Objective To clarify the association between rs1050450 polymorphism in Glutathione peroxidase-1 （GPx-1） and the risk of cardi-ovascular diseases （CVD） by performing a meta-analysis of published studies. There is g...Objective To clarify the association between rs1050450 polymorphism in Glutathione peroxidase-1 （GPx-1） and the risk of cardi-ovascular diseases （CVD） by performing a meta-analysis of published studies. There is growing evidence from different study types for an association of the GPx-1 polymorphism and cardiovascular outcomes, but observational studies have so far shown inconsistent results. Me-thods Relevant publications were searched through PubMed, Embase database databases and the Cochrane Library. We used odds ratios （ORs） with 95%confidence intervals （CIs） to assess the strength of association under the best genetic model. Both Q statistic and the I2 were used to check heterogeneity. Meta-regression analysis was performed to explore heterogeneity source. Sensitivity analysis, cumulative me-ta-analysis analysis and publication bias were used to test the reliability of the results. Results Data were available from two cohort studies and 8 case-control studies involving 1,430 cases and 3,767 controls. The pooled ORs for overall CVD risk was 1.36 with 95%CI：1.08-1.70 under a co-dominant model, and that for East Asian subgroup was 1.84 （95%CI：1.39-2.43）. Substantial heterogeneity for ORs were de-tected among all the included studies, mainly caused by ethnic differences between East Asian and non-East Asian populations. Although Egger＇s regression test suggested no statistical significant publication bias, Begg＇s funnel plot exhibited obvious asymmetry. The statistical significance disappeared after adjusting for potential publication bias in the overall studies. However, no substantial publication bias was found in the East Asian subgroup. Conclusions GPx-1 gene Pro198Leu and Pro197Leu polymorphisms considerably increased the risk of CVD in the East Asian population. Large-scale investigations are needed to confirm the results in different ethnicities.展开更多
BACKGROUND Colorectal cancer(CRC)is the third most common cancer and the second most common cause of cancer-related death worldwide.The 5-year survival rate of patients with early-stage CRC could reach 90%,but it is v...BACKGROUND Colorectal cancer(CRC)is the third most common cancer and the second most common cause of cancer-related death worldwide.The 5-year survival rate of patients with early-stage CRC could reach 90%,but it is very low in patients with advanced-stage CRC.Recent studies have shown that circular RNAs play important roles in regulating the migration and invasion of CRC cells.AIM To elucidate the role of circRNA_0084927(circ_0084927)in the migration and invasion of CRC cells and its underlying mechanism.METHODS Clinical tissue samples and cells were collected,and the expression of circ_0084927 was detected by quantitative polymerase chain reaction(qPCR).The diagnostic performance of circ_0084927 was assessed by receiver operating characteristic curve analysis.The role of circ_0084927 in CRC cell proliferation,migration,and invasion was determined using cell counting kit-8 assay,wound healing assay,and transwell assay,respectively.The regulatory relationship among circ_0084927,miRNA-20b-3p(miR-20b-3p),and glutathione S-transferase mu 5(GSTM5)was identified using databases,luciferase reporter assay,qPCR,and Western blot analysis.AKT-mTOR signaling was also verified after circ_0084927 knockdown or miR-20b-3p mimic treatment.RESULTS The expression of circ_0084927 was significantly increased in CRC tissues and cells,and it was higher in advanced-stage CRC compared with early-stage CRC.The area under the curve(AUC)of circ_0084927 was 0.806[95%confidence interval(CI):0.683-0.896].In addition,the AUC was 0.874(95%CI:0.738-0.956)in patients with advanced-stage CRC and 0.713(95%CI:0.555-0.840)in those with early-stage