulates ER stress of the infarcted heart and participates in ET-induced cardiac protective effects are still not well known.In this work,H9c2 cells were treated with hydrogen peroxide(H_(2)O_(2))and recombinant human Trx1 protein(TXN),meanwhile,adult male C57B6L mice were used to establish the MI model,and subjected to a six-week aerobic exercise training(AET)with or without the injection of Trx1 inhibitor,PX-12.Results showed that H_(2)O_(2)significantly increased reactive oxygen species(ROS)level and the expression of TXNIP,CHOP and cleaved caspase12,induced cell apoptosis;TXN intervention reduced ROS level and the expression of CHOP and cleaved caspase12,and inhibited cell apoptosis in H_(2)O_(2)-treated H9c2 cells.Furthermore,AET up-regulated endogenous Trx1 protein expression and down-regulated TXNIP expression,restored ROS level and the expression of ER stress-related proteins,inhibited cell apoptosis as well as improved cardiac fibrosis and heart function in mice after MI.PX-12 partly inhibited the AET-induced beneficial effects in the infarcted heart.This study demonstrates that Trx1 attenuates ER stress-induced cell apoptosis,and AET reduces MI-induced ROS overproduction,ER stress and cell apoptosis partly through up-regulating of Trx1 expression in mice with MI.
文摘目的 探究盐酸戊乙奎醚(PHC)对脑缺血糖尿病大鼠脑损伤的影响及其与核因子E2相关因子2(Nrf2)/血红素氧化酶1(HO-1)通路的关系。方法 选择SPF级雄性SD大鼠100只,采用链脲佐菌素复制糖尿病模型,在此基础上制作大脑中动脉闭塞模型,随机分为模型组、PHC组、HO-1抑制剂组,另设正常组和糖尿病组,每组20只。TTC染色测定脑梗死面积;称重测脑水肿程度;苏木精-伊红染色、TUNEL染色、髓过氧化物酶免疫组织化学染色观察脑组织损伤情况;试剂盒检测丙二醛、活性氧、总抗氧化能力(T-AOC)水平,Western blot检测Nrf2/HO-1通路及内质网应激相关蛋白表达,包括葡萄糖调节蛋白78(GRP78)、需肌醇酶1(IRE1)、磷酸化IRE1、蛋白激酶R样内质网激酶(PERK)、磷酸化PERK、激活转录因子6(ATF6)。结果 模型组神经功能评分、脑水肿程度、脑梗死面积、丙二醛、活性氧、GRP78、磷酸化IRE1/IRE1、磷酸化PERK/PERK、ATF6表达明显高于正常组和糖尿病组,T-AOC、核蛋白中Nrf2及总蛋白中Nrf2、HO-1表达明显低于正常组和糖尿病组(P<0.05)。PHC组核蛋白中Nrf2及总蛋白中Nrf2、HO-1表达明显高于模型组(0.59±0.07 vs 0.25±0.04,1.52±0.16 vs 0.94±0.11,2.09±0.25 vs 1.27±0.19,P<0.05);HO-1抑制剂组总蛋白中HO-1表达明显低于PHC组(P<0.05)。结论 PHC可能通过Nrf2/HO-1通路调节氧化应激和内质网应激,进而减轻脑缺血糖尿病大鼠脑损伤。
