Department of Hematology, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, Jiangsu, China.
Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
Environ Toxicol. 2024 Mar;39(3):1556-1566. doi: 10.1002/tox.24035. Epub 2023 Nov 27.
Bortezomib (BTZ) is a commonly used antitumor drug, but its peripheral neuropathy side effect poses a limitation on its dosage. Evodiamine (EVO) exhibits various biological activities, including antioxidant, anti-inflammatory, and anticancer effects. The purpose of this investigation is to confirm the impact of EVO on BTZ-induced peripheral neurotoxicity.
GeneCards and HERB were applied to analyze the targets of peripheral neurotoxicity and EVO. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis of the hub genes were identified by DAVID. Rat dorsal root ganglion neurons (DRGs) and rat RSC96 Schwann cells (SCs) were treated with BTZ to simulate peripheral neurotoxicity. BTZ-induced peripheral neurotoxicity was assessed by detecting cell viability, proliferation, oxidative stress, and ferroptosis in DRGs and SCs. The mitogen-activated protein kinase (MAPK) signaling was scrutinized by Western blot assay.
The Venn diagram for the overlapping targets of EVO and peripheral neurotoxicity showed that EVO might regulate peripheral neurotoxicity by influencing cell oxidative stress, ferroptosis, and MAPK signaling pathway. EVO attenuated BTZ-induced toxicity in DRGs and SCs. EVO attenuated BTZ-induced oxidative stress damage in DRGs and SCs by reducing reactive oxygen species and malondialdehyde levels and enhancing glutathione level. EVO attenuated BTZ-induced ferroptosis in DRGs and SCs. EVO inhibited BTZ-induced activation of the MAPK signaling in DRGs and SCs. Activation of the MAPK signaling reversed the neuroprotective effect of EVO on BTZ-induced oxidative stress injury and ferroptosis.
EVO attenuated oxidative stress and ferroptosis by inhibiting the MAPK signaling to improve BTZ-induced peripheral neurotoxicity.
硼替佐米（BTZ）是一种常用的抗肿瘤药物，但它的周围神经病变副作用限制了其剂量。吴茱萸碱（EVO）具有多种生物学活性，包括抗氧化、抗炎和抗癌作用。本研究旨在证实吴茱萸碱对 BTZ 诱导的周围神经毒性的影响。
使用 GeneCards 和 HERB 分析周围神经毒性和吴茱萸碱的靶点。通过 DAVID 对关键基因进行基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析。用 BTZ 处理大鼠背根神经节神经元（DRGs）和大鼠 RSC96 雪旺细胞（SCs）模拟周围神经毒性。通过检测 DRGs 和 SCs 中的细胞活力、增殖、氧化应激和铁死亡来评估 BTZ 诱导的周围神经毒性。通过 Western blot 检测丝裂原活化蛋白激酶（MAPK）信号通路。
EVO 与周围神经毒性的重叠靶点的 Venn 图表明，EVO 可能通过影响细胞氧化应激、铁死亡和 MAPK 信号通路来调节周围神经毒性。EVO 减轻了 DRGs 和 SCs 中 BTZ 诱导的毒性。EVO 通过降低活性氧和丙二醛水平，提高谷胱甘肽水平，减轻了 DRGs 和 SCs 中 BTZ 诱导的氧化应激损伤。EVO 减轻了 DRGs 和 SCs 中 BTZ 诱导的铁死亡。EVO 抑制了 DRGs 和 SCs 中 BTZ 诱导的 MAPK 信号激活。MAPK 信号的激活逆转了 EVO 对 BTZ 诱导的氧化应激损伤和铁死亡的神经保护作用。
EVO 通过抑制 MAPK 信号减轻氧化应激和铁死亡，改善 BTZ 诱导的周围神经毒性。