CRC.Knockdown of circ_0084927 inhibited the migration and invasion of HCT116 cells.Moreover,circ_0084927 was found to act as a sponge of miR-20b-3p.MiR-20b-3p activation reduced the circ_0084927 level,whereas miR-20b-3p inhibition increased the circ_0084927 level.But the effect was not found after circ_0084927 mutation.In addition,miR-20b-3p expression in CRC patients was also reduced and negatively correlated with circ_0084927 expression.The function of circ_0084927 in HCT116 cells with circ_0084927 knockdown was rescued by miR-20b-3p.Moreover,GSTM5 expression was significantly decreased after overexpressing miR-20b-3p or inhibiting circ_0084927,but its expression was rescued when circ_0084927 and miR-20b-3p were both inhibited.Finally,AKTmTOR signaling was markedly regulated by circ_0084927 and miR-20b-3p.CONCLUSION The expression of circ_0084927 is significantly increased in CRC and higher in advanced-stage CRC than in early-stage CRC.Moreover,circ_0084927 potentially regulates CRC cell migration and invasion via the miR-20b-3p/GSTM5/AKT/mTOR pathway.展开更多
OBJECTIVE Intracellular aggre⁃gation ofα-synuclein(SNCA)is one of the core pathological features of neurodegenerative disor⁃ders including Parkinson disease,whilst the detailed mechanism for consequently neuron loss ...OBJECTIVE Intracellular aggre⁃gation ofα-synuclein(SNCA)is one of the core pathological features of neurodegenerative disor⁃ders including Parkinson disease,whilst the detailed mechanism for consequently neuron loss has not been fully illustrated.Since the altered phospholipid homeostasis has been suggested to play a role in synucleinopathy,this study aims to depict the fully-featured status of phospholip⁃ids and the targets reposingα-synuclein-related neurotoxicity.METHODS SNCAA53T transgenic mice were utilized as the model of Parkinson disease.Behavioral tests including pole test,rotarod test and gait analysis were conducted to assess the motor features of Parkinsonism.Tyro⁃sine hydroxylase were determined by immunohis⁃tochemistry.Glutathione,dopamine,3,4-dihy⁃droxyphenylacetic acid and homovanillic acid were determined by HPLC-ECD analysis.Assess⁃ment of lipid peroxidation included MDA assay and Liperfluo staining.Phospholipid-omics was analyzed based on LC-MS/MS.Investigation on mechanism was relied on Western blotting and qPCR assay.The injection of AAV into midbrain was achieved by ultra-micro injection pump to obtain the target genotype.RESULTS SNCAA53T transgenic mice displayed progres⁃sively deteriorated motor coordination functions and the mechanisms were related with lipid per⁃oxidation and ferroptosis,which might help to explain the parkinsonism.These hydroperoxides were observed on plasm membrane and were further characterized by LC-MS/MS-based phos⁃pholipid-omics analysis.α-synucleinA53T trans⁃genic mice displayed distinct patterns of phos⁃pholipid peroxidation in midbrain regions com⁃pared to wild type littermates.Among different subtypes of oxidized phospholipids,oxidative phosphatidylcholine(PC-ox)was more promi⁃nently elevated.Phospholipid peroxidation is believed as a biomarker of ferroptosis,which is largely a specialized death program caused by insufficiency of glutathione peroxidase-4(GPX4),the only known enzyme that can reduce lipid hydroperoxides within biological membranes.The deficiency of Gpx4 was demonstrated to be responsible forα-synuclein-induced lipid peroxi⁃dation,and the cell lines and mouse models underwent genetic Gpx4 downregulation showed exacerbated dopaminergic neuron loss and par⁃kinsonism.On the other hand,the potentiation of Gpx4 expression remarkably inhibited dopami⁃nergic ferroptotic death and behavioral deficits in a mouse model with synucleinopathy.CONCLU⁃SION A cellular pathway that Gpx4 deficit-medi⁃ated phospholipid peroxidation and behavioral consequence participated in synucleinopathy,suggesting a potential strategy targeting Gpx4 to alleviate PD symptoms.展开更多
