目的探讨PHLPP2与EGFR+TP53共突变晚期肺腺癌(LUAD)患者靶向联合化疗疗效及与铁死亡的关系。方法回顾2018年8月至2023年8月的98例行靶向联合化疗治疗EGFR+TP53共突变晚期LUAD患者资料。分析PHLPP2突变情况,根据预后分为预后不良组(n=47...目的探讨PHLPP2与EGFR+TP53共突变晚期肺腺癌(LUAD)患者靶向联合化疗疗效及与铁死亡的关系。方法回顾2018年8月至2023年8月的98例行靶向联合化疗治疗EGFR+TP53共突变晚期LUAD患者资料。分析PHLPP2突变情况,根据预后分为预后不良组(n=47)和预后良好组(n=51)。限制性立方样条(RCS)模型分析铁死亡指标与预后不良的剂量反应关系。比较不同PHLPP2突变类型下铁死亡指标水平,及其与预后不良的关系。结果PHLPP2突变率为30.61%,主要为错义突变和点突变。预后不良组血清铁(SF)、丙二醛(MDA)、活性氧(ROS)低于预后良好组(P<0.05),谷胱甘肽过氧化酶4(GPX4)、谷胱甘肽(GSH)、PHLPP2突变类型高于预后良好组(P<0.05)。预后不良风险与SF、GPX4、GSH、MDA和ROS均呈非线性剂量-反应关系(P_(for non linear)<0.05)。野生型SF、MDA、ROS高于突变型(P<0.05),GPX4、GSH低于突变型(P<0.05)。不同PHLPP2突变类型、铁死亡指标下预后不良存在差异(P<0.05)。结论PHLPP2突变影响靶向联合化疗治疗EGFR+TP53共突变晚期LUAD临床疗效,且与铁死亡存在相关性。展开更多
Background:Triptolide(TP)exhibits various pharmacological activities.Our previous studies have confirmed the efficacy of TP against lung adenocarcinoma(LUAD).However,the potent pharmacological activity of TP is underp...Background:Triptolide(TP)exhibits various pharmacological activities.Our previous studies have confirmed the efficacy of TP against lung adenocarcinoma(LUAD).However,the potent pharmacological activity of TP is underpinned by its complex mechanisms.Exploring its potential mechanisms is of great value for promoting the clinical application of TP and extending its clinical use.Methods:Differentially expressed genes(DEGs)associated with LUAD were analyzed and acquired from the TCGA database,while DEGs related to TP were obtained through RNA sequencing.Hub genes were identified through LASSO and random forest models.The efficacy of TP against LUAD was validated using tumor-bearing mouse models and A549 cells.The validation of hub genes was conducted using RT-qPCR.The regulatory effect of hub genes on TP efficacy was validated through overexpression cell models.Furthermore,the potential mechanisms by which TP improves gemcitabine(GEM)resistance were explored using a GEM-resistant cell line in combination with the overexpression model.Results:This study validated the therapeutic effect of TP against LUAD in vivo and in vitro.Bioinformatics revealed that the mechanism of TP's effect against LUAD might be associated with amino acid-related biological processes.Five hub genes were screened and identified by combining bioinformatics methods and experiments.The overexpression model validated that PSAT1 plays an effective role in the efficacy of TP and in alleviating GEM resistance.Conclusion:This study preliminarily demonstrated that the anti-LUAD effect of TP was associated with the PSAT1-regulated serine biosynthesis pathway,and that TP effectively improves GEM resistance by inhibiting PSAT1 expression.展开更多
