AUTHOR=Wang Xiuhuan , Sun Youyi , Ling Ling , Ren Xueyang , Liu Xiaoyun , Wang Yu , Dong Ying , Ma Jiamu , Song Ruolan , Yu Axiang , Wei Jing , Fan Qiqi , Guo Miaoxian , Zhao Tiantian , Dao Rina , She Gaimei 

TITLE=Gaultheria leucocarpa var. yunnanensis for Treating Rheumatoid Arthritis—An Assessment Combining Machine Learning–Guided ADME Properties Prediction, Network Pharmacology, and Pharmacological Assessment

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.704040

DOI=10.3389/fphar.2021.704040

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Dianbaizhu (<italic>Gaultheria leucocarpa</italic> var. <italic>yunnanensis</italic>), a traditional Chinese/ethnic medicine (TC/EM), has been used to treat rheumatoid arthritis (RA) for a long time. The anti–rheumatic arthritis fraction (ARF) of <italic>G</italic>. <italic>yunnanensis</italic> has significant anti-inflammatory and analgesic activities and is mainly composed of methyl salicylate glycosides, flavonoids, organic acids, and others. The effective ingredients and rudimentary mechanism of ARF remedying RA have not been elucidated to date.</p><p><bold>Purpose:</bold> The aim of the present study is to give an insight into the effective components and mechanisms of Dianbaizhu in ameliorating RA, based on the estimation of the absorption, distribution, metabolism, and excretion (ADME) properties, analysis of network pharmacology, and <italic>in vivo</italic> and <italic>in vitro</italic> validations<italic>.</italic></p><p><bold>Study design and methods:</bold> The IL-1β–induced human fibroblast-like synoviocytes of RA (HFLS-RA) model and adjuvant-induced arthritis in the rat model were adopted to assess the anti-RA effect of ARF. The components in ARF were identified by using UHPLC-LTQ-Orbitrap-MS<sup>n</sup>. The quantitative structure–activity relationship (QSAR) models were developed by using five machine learning algorithms, alone or in combination with genetic algorithms for predicting the ADME properties of ARF. The molecular networks and pathways presumably referring to the therapy of ARF on RA were yielded by using common databases and visible software, and the experimental validations of the key targets conducted <italic>in vitro</italic>.</p><p><bold>Results:</bold> ARF effectively relieved RA <italic>in vivo</italic> and <italic>in vitro</italic>. The five optimized QSAR models that were developed showed robustness and predictive ability. The characterized 48 components in ARF had good biological potency. Four key signaling pathways were obtained, which were related to both cytokine signaling and cell immune response. ARF suppressed IL-1β–induced expression of EGFR, MMP 9, IL2, MAPK14, and KDR in the HFLS-RA .</p><p><bold>Conclusions</bold>: ARF has good druggability and high exploitation potential. Methyl salicylate glycosides and flavonoids play essential roles in attuning RA. ARF may partially attenuate RA by regulating the expression of multi-targets in the inflammation–immune system. These provide valuable information to rationalize ARF and other TC/EMs in the treatment of RA.</p>