2024 06 v.40 1274-1280
双氢青蒿素联合七氟醚调控PERK/CHOP通路对乙型脑炎病毒NS1蛋白诱导的小鼠神经病理性疼痛的影响
基金项目(Foundation):
邮箱(Email):
rojane1991@126.com;
DOI:
10.13242/j.cnki.bingduxuebao.004597
中文作者单位:
武汉大学中南医院;
摘要(Abstract):
乙型脑炎病毒（Japanese encephalitis virus, JEV）是病毒性脑炎的主要病因，其感染引起神经病理性疼痛的致病机制目前尚不明确。因此，迫切需要阐明其作用机制。治疗神经性疼痛的药物由于其不良反应多、疗效不佳等原因，寻找新的治疗药物显得尤为必要。本研究首先使用JEV感染小鼠，观察脑组织病理学变化、分析病原分布；检测机械缩足反射阈值（Mechanical withdrawal threshold,MWT）和热缩足反射潜伏期（Thermal withdrawal latency,TWL）；检测大脑中超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和丙二醛（MDA）含量；Western blot实验探究了NS1、 PERK、CHOP相关通路蛋白表达。随后我们选用了双氢青蒿素联合七氟醚的治疗方案，并对其疗效和作用机制进行了探究。实验结果显示，JEV感染后，荧光标记病毒周围大量小胶质细胞活化、神经元细胞坏死，小鼠MWT和TWL明显下降，脑组织出现明显病理损伤，SOD和CAT水平降低，MDA水平升高，NS1、PERK、CHOP表达明显上调。双氢青蒿素联合七氟醚治疗后，小鼠脑组织病理损伤显著缓解，且氧化损伤被抑制，小鼠MWT和TWL明显上升，NS1、PERK、CHOP表达明显下调。因此我们得出结论，双氢青蒿素联合七氟醚可通过PERK/CHOP通路抑制神经元细胞氧化应激损伤，进而发挥其神经病理性疼痛保护作用。本研究阐述了JEV感染机制，同时预估了JEV中的NS1蛋白具有作为神经病理性疼痛治疗靶点的潜在价值。
关键词(KeyWords):
双氢青蒿素;七氟醚;PERK/CHOP;乙型脑炎病毒;NS1蛋白;神经病理性疼痛
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参考文献
[1]殷启凯，王环宇，梁国栋.中国乙脑病毒研究进展[J].病毒学报，2024, 40(3):580-587. DOI:10. 13242/j. cnki. bingduxuebao. 004521.
[2] Yuan H, Rao J, Zhang J, et al. Japanese encephalitis virus inhibits superinfection of Zika virus in cells by the NS2B protein[J]. J Virol, 2024, 98(3):e0185923.DOI:10. 1128/jvi. 01859-23.
[3] Sarkar R, Chhabra S, Tanwar M, et al. Japanese encephalitis virus hijacks ER-associated degradation regulators for its replication[J]. J Gen Virol, 2024, 105(5). DOI:10. 1099/jgv. 0. 001995.
[4] Okoye CN, Koren SA, Wojtovich AP. Mitochondrial complex I ROS production and redox signaling in hypoxia[J]. Redox Biol, 2023, 67:102926. DOI:10. 1016/j. redox. 2023. 102926.
[5] Endale HT, Tesfaye W, Mengstie TA. ROS induced lipid peroxidation and their role in ferroptosis[J]. Front Cell Dev Biol, 2023, 11:1226044. DOI:10. 3389/fcell. 2023. 1226044.
[6] Peng C, Li X, Ao F, et al. Mitochondrial ROS driven by NOX4 upregulation promotes hepatocellular carcinoma cell survival after incomplete radiofrequency ablation by inducing of mitophagy via Nrf2/PINK1[J].J Transl Med, 2023, 21(1):218. DOI:10. 1186/s12967-023-04067-w.
[7] Liu P, Zhang X, Zhang F, et al. A virus-derived siRNA activates plant immunity by interfering with ROS scavenging[J]. Mol Plant, 2021, 14(7):1088-1103.DOI:10. 1016/j. molp. 2021. 03. 022.
[8] Zhang L, Qin Y, Chen M. Viral strategies for triggering and manipulating mitophagy[J]. Autophagy,2018, 14(10):1665-1673. DOI:10. 1080/15548627. 2018. 1466014.
[9]王贵霞，曾跃，余婷，等.内质网应激在乙型脑炎病毒诱导神经元细胞凋亡中的作用及机制研究[J].病毒学报，2021, 37(6):1420-1427. DOI:10. 13242/j. cnki.bingduxuebao. 004061.
[10]Ceconi M, Ari?n KK, Delputte P. Diagnosing arthropod-borne flaviviruses:non-structural protein 1(NS1)as a biomarker[J]. Trends Microbiol, 2024, 32(7):678-696. DOI:10. 1016/j. tim. 2023. 11. 016.
