目的探讨酰基辅酶A合成酶长链家族成员4(acyl-CoA syntbetase long chain family member 4,ACSL4)在七氟醚(sevoflurane,Sev)诱导的神经元细胞损伤中的作用及机制。方法以人神经母细胞瘤SH-SY5Y细胞为研究对象,分别设置对照组(二甲基亚...目的探讨酰基辅酶A合成酶长链家族成员4(acyl-CoA syntbetase long chain family member 4,ACSL4)在七氟醚(sevoflurane,Sev)诱导的神经元细胞损伤中的作用及机制。方法以人神经母细胞瘤SH-SY5Y细胞为研究对象,分别设置对照组(二甲基亚砜,10μmol/L)、Sev组和Sev+铁死亡抑制剂Ferrostatin-1(Fer-1,10μmol/L)组,采用CCK-8法检测细胞活性。体外构建4.1%Sev暴露的术后认知功能障碍模型,按照转染类别分为Ctrol组、Sev组、Sev+si-NC组、Sev+si-ACSL4组和Sev+si-ACSL4+compound C组。采用比色法检测各组细胞中丙二醛(malonaldehyde,MDA)、4-羟基壬烯醛(4-hydroxynonenal,4-HNE)、谷胱甘肽(glutathione,GSH)和Fe2+含量;2’,7’-二氯荧光素二乙酸盐(DCFH-DA)荧光探针检测活性氧水平;实时荧光定量PCR(qRT-PCR)检测ACSL4,谷胱甘肽过氧化酶4(glutathione peroxidase 4,GPX4)和溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11)mRNA表达;蛋白免疫印迹法(WB)检测ACSL4,GPX4,腺苷酸激活蛋白激酶(adenosine 5’-monophosphate-activated protein kinase,AMPK)、磷酸化(phosphorylated,p)-AMPK,哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin)mTOR和p-mTOR蛋白表达。结果CCK-8结果显示,Sev组细胞活力(0.41±0.11)较对照组(0.98±0.07)明显降低,Sev+Fer-1组细胞活力(0.83±0.09)较Sev组显著升高,差异具有统计学意义(t=7.572,5.118,均P<0.01)。Sev组细胞中Fe2+,MDA,4-HNE,ROS水平和p-AMPK/AMPK比率以及ACSL4的mRNA和蛋白表达高于Ctrol组(t=5.900,7.421,4.795,13.517,10.825,9.945,11.334),GSH,p-mTOR/mTOR比率以及SLC7A11,GPX4的mRNA和蛋白表达低于Ctrol组(t=20.438,3.551,11.460,12.211,6.845,8.287),差异具有统计学意义(均P<0.05)。Sev+siACSL4组Fe2+,MDA,4-HNE,ROS水平和p-AMPK/AMPK比率以及ACSL4的mRNA和蛋白表达低于Sev+siNC组(t=3.818,3.164,3.054,4.465,13.088,7.918,9.737),细胞活力、GSH含量、p-mTOR/mTOR比率以及SLC7A11,GPX4的蛋白表达高于Sev+si-NC组(t=2.912,7.248,7.574,20.092,5.915),差异具有统计学意义(均P<0.05)。Sev+si-ACSL4+compound C组细胞活力、GSH含量和SLC7A11,GPX4蛋白表达低于Sev+si-ACSL4组(t=4.435,8.521,4.522,8.767),而Fe2+,MDA,4-HNE和ROS水平高于Sev+si-ACSL4组(t=10.046,4.004,2.957,3.752),差异具有统计学意义(均P<0.05)。结论抑制ACSL4表达可通过激活AMPK/mTOR信号通路减轻Sev诱导的SH-SY5Y细胞铁死亡。展开更多
目的评价长链脂酰辅酶A合成酶4(acyl-CoA synthetase long-chain family member 4,ACSL4)对肝癌患者预后的影响。方法系统检索PubMed、Embase、Cochrane Library、Web of science、中国知网、万方医学与维普数据库,检索时间均从建库至2...目的评价长链脂酰辅酶A合成酶4(acyl-CoA synthetase long-chain family member 4,ACSL4)对肝癌患者预后的影响。方法系统检索PubMed、Embase、Cochrane Library、Web of science、中国知网、万方医学与维普数据库,检索时间均从建库至2023年2月,收集ACSL4表达对肝癌患者预后影响的队列研究。文献的筛选过程由2名评估员自主完成。将纳入的研究依据纽卡斯尔-渥太华质量评价量表(Newcastle Ottawa Scale,NOS)进行质量评估,提取文献中肝癌患者的临床病理特征、研究的结局指标及HR(95%CI)等相关数据。运用Stata17.0MP软件对文献数据进行统计分析,采用漏斗图与Egger’s检验探讨偏倚风险。结果共纳入6项队列试验(890例肝癌患者)。Meta分析表明,与ACSL4低表达组患者相比,ACSL4高表达组肝癌患者总生存期(overall survival,OS)较短(HR=1.274,95%CI:1.141~1.422,P<0.001);肝癌患者中,男性ACSL4高表达(OR=1.12,95%CI:1.008~1.224,P<0.05)。Egger’s检验表明研究间存在发表偏倚的可能性较小(P=0.055)。ACSL4表达水平与年龄、肿瘤分期、肿瘤大小和肿瘤包膜是否完整以及是否合并肝硬化的相关性无统计学意义(P均>0.05)。结论ACSL4高表达与肝癌患者较短OS的相关性具有统计学意义,但仍需要更多的高质量临床研究进行验证。展开更多
Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox...Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox homeostasis.Metformin is a classic drug used to treat type 2 diabetes that can inhibit ferroptosis.Previous studies have shown that,when used to treat cardiovascular and digestive system diseases,metformin can also upregulate heme oxygenase-1 expression.Therefore,we hypothesized that heme oxygenase-1 plays a significant role in mediating the beneficial effects of metformin on neuronal ferroptosis after spinal cord injury.To test this,we first performed a bioinformatics analysis based on the GEO database and found that heme oxygenase-1 was upregulated in the lesion of rats with spinal cord injury.Next,we confirmed this finding in a rat model of T9 spinal cord compression injury that exhibited spinal cord nerve cell ferroptosis.Continuous intraperitoneal injection of metformin for 14 days was found to both upregulate heme oxygenase-1 expression and reduce neuronal ferroptosis in rats with spinal cord injury.Subsequently,we used a lentivirus vector to knock down heme oxygenase-1 expression in the spinal cord,and found that this significantly reduced the effect of metformin on ferroptosis after spinal cord injury.Taken together,these findings suggest that metformin inhibits neuronal ferroptosis after spinal cord injury,and that this effect is partially dependent on upregulation of heme oxygenase-1.展开更多
文摘目的探讨酰基辅酶A合成酶长链家族成员4(acyl-CoA syntbetase long chain family member 4,ACSL4)在七氟醚(sevoflurane,Sev)诱导的神经元细胞损伤中的作用及机制。方法以人神经母细胞瘤SH-SY5Y细胞为研究对象,分别设置对照组(二甲基亚砜,10μmol/L)、Sev组和Sev+铁死亡抑制剂Ferrostatin-1(Fer-1,10μmol/L)组,采用CCK-8法检测细胞活性。体外构建4.1%Sev暴露的术后认知功能障碍模型,按照转染类别分为Ctrol组、Sev组、Sev+si-NC组、Sev+si-ACSL4组和Sev+si-ACSL4+compound C组。采用比色法检测各组细胞中丙二醛(malonaldehyde,MDA)、4-羟基壬烯醛(4-hydroxynonenal,4-HNE)、谷胱甘肽(glutathione,GSH)和Fe2+含量;2’,7’-二氯荧光素二乙酸盐(DCFH-DA)荧光探针检测活性氧水平;实时荧光定量PCR(qRT-PCR)检测ACSL4,谷胱甘肽过氧化酶4(glutathione peroxidase 4,GPX4)和溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11)mRNA表达;蛋白免疫印迹法(WB)检测ACSL4,GPX4,腺苷酸激活蛋白激酶(adenosine 5’-monophosphate-activated protein kinase,AMPK)、磷酸化(phosphorylated,p)-AMPK,哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin)mTOR和p-mTOR蛋白表达。结果CCK-8结果显示,Sev组细胞活力(0.41±0.11)较对照组(0.98±0.07)明显降低,Sev+Fer-1组细胞活力(0.83±0.09)较Sev组显著升高,差异具有统计学意义(t=7.572,5.118,均P<0.01)。Sev组细胞中Fe2+,MDA,4-HNE,ROS水平和p-AMPK/AMPK比率以及ACSL4的mRNA和蛋白表达高于Ctrol组(t=5.900,7.421,4.795,13.517,10.825,9.945,11.334),GSH,p-mTOR/mTOR比率以及SLC7A11,GPX4的mRNA和蛋白表达低于Ctrol组(t=20.438,3.551,11.460,12.211,6.845,8.287),差异具有统计学意义(均P<0.05)。