Hu Yonghe, Shen Xinxin, Liu Feifan, Zhu Weiguo
Department of Anesthesiology, Huzhou Central Hospital, No. 1558, Sanhuan North RoadZhejiang Province, Wuxing District, Huzhou City, 313099, China.
Department of Rheumatism, Huzhou Third People's Hospital, 2088 Tiaoxi East RoadZhejiang Province, Wuxing District, Huzhou City, 313002, No, China.
Neurotox Res. 2022 Apr;40(2):498-507. doi: 10.1007/s12640-022-00489-4. Epub 2022 Mar 17.
Drug dependence on morphine is commonly accompanied by neurodegenerative disorders. A previous study showed that prolonged exposure to morphine induces cellular senescence in neuronal cells by reducing telomere length. Phoenixin-14 is a newly discovered brain peptide with pleiotropic roles. However, it is unknown whether phoenixin-14 possesses a beneficial property against morphine-induced cellular senescence. Our results show that morphine reduced the expression of G protein-coupled receptor 173 (GPR173) in M17 neuronal cells. Therefore, we speculated that phoenixin-14, as a ligand for GPR173, may be involved in the morphine-mediated response in M17 cells. Further, we found that phoenixin-14 mitigated morphine-induced oxidative stress by reducing the reactive oxygen species (ROS) production and increasing superoxide dismutase (SOD) activity in M17 neuronal cells. The morphine-induced cellular senescence in M17 neuronal cells was prevented by phoenixin-14. Phoenixin-14 resolved the morphine-caused cell cycle arrest with significant changes in the expression levels of p21, cyclin-dependent kinases 6 (CDK6), and p-Rb. It also elevated the telomerase activity and restored the expressions of human telomerase reverse transcriptase (hTERT) and TERF2 in morphine-induced M17 neuronal cells. Furthermore, phoenixin-14 restored the yes-associated protein (YAP) expression against morphine in M17 neuronal cells. Knockdown of YAP abolished the beneficial effects of phoenixin-14 on cellular senescence against morphine induction. Taken together, these aggregate data demonstrate that phoenixin-14 prevented cellular senescence against morphine induction in M17 neuronal cells via regulating YAP expression.
对吗啡的药物依赖通常伴有神经退行性疾病。先前的一项研究表明，长期暴露于吗啡会通过缩短端粒长度诱导神经元细胞发生细胞衰老。Phoenixin-14是一种新发现的具有多种作用的脑肽。然而，尚不清楚phoenixin-14是否具有对抗吗啡诱导的细胞衰老的有益特性。我们的结果表明，吗啡降低了M17神经元细胞中G蛋白偶联受体173（GPR173）的表达。因此，我们推测phoenixin-14作为GPR173的配体，可能参与了M17细胞中吗啡介导的反应。此外，我们发现phoenixin-14通过减少活性氧（ROS）的产生和增加M17神经元细胞中的超氧化物歧化酶（SOD）活性来减轻吗啡诱导的氧化应激。Phoenixin-14预防了M17神经元细胞中吗啡诱导的细胞衰老。Phoenixin-14解决了吗啡引起的细胞周期停滞，p21、细胞周期蛋白依赖性激酶6（CDK6）和p-Rb的表达水平发生了显著变化。它还提高了端粒酶活性，并恢复了吗啡诱导的M17神经元细胞中人类端粒酶逆转录酶（hTERT）和TERF2的表达。此外，phoenixin-14恢复了M17神经元细胞中对吗啡的Yes相关蛋白（YAP）表达。敲低YAP消除了phoenixin-14对细胞衰老抵抗吗啡诱导的有益作用。综上所述，这些综合数据表明，phoenixin-14通过调节YAP表达预防了M17神经元细胞中吗啡诱导的细胞衰老。
