【摘要】 目的:基于内质网应激相关的跨膜蛋白激酶1α(IRE1α)/环磷腺苷效应元件结合蛋白(CREB)/NOD样受体1(NLRP1)通路探讨青蒿琥酯(ART)促进慢性粒细胞白血病(CML)细胞生长抑制、诱导凋亡的作用。方法:分别用浓度为0μg/mL、12.5μg/mL、25.0μg/mL、50.0μg/mL的ART干预K562细胞后,观察细胞生存情况和增殖活性,细胞凋亡后周期分布,谷胱甘肽(GSH)与活性氧(ROS)含量变化及IRE1α/CREB/NLRP1的表达量。结果:与对照组比较,12.5～50μg/mL浓度的ART可以显著抑制K562细胞的增殖、生长,诱导细胞凋亡(P<0.01);还可以使K562细胞内总GSH、GSH水平,谷胱甘肽还原酶(GSH-Rd)、谷胱甘肽过氧化物酶(GSH-Px)活力降低(P<0.05),ROS含量增加(P<0.05),IRE1α、p-CREB mRNA和蛋白表达下降(P<0.05),25.0μg/mL组、50.0μg/mL组CREB mRNA和蛋白表达增加(P<0.05),但对NLRP1 mRNA和蛋白表达均无显著影响。与12.5μg/mL的ART比较,50.0μg/mL的ART可使K562细胞内总GSH、GSH水平,GSH-Rd、GSH-Px活力,IRE1α、p-CREB mRNA和蛋白表达降低(P<0.05),25.0μg/mL组、50.0μg/mL组CREB mRNA和蛋白表达增加(P<0.05)。结论:ART可显著抑制K562细胞的活力和增殖,诱导其凋亡,并显著降低细胞中GSH含量,升高ROS含量,且可能是通过IRE1α/CREB/NLRP1通路实现的。更多还原

【Abstract】 Objective:To investigate the role of artesunate(ART) in inhibiting the growth of chronic myeloid leukemia(CML)cells and inducing its apoptosis based on endoplasmic reticulum stress related inositol requiring enzyme 1α(IRE1α)/cAMP-response element binding protein(CREB)/NOD-like receptor 1(NLRP1) pathway. Methods: After intervening K562 cells by ART with the concentration of 0 μg/mL,12.5 μg/mL,25.0 μg/mL,and 50.0 μg/mL respectively,the cell survival and proliferative activity, the cycle distribution after cell apoptosis, the changes in the contents of glutathione(GSH) and reactive oxygen species(ROS),and the expressions of IRE1α/CREB/NLRP1 were observed.Results:Compared with those in the control group respectively,ART with the concentration of 12.5～50 μg/mL could significantly inhibit the proliferation and growth of K562 cells and induce the apoptosis(P<0.01);the levels of total GSH and GSH,activity of glutathione reductase(GSH-Rd) and glutathione peroxidase(GSH-Px) in K562 cells was decreased(P<0.05); ROS content was increased(P<0.05); expressions of IRE1α, p-CREB mRNA and protein were decreased(P<0.05); expressions of CREB mRNA and protein were increased in the group of 25.0 μg/mL ART and 50.0 μg/mL ART(P<0.05);but there was no significant effect on expressions of NLRP1 mRNA and protein. Compared with 12.5 μg/mL ART,50.0 μg/mL ART can reduce the levels of total GSH and GSH,activity of GSH-Rd and GSH-Px as well as expressions of IRE1α,p-CREB mRNA and protein in K562 cells(P<0.05);the expressions of CREB mRNA and protein were increased in the group of 25.0 μg/mL ART and 50.0 μg/mL ART(P<0.05). Conclusion: ART can significantly inhibit the activity and proliferation of K562 cells, induce their apoptosis,significantly reduce the GSH contents in the cells and increase the ROS contents, which may be realized by IRE1α/CREB/NLRP1 pathway.更多还原