Exploring and characterizing a novel combination of paeoniflorin and talatizidine for the treatment of rheumatoid arthritis. (March 2020)

• Record Type: Journal Article
• Authors: Mao, Xia; Li, Weijie; Chen, Wenjia; Li, Yingfei; Wang, Qian; Wang, Xiaoyue; Pi, Zifeng; Wang, Danhua; Xu, Haiyu; Guo, Qiuyan; Wu, Siyang; Cheng, Wenhao; Zhang, Yanqiong; Lin, Na
• Is Part Of: Pharmacological research. Volume 153(2020)
• Publication Date: 2020-03
• Subjects: Paeoniflorin (PubChem CID: 442534) -- Talatizidine (CAS registry number: 7633-67-2); RA rheumatoid arthritis -- DMARDs disease-modifying antirheumatic drugs -- NSAIDs non-steroidal anti-inflammatory drugs -- TCM traditional Chinese medicine -- WTD Wutou decoction -- MTX methotrexate -- BACs bioactive compounds -- PAE paeoniflorin -- TLT talatizidine -- CIA collagen-induced arthritis -- AIA Adjuvant-induced arthritis -- DMSO dimethyl sulfoxide -- DEGs the differentially expressed genes -- FC fold change -- NCBI National Center of Biotechnology Information -- ADME absorption-distribution-metabolism-excretion -- HPLC-LTQ-Orbitrap high-performance liquid chromatography coupled with electrospray ionization hybrid linear trap quadrupole orbitrap mass spectrometry -- Papp the apparent permeability coefficient -- ESI An electrospray ionization -- eHiTS electronic high-throughput screening -- UPLC-MS/MS Ultra Performance Liquid Chromatography-Mass spectrum/ Mass spectrum -- SPR Surface plasmon resonance -- IHC Immunohistochemical -- HFLS-RA Human fibroblast-like synoviocytes-RA -- FBS fetal bovine serum -- DMEM Dulbeco's modified Eagle's medium -- PBS phosphate-buffered saline -- MTT methyl thiazolyl tetrazolium -- ALOX15B arachidonate 15-lipoxygenase type B -- PPAR-γ peroxisome proliferator activated receptor gamma -- IL-1β interleukin 1 beta -- PTGS2 prostaglandin-endoperoxide synthase 2 -- BAT brown adipose tissues -- WAT white adipose tissues depots. MMP13 matrix metalloproteinase 13 -- TGF-β1 transforming growth factor beta 1 -- FGF2 fibroblast growth factor 2 -- AIC AkaikeInformation Criterion -- PGC 1α PPARγ coactivator 1alpha -- UCP1 uncoupling protein 1 -- PRDM16 PR domain containing 16 -- IL-1β interleukin-1 beta -- TNF-α tumor necrosis factor alpha -- IL-6 interleukin-6 -- IL-17 interleukin-17 -- SDH succinate dehydrogenase -- LDH lactate dehydrogenase -- T3 thyroid hormone 3 -- T4 thyroid hormone 4 -- TRH hyrotropin releasing hormone -- TSH thyroid stimulating hormone -- ALT alanine aminotransferase -- AST aspertate aminotransferase -- CREA creatinine; Drug combination -- Rheumatoid arthritis -- Bioactive compound -- Wutou decoction -- Network pharmacology; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.104658
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Wutou Decoction (WTD) achieves favorable therapeutic response in treating rheumatoid arthritis (RA), especially for wind-cold-dampness stimulating RA. However, its material basis and molecular mechanisms remain unclear. To address this problem, the main bioactive compounds (BACs) of WTD against RA and the candidate targets were identified in the current study via transcriptional regulatory network analysis, computational structure-based methods, as well as in vivo and in vitro experimental validations. As a result, we successfully established a RA rat model named AIA-S, which simulated the clinical manifestations and pathological changes of wind-cold-dampness stimulating RA, and also displayed the distinctive characteristics and biological basis of inflammatory-immune system imbalance and abnormal energy metabolism changes. In addition, ALOX15B-PPAR-γ-PTGS2-FGF2-IL-1β-c-JUN-MMP13-TGF-β1 signal axis, involved into thermogenesis and energy metabolism, as well as maintaining the balance of inflammation-immune system, was identified as a candidate target of WTD against RA, according to the transcriptional regulatory network analysis on "RA-related gene-WTD-effective gene interaction network". Moreover, Paeoniflorin (PAE) and Talatizidine (TLT) were demonstrated to be the main BACs of WTD against RA for the following reasons: firstly, both PAE and TLT were the BACs of WTD according to ADME analysis in silico and the pharmacokinetics analysis in vivo . Secondly, both PAE and TLT were able to bind with PPAR-γ, c-JUN, MMP13 and TGF-β1, which were the candidate targets of WTD against RA, with the strong binding affinity. Thirdly, the PAE and TLT combination exerted significant therapeutic effects on AIA-S rats through reversing the imbalance of inflammatory-immune system, and the disturbance of thermogenesis and energy metabolism, which were similar to WTD. More importantly, the administration of TLT or PAE alone didn't exert as prominently therapeutic effects as that of the two-BAC-combination did. Fourthly, the PAE and TLT combination promoted adipogenesis and lipogenesis by upregulating the PPAR-γ-induced lipogenic proteins. In conclusion, this study identified PAE and TLT as the main BACs of WTD in alleviating the severity of RA, and also developed a novel combination of PAE and TLT as a promising candidate drug for RA therapy.