Ursodeoxycholic acid(UDCA)is a naturally occurring,low-toxicity,and hydrophilic bile acid(BA)in the human body that is converted by intestinal flora using primary BA.Solute carrier family 7 member 11(SLC7A11)functions...Ursodeoxycholic acid(UDCA)is a naturally occurring,low-toxicity,and hydrophilic bile acid(BA)in the human body that is converted by intestinal flora using primary BA.Solute carrier family 7 member 11(SLC7A11)functions to uptake extracellular cystine in exchange for glutamate,and is highly expressed in a variety of human cancers.Retroperitoneal liposarcoma(RLPS)refers to liposarcoma originating from the retroperitoneal area.Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects.The augmentation of UDCA concentration(≥25 mg/mL)demonstrated a suppressive effect on the proliferation of liposarcoma cells.[15N2]-cystine and[13C5]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione(GSH)synthesis.Mechanistically,UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis,leading to reactive oxygen species(ROS)accumulation and mitochondrial oxidative damage.Furthermore,UDCA can promote the anti-cancer effects of ferroptosis inducers(Erastin,RSL3),the murine double minute 2(MDM2)inhibitors(Nutlin 3a,RG7112),cyclin dependent kinase 4(CDK4)inhibitor(Abemaciclib),and glutaminase inhibitor(CB839).Together,UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity,and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA.More importantly,in combination with other antitumor chemotherapy or physiotherapy treatments,UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.展开更多
为了挖掘新的小麦抗叶锈菌相关基因,本试验利用cDNA末端快速扩增(rapid amplification of cDNA ends,RACE)技术从小麦抗叶锈近等基因系TcLr26中克隆得到抗病相关基因TaGSO1,对其进行生物信息学分析,并对其在小麦与叶锈菌互作过程中的转...为了挖掘新的小麦抗叶锈菌相关基因,本试验利用cDNA末端快速扩增(rapid amplification of cDNA ends,RACE)技术从小麦抗叶锈近等基因系TcLr26中克隆得到抗病相关基因TaGSO1,对其进行生物信息学分析,并对其在小麦与叶锈菌互作过程中的转录水平表达模式进行检测。分析结果显示,该基因全长2598bp,编码866个氨基酸,其蛋白结构包含7个LRRs结构域和1个跨膜区以及1个短的细胞质结构,属于典型的LRR-RLPs受体蛋白;系统发育分析表明,TaGSO1基因与来自乌拉尔图小麦的EMS54105.1基因亲缘关系最近。RT-qPCR分析结果表明,该基因在TcLr26与叶锈菌的不亲和互作过程其表达量随接种时间延长明显升高,而在亲和组合中该基因的表达量很低,并且随着侵染时间的延长表达量几乎没有变化。外施SA发现TaGSO1的表达受SA诱导,推测该基因可能介导了SA信号传导途径。展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant NOs.:82272935,91957120 and 21974114)the Postdoctoral Fellowship Program of CPSF(Program No.:GZC20240901)+5 种基金the Xiamen Medical Industry Combined Guidance Project,China(Project No.:3502Z20244ZD2022)the Scientific Research Foundation for Advanced Talents,Xiang'an Hospital of Xiamen University,China(Grant No.:PM20180917008)the Fundamental Research Funds for the Central Universities,China(Grant No.:20720210001)Major Science and Technology Special Project of Fujian Province,China(Project No.:2022YZ036012)Joint Laboratory of School of Medicine,Xiamen University-Shanghai Jiangxia Blood Technology Co.,Ltd.,China(Grant No.:XDHT2020010C)Joint Research Center of School of Medicine,Xiamen University-Jiangsu Charity Biotech Co.,Ltd.,China(Grant No.:20233160C0002).
文摘Ursodeoxycholic acid(UDCA)is a naturally occurring,low-toxicity,and hydrophilic bile acid(BA)in the human body that is converted by intestinal flora using primary BA.Solute carrier family 7 member 11(SLC7A11)functions to uptake extracellular cystine in exchange for glutamate,and is highly expressed in a variety of human cancers.Retroperitoneal liposarcoma(RLPS)refers to liposarcoma originating from the retroperitoneal area.Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects.The augmentation of UDCA concentration(≥25 mg/mL)demonstrated a suppressive effect on the proliferation of liposarcoma cells.[15N2]-cystine and[13C5]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione(GSH)synthesis.Mechanistically,UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis,leading to reactive oxygen species(ROS)accumulation and mitochondrial oxidative damage.Furthermore,UDCA can promote the anti-cancer effects of ferroptosis inducers(Erastin,RSL3),the murine double minute 2(MDM2)inhibitors(Nutlin 3a,RG7112),cyclin dependent kinase 4(CDK4)inhibitor(Abemaciclib),and glutaminase inhibitor(CB839).Together,UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity,and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA.More importantly,in combination with other antitumor chemotherapy or physiotherapy treatments,UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.
文摘为了挖掘新的小麦抗叶锈菌相关基因,本试验利用cDNA末端快速扩增(rapid amplification of cDNA ends,RACE)技术从小麦抗叶锈近等基因系TcLr26中克隆得到抗病相关基因TaGSO1,对其进行生物信息学分析,并对其在小麦与叶锈菌互作过程中的转录水平表达模式进行检测。分析结果显示,该基因全长2598bp,编码866个氨基酸,其蛋白结构包含7个LRRs结构域和1个跨膜区以及1个短的细胞质结构,属于典型的LRR-RLPs受体蛋白;系统发育分析表明,TaGSO1基因与来自乌拉尔图小麦的EMS54105.1基因亲缘关系最近。RT-qPCR分析结果表明,该基因在TcLr26与叶锈菌的不亲和互作过程其表达量随接种时间延长明显升高,而在亲和组合中该基因的表达量很低,并且随着侵染时间的延长表达量几乎没有变化。外施SA发现TaGSO1的表达受SA诱导,推测该基因可能介导了SA信号传导途径。