Sev+siACSL4组Fe2+,MDA,4-HNE,ROS水平和p-AMPK/AMPK比率以及ACSL4的mRNA和蛋白表达低于Sev+siNC组(t=3.818,3.164,3.054,4.465,13.088,7.918,9.737),细胞活力、GSH含量、p-mTOR/mTOR比率以及SLC7A11,GPX4的蛋白表达高于Sev+si-NC组(t=2.912,7.248,7.574,20.092,5.915),差异具有统计学意义(均P<0.05)。Sev+si-ACSL4+compound C组细胞活力、GSH含量和SLC7A11,GPX4蛋白表达低于Sev+si-ACSL4组(t=4.435,8.521,4.522,8.767),而Fe2+,MDA,4-HNE和ROS水平高于Sev+si-ACSL4组(t=10.046,4.004,2.957,3.752),差异具有统计学意义(均P<0.05)。结论抑制ACSL4表达可通过激活AMPK/mTOR信号通路减轻Sev诱导的SH-SY5Y细胞铁死亡。
文摘目的评价长链脂酰辅酶A合成酶4(acyl-CoA synthetase long-chain family member 4,ACSL4)对肝癌患者预后的影响。方法系统检索PubMed、Embase、Cochrane Library、Web of science、中国知网、万方医学与维普数据库,检索时间均从建库至2023年2月,收集ACSL4表达对肝癌患者预后影响的队列研究。文献的筛选过程由2名评估员自主完成。将纳入的研究依据纽卡斯尔-渥太华质量评价量表(Newcastle Ottawa Scale,NOS)进行质量评估,提取文献中肝癌患者的临床病理特征、研究的结局指标及HR(95%CI)等相关数据。运用Stata17.0MP软件对文献数据进行统计分析,采用漏斗图与Egger’s检验探讨偏倚风险。结果共纳入6项队列试验(890例肝癌患者)。Meta分析表明,与ACSL4低表达组患者相比,ACSL4高表达组肝癌患者总生存期(overall survival,OS)较短(HR=1.274,95%CI:1.141~1.422,P<0.001);肝癌患者中,男性ACSL4高表达(OR=1.12,95%CI:1.008~1.224,P<0.05)。Egger’s检验表明研究间存在发表偏倚的可能性较小(P=0.055)。ACSL4表达水平与年龄、肿瘤分期、肿瘤大小和肿瘤包膜是否完整以及是否合并肝硬化的相关性无统计学意义(P均>0.05)。结论ACSL4高表达与肝癌患者较短OS的相关性具有统计学意义,但仍需要更多的高质量临床研究进行验证。
文摘Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox homeostasis.Metformin is a classic drug used to treat type 2 diabetes that can inhibit ferroptosis.Previous studies have shown that,when used to treat cardiovascular and digestive system diseases,metformin can also upregulate heme oxygenase-1 expression.Therefore,we hypothesized that heme oxygenase-1 plays a significant role in mediating the beneficial effects of metformin on neuronal ferroptosis after spinal cord injury.To test this,we first performed a bioinformatics analysis based on the GEO database and found that heme oxygenase-1 was upregulated in the lesion of rats with spinal cord injury.Next,we confirmed this finding in a rat model of T9 spinal cord compression injury that exhibited spinal cord nerve cell ferroptosis.Continuous intraperitoneal injection of metformin for 14 days was found to both upregulate heme oxygenase-1 expression and reduce neuronal ferroptosis in rats with spinal cord injury.Subsequently,we used a lentivirus vector to knock down heme oxygenase-1 expression in the spinal cord,and found that this significantly reduced the effect of metformin on ferroptosis after spinal cord injury.Taken together,these findings suggest that metformin inhibits neuronal ferroptosis after spinal cord injury,and that this effect is partially dependent on upregulation of heme oxygenase-1.