[11]Xie S, Yang X, Yang X, et al. Japanese encephalitis virus NS1 and NS1'proteins induce vimentin rearrangement via the CDK1-PLK1 axis to promote viral replication[J]. J Virol, 2024, 98(5):e0019524. DOI:10. 1128/jvi. 00195-24.
[12]Liu Y, Wang WL, Zhang GX, et al. Interventional effect and inflammatory regulation mechanism of dihydroartemisinin combined with pregabalin on neuropathic pain mice[J]. Zhongguo Zhong Yao Za Zhi,2024, 49(6):1570-1578. DOI:10. 19540/j. cnki.cjcmm. 20231114. 703.
[13]Zhu C, Zhu Y, Zhang G, et al. The analgesic and antidepressant properties of dihydroartemisinine in the neuropathic pain mice:by the downregulation of HnRNPA1 in the spinal cord and hippocampus[J]. Clin Transl Med, 2022, 12(2):e751. DOI:10. 1002/ctm2. 751.
[14]?zkan D, Cemalo?lu S，?atma F, et al. Effects of suprascapular and axillary nerve block on postoperative pain relief sevoflurane consumption and visual clarity in arthroscopic shoulder surgery. Supraskapular ve aksiller sinir blo?unun artroskopik omuz cerrahisinde postoperative a?r?，sevofluran tüketimi ve g?rsel netli?e etkileri[J] Agri. 2020, 32(1):1-7. DOI:10. 14744/agri. 2019. 04875.
[15]Xie A, Zhang X, Ju F, et al. Sevoflurane impedes neuropathic pain by maintaining endoplasmic reticulum stress and oxidative stress homeostasis through inhibiting the activation of the PLCγ/CaMKII/IP3R signaling pathway[J]. Aging(Albany NY), 2024, 16(13):11062-11071. DOI:10. 18632/aging. 206001.
[16]Chen HW, Zhang YG, Zhang WJ, et al.Palmitoylation of hIFITM1 inhibits JEV infection and contributes to BBB stabilization[J]. Int J Biol Macromol, 2024, 262(Pt 1):129731. DOI:10. 1016/j. ijbiomac. 2024. 129731.
[17]Rani A, Ergün S, Karnati S, et al. Understanding the link between neurotropic viruses, BBB permeability,and MS pathogenesis[J]. J Neurovirol, 2024, 30(1):22-38. DOI:10. 1007/s13365-023-01190-8.
[18]Yang H, Wang X, Wang Z, et al. Peripheral nerve injury induced by Japanese encephalitis virus in C57BL/6 mouse[J]. J Virol, 2023, 97(5):e0165822. DOI:10. 1128/jvi. 01658-22.
[19]Zhaohui C, Cifei T, Di H, et al. ROS-mediated PERKCHOP pathway plays an important role in cadmiuminduced HepG2 cells apoptosis[J]. Environ Toxicol,2023, 38(9):2271-2280. DOI:10. 1002/tox. 23866.
[20]Xu D, Liu L, Zhao Y, et al. Melatonin protects mouse testes from palmitic acid-induced lipotoxicity by attenuating oxidative stress and DNA damage in a SIRT1-dependent manner[J]. J Pineal Res, 2020, 69(4):e12690. DOI:10. 1111/jpi. 12690.
[2] Yuan H, Rao J, Zhang J, et al. Japanese encephalitis virus inhibits superinfection of Zika virus in cells by the NS2B protein[J]. J Virol, 2024, 98(3):e0185923.DOI:10. 1128/jvi. 01859-23.
[3] Sarkar R, Chhabra S, Tanwar M, et al. Japanese encephalitis virus hijacks ER-associated degradation regulators for its replication[J]. J Gen Virol, 2024, 105(5). DOI:10. 1099/jgv. 0. 001995.
[4] Okoye CN, Koren SA, Wojtovich AP. Mitochondrial complex I ROS production and redox signaling in hypoxia[J]. Redox Biol, 2023, 67:102926. DOI:10. 1016/j. redox. 2023. 102926.
[5] Endale HT, Tesfaye W, Mengstie TA. ROS induced lipid peroxidation and their role in ferroptosis[J]. Front Cell Dev Biol, 2023, 11:1226044. DOI:10. 3389/fcell. 2023. 1226044.
[6] Peng C, Li X, Ao F, et al. Mitochondrial ROS driven by NOX4 upregulation promotes hepatocellular carcinoma cell survival after incomplete radiofrequency ablation by inducing of mitophagy via Nrf2/PINK1[J].J Transl Med, 2023, 21(1):218. DOI:10. 1186/s12967-023-04067-w.
