Systems Pharmacology Dissection of Multiscale Mechanisms of Action for Herbal Medicines in Treating Rheumatoid Arthritis

Abstract

As a chronic inflammatory and angiogenic disease with increased morbidity and mortality, rheumatoid arthritis (RA) is characterized by the proliferation of synovial tissue and the accumulation of excessive mononuclear infiltration, which always results in the joint deformity, disability, and eventually the destruction of the bone and cartilage. Traditional Chinese Medicine (TCM), with rich history of proper effectiveness in treating the inflammatory joint disease containing RA, has long combated such illness from, actually, an integrative and holistic point of view. However, its "multi-components" and "multi-targets" features make it very difficult to decipher the molecular mechanisms of RA from a systematic perspective if employing only routine methods. Presently, an innovative systems-pharmacology approach was introduced, which combined the ADME screening model, drug targeting, and network pharmacology, to explore the action mechanisms of botanic herbs for the treatment of RA. As a result, we uncovered 117 active compounds and 85 key molecular targets from seven RA-related herbs, which are mainly implicated in four signaling pathways, that is, vascular endothelial growth factor, PI3K-Akt, Toll-like receptor, and T-cell-receptor pathways. Additionally, the network relationships among the active components, target proteins, and pathways were further built to uncover the pharmacological characters of these herbs. Besides, molecular dynamics (MD) simulations and molecular mechanics-Poisson-Boltzmann surface area calculations were carried out to explore the binding interactions between the compounds and their receptors as well as to investigate the binding affinity of the ligand to their protein targets. In vitro experiments by ligand binding assays validate the reliability of the drug-target interactions as well as the MD results. The high binding affinities and good inhibitions of the active compounds indicate that the potential therapeutic effects of these herbal medicines for treating RA are exerted probably through the modulation of these relevant proteins, which further validates the rationality and reliability of the drug-target interactions as well as our the network-based analytical methods. This work may be of help for not only understanding the action mechanisms of TCM and for discovering new drugs from plants for the treatment of RA, but also providing a novel potential method for modern medicine in treating complex diseases.

A Systems Pharmacology Approach for Identifying the Multiple Mechanisms of Action for the Rougui‐Fuzi Herb Pair in the Treatment of Cardiocerebral Vascular Diseases

“…Finally, we used UPLC-Q-Exactive-MS E and GC-MS to analyze the potential ingredients of rougui-fuzi in the treatment of CCVDs. Collectively, herbal medicines always contain huge numbers of ingredients, diversified bioactive compounds of TCM with their related multiple targets, and multiple pathways, making it difficult to uncover the mechanisms of their interactions employing only traditional experimental approaches [70]. Systems pharmacology can offer an integrated system-level method to identify multichemicals, multitargets, and multipathways of Chinese herbs, which provided an alternative to understanding the scientific therapeutic mechanisms of Chinese herbs in treating complex diseases [21,71].…”

Network Pharmacology-Based Investigation into the Mechanisms of Quyushengxin Formula for the Treatment of Ulcerative Colitis

“…Previous reports showed that the TCMSP-based method was reliable for screening out bioactive compounds of TCM for treatment of thrombosis [35], gastric precancerous lesions [36], cardiocerebrovascular disease [37], and rheumatoid arthritis [38]. In this study, 41 bioactive compounds of Quyushengxin formula were selected out by using TCMSP database in combination with ADME properties.…”

Recent Advances in Nanotheranostics for Treat‐to‐Target of Rheumatoid Arthritis

“…Recently, nanomedicines have been proven an effective way for specific delivery to the site of inflammation in T2T of RA. Meanwhile, the drug‐loading system with specific ligands aims to improve the therapeutic efficiency of RA and reduce damage to normal tissues 26–29. Moreover, compared with conventional treatment, application of nanomaterial‐based drugs in T2T of RA achieves better therapeutic outcomes and saves more costs in the long run.…”

“…Meanwhile, the drug-loading system with specific ligands aims to improve the therapeutic efficiency of RA and reduce damage to normal tissues. [26][27][28][29] Moreover, compared with conventional treatment, application of nanomaterial-based drugs in T2T of RA achieves better therapeutic outcomes and saves more costs in the long run. A previous study has reported that liposomes loading GC to the inflamed joints can enhance the antiinflammatory activity in RA treatment.…”