Chen Jinfeng, Zhang An, Nie Anzheng, Zuo Xiaoxiao, Zhang Lei, Jiao Yuxue, Wang Lulu, Yang Yang, Liu Kun, Xue Xinli, Zhuang Yuanyuan, Meng Yansha, Yang Jing-Hua
Research Center for Clinical Systems Biology, Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Institute of Infection and Immunity, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan, China.
Front Pharmacol. 2024 Aug 16;15:1447283. doi: 10.3389/fphar.2024.1447283. eCollection 2024.
has been used for treating rheumatic diseases for thousands of years in rural areas of China. Several studies have found that tetrandrine and fangchinoline can inactivate the PI3K/Akt signaling pathway by reducing the expression and phosphorylation of AKT. However, the mechanism underlying the therapeutic actions of on RA is not well known. In this study, we determined the molecular mechanism of the therapeutic effects of the multiple ingredients of extract (STE) on collagen-induced arthritic (CIA) rats by integrating pharmacometabolomics, proteomics, and PTMomics. In the multi-omics joint analysis, first, the expression signatures of proteins, PTMs, metabolites, and STE ingredients were profiled in CIA rats PBMCs that underwent STE treatment. Bioinformatics analysis were subsequently probed that STE mainly regulated tryptophan metabolism, inflammatory response, and cell adhesion pathways in CIA rats. The interrelated pathways were further constructed, and the findings revealed that STE attenuated the inflammatory response and proliferation of PBMCs in CIA rats by mediating the key targets of the PI3K/Akt pathway, including Hint1, ACP1, FGR, HSP90@157W + dioxidation, and Prkca@220N + 845.4540 Da. The rheumatic functions of Hint1 and ACP1 were further confirmed by applying a transcriptomic data of RA patients who clinically received abatacept therapy. Furthermore, a cross-ome correlation analysis was performed and major ingredients of STE, including coclaurine--glucuronide, Me,coclaurine--glc, -gluA-schefferine, corydamine, corypamine, tetrandrine, and fangchiniline, were found to act on these targerts to inactivate the PI3K/Akt pathway. Conclusion: These results elucidated the molecular mechanism by which the ingredients of STE mediate the expression of the key targets in the PI3K/Akt pathway, leading to anti-rheumatic functions. The findings of this study provided new insights into the synergistic effect of STE against arthritis in rats.
在中国农村地区，它已被用于治疗风湿性疾病数千年。多项研究发现，粉防己碱和防己诺林碱可通过降低AKT的表达和磷酸化来使PI3K/Akt信号通路失活。然而，其对类风湿关节炎（RA）治疗作用的潜在机制尚不清楚。在本研究中，我们通过整合药物代谢组学、蛋白质组学和翻译后修饰组学，确定了防己提取物（STE）多种成分对胶原诱导性关节炎（CIA）大鼠治疗作用的分子机制。在多组学联合分析中，首先，对接受STE治疗的CIA大鼠外周血单核细胞（PBMCs）中的蛋白质、翻译后修饰、代谢物和STE成分的表达特征进行了分析。随后进行生物信息学分析，发现STE主要调节CIA大鼠的色氨酸代谢、炎症反应和细胞黏附途径。进一步构建了相互关联的途径，结果显示STE通过介导PI3K/Akt途径的关键靶点，包括Hint1、ACP1、FGR、HSP90@157W + 二氧化、Prkca@220N + 845.4540 Da，减轻CIA大鼠PBMCs的炎症反应和增殖。通过应用临床接受阿巴西普治疗的RA患者的转录组数据，进一步证实了Hint1和ACP1的风湿功能。此外，进行了跨组学相关性分析，发现STE的主要成分，包括氢化小檗碱 - 葡萄糖醛酸苷、甲基氢化小檗碱 - 葡萄糖、- 葡萄糖醛酸 - 谢弗林碱、紫堇胺、紫堇帕明、粉防己碱和防己诺林碱，作用于这些靶点使PI3K/Akt途径失活。结论：这些结果阐明了STE成分介导PI3K/Akt途径关键靶点表达从而产生抗风湿功能的分子机制。本研究结果为STE对大鼠关节炎的协同作用提供了新的见解。
