School of Pharmacy, Key Laboratory of Medicinal Materials, Chinese Academy of Sciences, Key Laboratory of Basic and Applied Research of Northern Medicine, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, 150040, China.
Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, 150040, China.
J Ethnopharmacol. 2022 Mar 1;285:114895. doi: 10.1016/j.jep.2021.114895. Epub 2021 Dec 4.
Datura metel L. has been used as an anesthetic in clinic for more than 1800 years in China, and the main efficacy of D. metel L. flower is relieving asthma and cough, relieving spasm and relieving pain. From 1978 to 1980, Datura metel L. was used as an anesthetic agent and occasionally cured psoriasis patients during anesthesia clinically, and our group confirmed that the effective portion is total withanolides (YWS). Moreover, the new drug "Datura metel L. capsule" composed of YWS has since been approved and used for the treatment of more than 3,000 psoriasis patients, with efficacy and cure rates greater than 90% and 65%. However, the immunological mechanism has not been elucidated.
Nowadays, although total withanolides from Datura metel L. have a better clinical efficacy in the treatment of psoriasis, there is a lack of overall understanding of the mechanism of their treatment, especially about some immune cells and proteins closely related to psoriasis and their relationship in executive function and biological significance. This study focused on investigating the mechanism of psoriasis treatment by YWS and determined the biochemical processes in the treatment of psoriasis based on Treg/Th17 axis cell-mediated bidirectional immunoregulatory functions, which provides an important scientific basis for understanding the mechanism underlying the treatment of psoriasis by YWS.
The effects of YWS on the lesion pathology of IMQ-induced psoriasis mice and the underlying molecular mechanism were assessed directly using HE staining, the PASI score and the animal body mass. We also investigated the effects of YWS on the Treg/Th17 axis and their critical functions in psoriasis pathogenesis via molecular biological methods. Finally, we performed differential proteomics analysis on skin in IMQ-induced psoriasis mice to clarify the effect of YWS by incorporates mass spectrometry-bioinformatics and annotated the functions and pathways associated with the differential proteins through GO enrichment, KEGG pathway analysis and PPI networks analysis, respectively.
YWS regulated the imbalance of the Treg/Th17 axis. And proteomic analysis showed that YWS up-regulated 46 and down-regulated 37 proteins. According to the bioinformatics analysis, the improvement of Treg/Th17 imbalance may be the key immunological mechanism of YWS in the treatment of psoriasis by up-regulating the butyrate metabolism pathway, down-regulating leukocyte migration, inhibiting the phagocytic function of natural killer cells, suppressing osteoclast differentiation and interfering with chemokine activity, and the critical proteins involved are Lyn, HMGCS2, ABAT, ITGβ2, PRKCβ, MMP9, NCF1, JUNβ, and Hck.
This research clarified that the improvement of the imbalance of the Treg/Th17 axis may be the key immunological mechanism of YWS in the treatment of psoriasis through metabolic pathways and influencing key proteins. The results not only expand the therapeutic targets and approaches for the treatment of psoriasis, which is a challenging and complex disease, but also deepens the understanding of the mechanism of YWS in the treatment of psoriasis and other important conditions to open up a new way of thinking for research on YWS in the treatment of psoriasis.
在中国，曼陀罗已被用作临床麻醉剂超过 1800 年，曼陀罗花的主要功效是平喘止咳、解痉止痛。1978 年至 1980 年，曼陀罗被用作麻醉剂，临床麻醉时偶尔治愈银屑病患者，我们小组证实有效部位是总麦角甾烷（YWS）。此外，由 YWS 组成的新药“曼陀罗胶囊”已获批准并用于治疗 3000 多名银屑病患者，疗效和治愈率均大于 90%和 65%。然而，其免疫机制尚未阐明。
如今，虽然曼陀罗总麦角甾烷在治疗银屑病方面具有更好的临床疗效，但对其治疗机制缺乏全面的认识，特别是对一些与银屑病密切相关的免疫细胞和蛋白及其在执行功能和生物学意义中的关系。本研究重点研究 YWS 治疗银屑病的机制，并基于 Treg/Th17 轴细胞介导的双向免疫调节功能，确定治疗银屑病的生化过程，为理解 YWS 治疗银屑病的机制提供了重要的科学依据。
直接使用 HE 染色、PASI 评分和动物体重评估 YWS 对咪喹莫特诱导的银屑病小鼠病变病理的影响及其潜在的分子机制。我们还通过分子生物学方法研究了 YWS 对 Treg/Th17 轴及其在银屑病发病机制中的关键功能的影响。最后，我们对咪喹莫特诱导的银屑病小鼠皮肤进行差异蛋白质组学分析，通过质谱-生物信息学整合阐明 YWS 的作用，并通过 GO 富集、KEGG 通路分析和 PPI 网络分析分别注释与差异蛋白相关的功能和途径。
YWS 调节了 Treg/Th17 轴的失衡。蛋白质组学分析表明，YWS 上调了 46 个蛋白，下调了 37 个蛋白。根据生物信息学分析，Treg/Th17 失衡的改善可能是 YWS 通过上调丁酸盐代谢途径、下调白细胞迁移、抑制自然杀伤细胞吞噬功能、抑制破骨细胞分化和干扰趋化因子活性来治疗银屑病的关键免疫机制，涉及的关键蛋白包括 Lyn、HMGCS2、ABAT、ITGβ2、PRKCβ、MMP9、NCF1、JUNβ和 Hck。
本研究阐明了通过代谢途径和影响关键蛋白，改善 Treg/Th17 轴失衡可能是 YWS 治疗银屑病的关键免疫机制。研究结果不仅拓展了治疗银屑病这一具有挑战性和复杂性疾病的治疗靶点和方法，而且加深了对 YWS 治疗银屑病及其它重要疾病的机制的理解，为 YWS 治疗银屑病的研究开辟了新的思路。