DL-3-n-butylphthalide(NBP)-a compound isolated from Apium graveolens seeds-is protective against brain ischemia via various mechanisms in humans and has been approved for treatment of acute ischemic stroke.NBP has sho...DL-3-n-butylphthalide(NBP)-a compound isolated from Apium graveolens seeds-is protective against brain ischemia via various mechanisms in humans and has been approved for treatment of acute ischemic stroke.NBP has shown recent potential as a treatment for Parkinson’s disease.However,the underlying mechanism of action of NBP remains poorly understood.In this study,we established a rat model of Parkinson’s disease by intraperitoneal injection of rotenone for 28 successive days,followed by intragastric injection of NBP for 14-28 days.We found that NBP greatly alleviated rotenone-induced motor disturbance in the rat model of Parkinson’s disease,inhibited loss of dopaminergic neurons and aggregation ofα-synuclein,and reduced iron deposition in the substantia nigra and iron content in serum.These changes were achieved by alterations in the expression of the iron metabolism-related proteins transferrin receptor,ferritin light chain,and transferrin 1.NBP also inhibited oxidative stress in the substantia nigra and protected mitochondria in the rat model of Parkinson’s disease.Our findings suggest that NBP alleviates motor disturbance by inhibition of iron deposition,oxidative stress,and ferroptosis in the substantia nigra.展开更多
目的观察羧甲司坦对慢性气道炎症大鼠肺组织中磷脂酰肌醇-3-激酶(PI3K)/蛋白激酶B(AKT)和γ-谷氨酰半胱氨酸合酶(γ-GCS)表达的影响。方法将30只健康雄性SD大鼠随机分为对照组、模型组和羧甲司坦治疗组。模型组及羧甲司坦治疗组大鼠用...目的观察羧甲司坦对慢性气道炎症大鼠肺组织中磷脂酰肌醇-3-激酶(PI3K)/蛋白激酶B(AKT)和γ-谷氨酰半胱氨酸合酶(γ-GCS)表达的影响。方法将30只健康雄性SD大鼠随机分为对照组、模型组和羧甲司坦治疗组。模型组及羧甲司坦治疗组大鼠用气管内注入脂多糖和熏香烟法制成慢性气道炎症大鼠模型,羧甲司坦治疗组大鼠在第17～30天吸烟前30min给予羧甲司坦(500mg/kg)灌胃。计数各组大鼠支气管肺泡灌洗液(BALF)细胞,观察肺组织的病理变化;用免疫组织化学检测肺组织γ-GCS及磷酸化AKT(p-AKT)的表达水平;用逆转录聚合酶链反应(RT-PCR)检测PI3 K mRNA、γ-GCS mRNA的表达。结果与模型组比较,羧甲司坦治疗组大鼠支气管、肺组织中炎症浸润及BALF中中性粒细胞数明显降低(P<0.05),p-AKT蛋白、γ-GCS蛋白、PI3 K mRNA及γ-GCS mRNA的表达明显降低(P<0.05),谷胱甘肽(GSH)、活性氧(ROS)含量明显减少,总抗氧化能力明显上升(P<0.05)。结论羧甲司坦可能通过PI3K/AKT通路促进γ-GCS蛋白的表达,减轻被动吸烟大鼠肺部的炎症和氧化应激。展开更多
文摘Objective To clarify the association between rs1050450 polymorphism in Glutathione peroxidase-1 （GPx-1） and the risk of cardi-ovascular diseases （CVD） by performing a meta-analysis of published studies. There is growing evidence from different study types for an association of the GPx-1 polymorphism and cardiovascular outcomes, but observational studies have so far shown inconsistent results. Me-thods Relevant publications were searched through PubMed, Embase database databases and the Cochrane Library. We used odds ratios （ORs） with 95%confidence intervals （CIs） to assess the strength of association under the best genetic model. Both Q statistic and the I2 were used to check heterogeneity. Meta-regression analysis was performed to explore heterogeneity source. Sensitivity analysis, cumulative me-ta-analysis analysis and publication bias were used to test the reliability of the results. Results Data were available from two cohort studies and 8 case-control studies involving 1,430 cases and 3,767 controls. The pooled ORs for overall CVD risk was 1.36 with 95%CI：1.08-1.70 under a co-dominant model, and that for East Asian subgroup was 1.84 （95%CI：1.39-2.43）. Substantial heterogeneity for ORs were de-tected among all the included studies, mainly caused by ethnic differences between East Asian and non-East Asian populations. Although Egger＇s regression test suggested no statistical significant publication bias, Begg＇s funnel plot exhibited obvious asymmetry. The statistical significance disappeared after adjusting for potential publication bias in the overall studies. However, no substantial publication bias was found in the East Asian subgroup. Conclusions GPx-1 gene Pro198Leu and Pro197Leu polymorphisms considerably increased the risk of CVD in the East Asian population. Large-scale investigations are needed to confirm the results in different ethnicities.
