Formononetin ameliorates oxaliplatin-induced peripheral neuropathy via the KEAP1-NRF2-GSTP1 axis
Formononetin ameliorates oxaliplatin-induced peripheral neuropathy via the KEAP1-NRF2-GSTP1 axis
复制标题
芒柄花素通过 KEAP1-NRF2-GSTP1 轴改善奥沙利铂诱导的周围神经病变
DOI：
10.1016/j.redox.2020.101677
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发表时间：
2020-09-01
期刊：
影响因子：
11.4
通讯作者：
Cao, Peng
中科院分区：
文献类型：
--
作者：
Fang, Yuan;Ye, Juan;Cao, Peng
奥沙利铂诱导的周围神经病变（OIPN）的管理已被证明具有挑战性，因为任何OIPN预防剂也可能降低化疗剂的疗效，并无法逆转已建立的神经元损伤。然而，靶向氧化还原信号通路构成了OIPN的一种有前途的治疗方法，我们以前已经证明了核因子红细胞相关因子2（NRF 2）在这种疾病中的保护作用。在这里，我们研究了刺芒柄花素（FN），一种临床制剂提取物，在OIPN中的保护特性。RNA干扰实验表明，FN通过激活NRF 2途径直接保护OIPN。进一步的表达谱测序显示，FN通过NRF 2下游奥沙利铂代谢酶GST P1发挥其保护作用。我们还证明了FN不影响奥沙利铂的化疗功能，因为NRF 2在结直肠细胞系下游表现出与神经元不同的药物代谢酶活化状态。在合成Bio-FN以筛选靶结合蛋白之后，我们发现FN选择性地结合KEAP 1的BTB结构域中的His 129和Lys 131。体内实验表明，FN诱导的NRF 2信号通路的激活减轻了小鼠的伤害性感觉。我们的研究结果强调了一个新的结合机制之间的KEAP 1和α-胆甾酮的NRF 2系统的激活，并建议，药理学或治疗激活的NRF 2-GSTP 1轴可能作为一种有效的策略，以防止或减轻OIPN的进展。
Management of oxaliplatin-induced peripheral neuropathy (OIPN) has proven challenging owing to the concern that any OIPN-preventing agents may also decrease the efficacy of the chemotherapeutic agent and fail to reverse established neuronal damage. Nevertheless, targeting redox signaling pathways constitutes a promising therapy in OIPN and we have previously demonstrated the protective role of nuclear factor erythroid-2 related factor 2 (NRF2) in this disorder. Here, we investigated the protective properties of formononetin (FN), a clinical preparation extract, in OIPN. RNA interference experiments revealed that FN protects against OIPN directly through activation of the NRF2 pathway. Further expression profile sequencing showed that FN exerts its protective effect via the NRF2 downstream-oxaliplatin metabolism enzyme, GSTP1. We also demonstrated that FN does not influence the chemotherapeutic function of oxaliplatin, as NRF2 exhibits a different drug metabolic enzyme activation state downstream in colorectal cell lines than that in neurons. Following synthesis of Bio-FN to screen the target binding proteins, we found that FN selectively binds to His129 and Lys131 in the BTB domain of KEAP1. In vivo experiments revealed that FN-induced activation of the NRF2 signaling pathway alleviated the nociceptive sensations in mice. Our findings highlight a new binding mechanism between KEAP1 and isoflavones for activation of the NRF2 system and suggest that pharmacological or therapeutic activation of the NRF2-GSTP1 axis may serve as an effective strategy to prevent or attenuate the progression of OIPN.