文摘目的探讨PHLPP2与EGFR+TP53共突变晚期肺腺癌(LUAD)患者靶向联合化疗疗效及与铁死亡的关系。方法回顾2018年8月至2023年8月的98例行靶向联合化疗治疗EGFR+TP53共突变晚期LUAD患者资料。分析PHLPP2突变情况,根据预后分为预后不良组(n=47)和预后良好组(n=51)。限制性立方样条(RCS)模型分析铁死亡指标与预后不良的剂量反应关系。比较不同PHLPP2突变类型下铁死亡指标水平,及其与预后不良的关系。结果PHLPP2突变率为30.61%,主要为错义突变和点突变。预后不良组血清铁(SF)、丙二醛(MDA)、活性氧(ROS)低于预后良好组(P<0.05),谷胱甘肽过氧化酶4(GPX4)、谷胱甘肽(GSH)、PHLPP2突变类型高于预后良好组(P<0.05)。预后不良风险与SF、GPX4、GSH、MDA和ROS均呈非线性剂量-反应关系(P_(for non linear)<0.05)。野生型SF、MDA、ROS高于突变型(P<0.05),GPX4、GSH低于突变型(P<0.05)。不同PHLPP2突变类型、铁死亡指标下预后不良存在差异(P<0.05)。结论PHLPP2突变影响靶向联合化疗治疗EGFR+TP53共突变晚期LUAD临床疗效,且与铁死亡存在相关性。
基金National Natural Science Foundation of China,Grant/Award Number:No.82560858Beijing Science and Technology New Star Program Cross-cooperation Project,Grant/Award Number:No.20240484711Jiangxi Provincial Natural Science Foundation,Grant/Award Number:20252BAC200586。
文摘Background:Triptolide(TP)exhibits various pharmacological activities.Our previous studies have confirmed the efficacy of TP against lung adenocarcinoma(LUAD).However,the potent pharmacological activity of TP is underpinned by its complex mechanisms.Exploring its potential mechanisms is of great value for promoting the clinical application of TP and extending its clinical use.Methods:Differentially expressed genes(DEGs)associated with LUAD were analyzed and acquired from the TCGA database,while DEGs related to TP were obtained through RNA sequencing.Hub genes were identified through LASSO and random forest models.The efficacy of TP against LUAD was validated using tumor-bearing mouse models and A549 cells.The validation of hub genes was conducted using RT-qPCR.The regulatory effect of hub genes on TP efficacy was validated through overexpression cell models.Furthermore,the potential mechanisms by which TP improves gemcitabine(GEM)resistance were explored using a GEM-resistant cell line in combination with the overexpression model.Results:This study validated the therapeutic effect of TP against LUAD in vivo and in vitro.Bioinformatics revealed that the mechanism of TP's effect against LUAD might be associated with amino acid-related biological processes.Five hub genes were screened and identified by combining bioinformatics methods and experiments.The overexpression model validated that PSAT1 plays an effective role in the efficacy of TP and in alleviating GEM resistance.Conclusion:This study preliminarily demonstrated that the anti-LUAD effect of TP was associated with the PSAT1-regulated serine biosynthesis pathway,and that TP effectively improves GEM resistance by inhibiting PSAT1 expression.
文摘目的构建温敏型介孔聚多巴胺(mesoporous polydopamine,MPDA)载雷公藤甲素(Triptolide,TP)复合水凝胶(TP@MPDA hydrogel),用于糖尿病皮肤伤口的光热抗菌-抗炎联合治疗。方法利用布鲁克海文粒度测定仪(Brookhaven instruments)和透射电子显微镜(transmission electron microscope,TEM)等评估MPDA、TP@MPDA的粒径分布、微观形貌,使用扫描电子显微镜(scanning electron microscope,SEM)评估空白水凝胶、TP@MPDA水凝胶的微观形貌;通过近红外热成像和实时定温监测研究TP@MPDA水凝胶的温和光热效应;通过DCFH-DA探针检测细胞内活性氧(reactive oxygen species,ROS)消除水平,并采用流式细胞术定量分析ROS清除程度,以评估体外抗炎活性;利用HE染色评估TP@MPDA水凝胶的生物安全性。结果成功制备介孔聚多巴胺载雷公藤甲素水凝胶体系,并通过体内实验验证了该体系的生物安全性,为后续实验奠定基础;细胞、细菌水平实验结果表明该体系具有良好的ROS清除能力和抗菌-抗炎协同作用,从而实现较理想的促进糖尿病伤口愈合的联合治疗效果。结论TP@MPDA水凝胶具有良好的光热效果和抗菌-抗炎作用,为伤口愈合治疗提供新思路。