文摘BACKGROUND Colorectal cancer(CRC)is the third most common cancer and the second most common cause of cancer-related death worldwide.The 5-year survival rate of patients with early-stage CRC could reach 90%,but it is very low in patients with advanced-stage CRC.Recent studies have shown that circular RNAs play important roles in regulating the migration and invasion of CRC cells.AIM To elucidate the role of circRNA_0084927(circ_0084927)in the migration and invasion of CRC cells and its underlying mechanism.METHODS Clinical tissue samples and cells were collected,and the expression of circ_0084927 was detected by quantitative polymerase chain reaction(qPCR).The diagnostic performance of circ_0084927 was assessed by receiver operating characteristic curve analysis.The role of circ_0084927 in CRC cell proliferation,migration,and invasion was determined using cell counting kit-8 assay,wound healing assay,and transwell assay,respectively.The regulatory relationship among circ_0084927,miRNA-20b-3p(miR-20b-3p),and glutathione S-transferase mu 5(GSTM5)was identified using databases,luciferase reporter assay,qPCR,and Western blot analysis.AKT-mTOR signaling was also verified after circ_0084927 knockdown or miR-20b-3p mimic treatment.RESULTS The expression of circ_0084927 was significantly increased in CRC tissues and cells,and it was higher in advanced-stage CRC compared with early-stage CRC.The area under the curve(AUC)of circ_0084927 was 0.806[95%confidence interval(CI):0.683-0.896].In addition,the AUC was 0.874(95%CI:0.738-0.956)in patients with advanced-stage CRC and 0.713(95%CI:0.555-0.840)in those with early-stage CRC.Knockdown of circ_0084927 inhibited the migration and invasion of HCT116 cells.Moreover,circ_0084927 was found to act as a sponge of miR-20b-3p.MiR-20b-3p activation reduced the circ_0084927 level,whereas miR-20b-3p inhibition increased the circ_0084927 level.But the effect was not found after circ_0084927 mutation.In addition,miR-20b-3p expression in CRC patients was also reduced and negatively correlated with circ_0084927 expression.The function of circ_0084927 in HCT116 cells with circ_0084927 knockdown was rescued by miR-20b-3p.Moreover,GSTM5 expression was significantly decreased after overexpressing miR-20b-3p or inhibiting circ_0084927,but its expression was rescued when circ_0084927 and miR-20b-3p were both inhibited.Finally,AKTmTOR signaling was markedly regulated by circ_0084927 and miR-20b-3p.CONCLUSION The expression of circ_0084927 is significantly increased in CRC and higher in advanced-stage CRC than in early-stage CRC.Moreover,circ_0084927 potentially regulates CRC cell migration and invasion via the miR-20b-3p/GSTM5/AKT/mTOR pathway.
基金National Key Research and Development Program of China(2017YFC1700404)Natural Science Foundation of China(81873209)+8 种基金Natural Science Foundation of China(U1801284)Natural Science Foundation of China(81903821)Natural Science Foundation of China(81973718)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036)GDUPS(2019),Fun⁃damental Research Funds for the Central Univer⁃sities(21620448)Natural Science Foundation of Guangdong Province(2019A 1515010909)Nat⁃ural Science Foundation of Guangdong Prov⁃ince(2021A1515011297)Science and Tech⁃nology Program of Guangzhou(201903010062)Science and Technology Program of Guang⁃zhou(907158833068),and the Innovation Team Project of Guangdong Provincial Department of Education(2020KCXT D003)。
文摘OBJECTIVE Intracellular aggre⁃gation ofα-synuclein(SNCA)is one of the core pathological features of neurodegenerative disor⁃ders including Parkinson disease,whilst the detailed mechanism for consequently neuron loss has not been fully illustrated.Since the altered phospholipid homeostasis has been suggested to play a role in synucleinopathy,this study aims to depict the fully-featured status of phospholip⁃ids and the targets reposingα-synuclein-related neurotoxicity.METHODS SNCAA53T transgenic mice were utilized as the model of Parkinson disease.Behavioral tests including pole test,rotarod test and gait analysis