网络药理学与转录组学的联合分析揭示了黄芪桂枝五物汤通过调节Sirt1减轻奥沙利铂诱导的周围神经病变的药理机制。

Combined analysis of network pharmacology and transcriptomics deciphers the pharmacological mechanism of Huangqi Guizhi Wuwu decoction attenuates oxaliplatin-induced peripheral neuropathy via regulating Sirt1.

作者信息

Mao Runwen, Shen Jiayun, Wu Yuze, Wang Yue, Dai Jingya, Fan Haizhen, Lv Zhangming, Cheng Xiaolan, Gao Xuejiao, Cao Peng

机构信息

State Key Laboratory of Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, 210023, China; College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210029, China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China.

College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210029, China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China.

出版信息

J Ethnopharmacol. 2025 Aug 25;354:120486. doi: 10.1016/j.jep.2025.120486.

DOI:10.1016/j.jep.2025.120486

PMID:40865660

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Huangqi Guizhi Wuwu decoction (HGWD) is firstly recorded in the ancient Chinese ethnomedical manuscript "Synopsis of the Golden Chamber" with nourishing qi and blood for the treatment of limb numbness and ache in patients. Nowadays, accumulating evidence suggests that it could effectively alleviate symptoms of pain in oxaliplatin-induced peripheral neuropathy (OIPN). However, the therapeutic mechanism of HGWD against OIPN is necessary to be further clarified.

METHODS

The mice model of OIPN was established using the behavioral tests and histopathological observation to assess the therapeutic effect of HGWD against OIPN in vivo. The UHPLC-ESI-Q-TOF-MS/MS was used to identify the potential bioactive components from HGWD in drug-containing rat plasma. The integrated network pharmacology and transcriptomics strategy was performed to deciphers the mechanism of HGWD against OIPN with experimental verification.

RESULTS

HGWD could improve pain sensitivity symptom and alleviate the damage of dorsal root ganglia (DRG) neurons or intraepidermal nerve fibers in the mice model of OIPN. Through the integrated analysis of transcriptome and network pharmacology, Sirtuin 1 (Sirt1) was considered as the vital target for HGWD against OIPN. Via virtual screening and the ND7 cell viability assay, Formononetin (FN) and Oxypaeoniflorin (OPRA) from HGWD showed preliminary neuroprotective effects. In addition, OPRA can reduce Sterile alpha and toll interleukin receptor motif-containing protein 1 (SARM1) levels, improve axonal degeneration, and alleviate OIPN through the Sirt1 pathway.

CONCLUSION

HGWD could effectively alleviate the pain and nerve injury symptoms in mice with oxaliplatin-induced peripheral neuropathy. The therapeutic mechanism of HGWD against OIPN was relevant to the Sirt1 for the function of anti-oxidative stress in DRG. OPRA can reduce SARM1 levels, improve axonal degeneration, and alleviate OIPN through the Sirt1 pathway.

摘要

民族药理学相关性

黄芪桂枝五物汤（HGWD）最早记载于中国古代民族医学典籍《金匮要略》，用于益气养血，治疗患者肢体麻木和疼痛。如今，越来越多的证据表明，它可以有效缓解奥沙利铂诱导的周围神经病变（OIPN）的疼痛症状。然而，HGWD治疗OIPN的作用机制仍需进一步阐明。

方法

采用行为学测试和组织病理学观察建立OIPN小鼠模型，以评估HGWD对OIPN的体内治疗效果。利用超高效液相色谱-电喷雾电离-四极杆-飞行时间串联质谱（UHPLC-ESI-Q-TOF-MS/MS）鉴定含药大鼠血浆中HGWD的潜在生物活性成分。采用综合网络药理学和转录组学策略，通过实验验证来解读HGWD治疗OIPN的机制。

结果

HGWD可改善OIPN小鼠模型的疼痛敏感性症状，减轻背根神经节（DRG）神经元或表皮内神经纤维的损伤。通过转录组和网络药理学的综合分析，沉默调节蛋白1（Sirt1）被认为是HGWD治疗OIPN的关键靶点。通过虚拟筛选和ND7细胞活力测定，HGWD中的芒柄花素（FN）和芍药苷（OPRA）显示出初步的神经保护作用。此外，OPRA可降低含无菌α和Toll样白细胞介素受体基序蛋白1（SARM1）水平，改善轴突变性，并通过Sirt1途径减轻OIPN。