损伤特异性DNA结合蛋白2(damage-specific DNA binding protein 2,DDB2)是损伤特异性DNA结合异二聚体复合物的一个组成部分,与其他蛋白质合作修复紫外线诱导的DNA损伤,通过影响核苷酸切除修复(nucleotide excision repair,NER)、细胞凋...损伤特异性DNA结合蛋白2(damage-specific DNA binding protein 2,DDB2)是损伤特异性DNA结合异二聚体复合物的一个组成部分,与其他蛋白质合作修复紫外线诱导的DNA损伤,通过影响核苷酸切除修复(nucleotide excision repair,NER)、细胞凋亡和过早衰老参与癌症的发生和发展,并且影响癌细胞对放疗和化疗的敏感性。多项研究发现DDB2参与结直肠癌、胃癌、乳腺癌等癌症癌变的进程,并在肿瘤抑制中发挥着关键作用。该文就涉及DDB2的不同生物过程的分子机制进行综述,以求为研究靶向DDB2的药物提供理论支持。展开更多
The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes.Progestin and adipoQ receptor 3(PAQR3),a key regulator of inflammation and metabolism,can negatively regulate the ...The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes.Progestin and adipoQ receptor 3(PAQR3),a key regulator of inflammation and metabolism,can negatively regulate the PI3 K/AKT signaling pathway.Here,we report that gentiopicroside(GPS),the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa,decreased lipid synthesis and increased glucose utilization in palmitic acid(PA) treated HepG2 cells.Additionally,GPS improved glycolipid metabolism in streptozotocin(STZ) treated high-fat diet(HFD)-induced diabetic mice.Our findings revealed that GPS promoted the activation of the PI3 K/AKT axis by facilitating DNA-binding protein 2(DDB2)-mediated PAQR3 ubiquitinated degradation.Moreover,results of surface plasmon resonance(SPR),microscale thermophoresis(MST) and thermal shift assay(TSA) indicated that GPS directly binds to PAQR3.Results of molecular docking and cellular thermal shift assay(CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40,Asp42,Glu69,Tyr125 and Ser129,and spatially inhibited the interaction between PAQR3 and the PI3 K catalytic subunit(P110α) to restore the PI3 K/AKT signaling pathway.In summary,our study identified GPS,which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway,as a potential drug candidate for the treatment of diabetes.展开更多
文摘损伤特异性DNA结合蛋白2(damage-specific DNA binding protein 2,DDB2)是损伤特异性DNA结合异二聚体复合物的一个组成部分,与其他蛋白质合作修复紫外线诱导的DNA损伤,通过影响核苷酸切除修复(nucleotide excision repair,NER)、细胞凋亡和过早衰老参与癌症的发生和发展,并且影响癌细胞对放疗和化疗的敏感性。多项研究发现DDB2参与结直肠癌、胃癌、乳腺癌等癌症癌变的进程,并在肿瘤抑制中发挥着关键作用。该文就涉及DDB2的不同生物过程的分子机制进行综述,以求为研究靶向DDB2的药物提供理论支持。
基金supported by research grants from the National Natural Science Foundation of China (No.81770816 and 81973375)the Key Project of Natural Science Foundation of Guangdong Province,China (No.2017A030311036)+1 种基金Seed Program of Guangdong Province (No.2017B090903004,China)Guangdong Provincial Key Field and Program Project (No.2020B1111100004,China)。
文摘The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes.Progestin and adipoQ receptor 3(PAQR3),a key regulator of inflammation and metabolism,can negatively regulate the PI3 K/AKT signaling pathway.Here,we report that gentiopicroside(GPS),the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa,decreased lipid synthesis and increased glucose utilization in palmitic acid(PA) treated HepG2 cells.Additionally,GPS improved glycolipid metabolism in streptozotocin(STZ) treated high-fat diet(HFD)-induced diabetic mice.Our findings revealed that GPS promoted the activation of the PI3 K/AKT axis by facilitating DNA-binding protein 2(DDB2)-mediated PAQR3 ubiquitinated degradation.Moreover,results of surface plasmon resonance(SPR),microscale thermophoresis(MST) and thermal shift assay(TSA) indicated that GPS directly binds to PAQR3.Results of molecular docking and cellular thermal shift assay(CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40,Asp42,Glu69,Tyr125 and Ser129,and spatially inhibited the interaction between PAQR3 and the PI3 K catalytic subunit(P110α) to restore the PI3 K/AKT signaling pathway.In summary,our study identified GPS,which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway,as a potential drug candidate for the treatment of diabetes.