were conducted to assess the motor features of Parkinsonism.Tyro⁃sine hydroxylase were determined by immunohis⁃tochemistry.Glutathione,dopamine,3,4-dihy⁃droxyphenylacetic acid and homovanillic acid were determined by HPLC-ECD analysis.Assess⁃ment of lipid peroxidation included MDA assay and Liperfluo staining.Phospholipid-omics was analyzed based on LC-MS/MS.Investigation on mechanism was relied on Western blotting and qPCR assay.The injection of AAV into midbrain was achieved by ultra-micro injection pump to obtain the target genotype.RESULTS SNCAA53T transgenic mice displayed progres⁃sively deteriorated motor coordination functions and the mechanisms were related with lipid per⁃oxidation and ferroptosis,which might help to explain the parkinsonism.These hydroperoxides were observed on plasm membrane and were further characterized by LC-MS/MS-based phos⁃pholipid-omics analysis.α-synucleinA53T trans⁃genic mice displayed distinct patterns of phos⁃pholipid peroxidation in midbrain regions com⁃pared to wild type littermates.Among different subtypes of oxidized phospholipids,oxidative phosphatidylcholine(PC-ox)was more promi⁃nently elevated.Phospholipid peroxidation is believed as a biomarker of ferroptosis,which is largely a specialized death program caused by insufficiency of glutathione peroxidase-4(GPX4),the only known enzyme that can reduce lipid hydroperoxides within biological membranes.The deficiency of Gpx4 was demonstrated to be responsible forα-synuclein-induced lipid peroxi⁃dation,and the cell lines and mouse models underwent genetic Gpx4 downregulation showed exacerbated dopaminergic neuron loss and par⁃kinsonism.On the other hand,the potentiation of Gpx4 expression remarkably inhibited dopami⁃nergic ferroptotic death and behavioral deficits in a mouse model with synucleinopathy.CONCLU⁃SION A cellular pathway that Gpx4 deficit-medi⁃ated phospholipid peroxidation and behavioral consequence participated in synucleinopathy,suggesting a potential strategy targeting Gpx4 to alleviate PD symptoms.
基金funded by the National Natural Science Foundation of China, No. 81873924 (to QQL), No. 82171190 (to GHW)Nantong Science and Technology Project of China, No. MS22021010 (to LHS)High-level Innovation and Entrepreneurship Talents Introduction Program of Jiangsu Province of China (to QQL)
文摘DL-3-n-butylphthalide(NBP)-a compound isolated from Apium graveolens seeds-is protective against brain ischemia via various mechanisms in humans and has been approved for treatment of acute ischemic stroke.NBP has shown recent potential as a treatment for Parkinson’s disease.However,the underlying mechanism of action of NBP remains poorly understood.In this study,we established a rat model of Parkinson’s disease by intraperitoneal injection of rotenone for 28 successive days,followed by intragastric injection of NBP for 14-28 days.We found that NBP greatly alleviated rotenone-induced motor disturbance in the rat model of Parkinson’s disease,inhibited loss of dopaminergic neurons and aggregation ofα-synuclein,and reduced iron deposition in the substantia nigra and iron content in serum.These changes were achieved by alterations in the expression of the iron metabolism-related proteins transferrin receptor,ferritin light chain,and transferrin 1.NBP also inhibited oxidative stress in the substantia nigra and protected mitochondria in the rat model of Parkinson’s disease.Our findings suggest that NBP alleviates motor disturbance by inhibition of iron deposition,oxidative stress,and ferroptosis in the substantia nigra.
文摘目的观察羧甲司坦对慢性气道炎症大鼠肺组织中磷脂酰肌醇-3-激酶(PI3K)/蛋白激酶B(AKT)和γ-谷氨酰半胱氨酸合酶(γ-GCS)表达的影响。方法将30只健康雄性SD大鼠随机分为对照组、模型组和羧甲司坦治疗组。模型组及羧甲司坦治疗组大鼠用气管内注入脂多糖和熏香烟法制成慢性气道炎症大鼠模型,羧甲司坦治疗组大鼠在第17～30天吸烟前30min给予羧甲司坦(500mg/kg)灌胃。计数各组大鼠支气管肺泡灌洗液(BALF)细胞,观察肺组织的病理变化;用免疫组织化学检测肺组织γ-GCS及磷酸化AKT(p-AKT)的表达水平;用逆转录聚合酶链反应(RT-PCR)检测PI3 K mRNA、γ-GCS mRNA的表达。结果与模型组比较,羧甲司坦治疗组大鼠支气管、肺组织中炎症浸润及BALF中中性粒细胞数明显降低(P<0.05),p-AKT蛋白、γ-GCS蛋白、PI3 K mRNA及γ-GCS mRNA的表达明显降低(P<0.05),谷胱甘肽(GSH)、活性氧(ROS)含量明显减少,总抗氧化能力明显上升(P<0.05)。结论羧甲司坦可能通过PI3K/AKT通路促进γ-GCS蛋白的表达,减轻被动吸烟大鼠肺部的炎症和氧化应激。