[7] Liu P, Zhang X, Zhang F, et al. A virus-derived siRNA activates plant immunity by interfering with ROS scavenging[J]. Mol Plant, 2021, 14(7):1088-1103.DOI:10. 1016/j. molp. 2021. 03. 022.
[8] Zhang L, Qin Y, Chen M. Viral strategies for triggering and manipulating mitophagy[J]. Autophagy,2018, 14(10):1665-1673. DOI:10. 1080/15548627. 2018. 1466014.
[9]王贵霞，曾跃，余婷，等.内质网应激在乙型脑炎病毒诱导神经元细胞凋亡中的作用及机制研究[J].病毒学报，2021, 37(6):1420-1427. DOI:10. 13242/j. cnki.bingduxuebao. 004061.
[10]Ceconi M, Ari?n KK, Delputte P. Diagnosing arthropod-borne flaviviruses:non-structural protein 1(NS1)as a biomarker[J]. Trends Microbiol, 2024, 32(7):678-696. DOI:10. 1016/j. tim. 2023. 11. 016.
[11]Xie S, Yang X, Yang X, et al. Japanese encephalitis virus NS1 and NS1'proteins induce vimentin rearrangement via the CDK1-PLK1 axis to promote viral replication[J]. J Virol, 2024, 98(5):e0019524. DOI:10. 1128/jvi. 00195-24.
[12]Liu Y, Wang WL, Zhang GX, et al. Interventional effect and inflammatory regulation mechanism of dihydroartemisinin combined with pregabalin on neuropathic pain mice[J]. Zhongguo Zhong Yao Za Zhi,2024, 49(6):1570-1578. DOI:10. 19540/j. cnki.cjcmm. 20231114. 703.
[13]Zhu C, Zhu Y, Zhang G, et al. The analgesic and antidepressant properties of dihydroartemisinine in the neuropathic pain mice:by the downregulation of HnRNPA1 in the spinal cord and hippocampus[J]. Clin Transl Med, 2022, 12(2):e751. DOI:10. 1002/ctm2. 751.
[14]?zkan D, Cemalo?lu S，?atma F, et al. Effects of suprascapular and axillary nerve block on postoperative pain relief sevoflurane consumption and visual clarity in arthroscopic shoulder surgery. Supraskapular ve aksiller sinir blo?unun artroskopik omuz cerrahisinde postoperative a?r?，sevofluran tüketimi ve g?rsel netli?e etkileri[J] Agri. 2020, 32(1):1-7. DOI:10. 14744/agri. 2019. 04875.
[15]Xie A, Zhang X, Ju F, et al. Sevoflurane impedes neuropathic pain by maintaining endoplasmic reticulum stress and oxidative stress homeostasis through inhibiting the activation of the PLCγ/CaMKII/IP3R signaling pathway[J]. Aging(Albany NY), 2024, 16(13):11062-11071. DOI:10. 18632/aging. 206001.
[16]Chen HW, Zhang YG, Zhang WJ, et al.Palmitoylation of hIFITM1 inhibits JEV infection and contributes to BBB stabilization[J]. Int J Biol Macromol, 2024, 262(Pt 1):129731. DOI:10. 1016/j. ijbiomac. 2024. 129731.
[17]Rani A, Ergün S, Karnati S, et al. Understanding the link between neurotropic viruses, BBB permeability,and MS pathogenesis[J]. J Neurovirol, 2024, 30(1):22-38. DOI:10. 1007/s13365-023-01190-8.
[18]Yang H, Wang X, Wang Z, et al. Peripheral nerve injury induced by Japanese encephalitis virus in C57BL/6 mouse[J]. J Virol, 2023, 97(5):e0165822. DOI:10. 1128/jvi. 01658-22.
[19]Zhaohui C, Cifei T, Di H, et al. ROS-mediated PERKCHOP pathway plays an important role in cadmiuminduced HepG2 cells apoptosis[J]. Environ Toxicol,2023, 38(9):2271-2280. DOI:10. 1002/tox. 23866.
[20]Xu D, Liu L, Zhao Y, et al. Melatonin protects mouse testes from palmitic acid-induced lipotoxicity by attenuating oxidative stress and DNA damage in a SIRT1-dependent manner[J]. J Pineal Res, 2020, 69(4):e12690. DOI:10. 1111/jpi. 12690.
基本信息:
DOI：10.13242/j.cnki.bingduxuebao.004597
中图分类号:R512.62
引用信息:
[1]罗琼,彭思思,罗晶.双氢青蒿素联合七氟醚调控PERK/CHOP通路对乙型脑炎病毒NS1蛋白诱导的小鼠神经病理性疼痛的影响[J].病毒学报,2024,40(06):1274-1280.DOI:10.13242/j.cnki.bingduxuebao.004597.
基金信息:
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