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Traditional Chinese medicinal shenjinhuoxue mixture (SHM) shows anti\u2010inflammatory and analgesic effects against OA with remarkable clinical efficacy. This study explored the mechanism underlying anti\u2010OA properties of SHM and evaluated its efficacy and safety via in vivo experiments. Through network pharmacology and published literature, we identified the key active phytochemicals in SHM, including <jats:italic>\u03b2<\/jats:italic>\u2010sitosterol, oleanolic acid, licochalcone A, quercetin, isorhamnetin, kaempferol, morusin, lupeol, and pinocembrin; the pivotal targets of which are TLR\u20104 and NF\u2010<jats:italic>\u03ba<\/jats:italic>B, eliciting anti\u2010OA activity. These phytochemicals can enter the active pockets of TLR\u20104 and NF\u2010<jats:italic>\u03ba<\/jats:italic>B with docking score \u2264 \u22123.86\u2009kcal\/mol, as shown in molecular docking models. By using surface plasmon resonance assay, licochalcone A and oleanolic acid were found to have good TLR\u20104\u2010binding affinity. In OA rats, oral SHM at mid and high doses (8.72\u2009g\/kg and 26.2\u2009g\/kg) over 6 weeks significantly alleviated mechanical and thermal hyperalgesia (<jats:italic>P<\/jats:italic> &lt; 0.0001). Accordingly, the expression of inflammatory mediators (TLR\u20104, interleukin (IL\u2010) 1 receptor\u2010associated kinase 1 (IRAK1), NF\u2010<jats:italic>\u03ba<\/jats:italic>B\u2010p65, tumor necrosis factor (TNF\u2010) <jats:italic>\u03b1<\/jats:italic>, IL\u20106, and IL\u20101<jats:italic>\u03b2<\/jats:italic>), receptor activator of the NF\u2010<jats:italic>\u03ba<\/jats:italic>B ligand (RANKL), and transient receptor potential vanilloid 1 (TRPV1) in the synovial and cartilage tissue of OA rats was significantly decreased (<jats:italic>P<\/jats:italic> &lt; 0.05). Moreover, pathological observation illustrated amelioration of cartilage degeneration and joint injury. In chronic toxicity experiment of rats, SHM at 60\u2009mg\/kg demonstrated the safety. SHM had an anti\u2010inflammatory effect through a synergistic combination of active phytochemicals to attenuate pain and cartilage degeneration by inhibiting TLR\u20104 and NF\u2010<jats:italic>\u03ba<\/jats:italic>B activation. This study provided the experimental foundation for the development of SHM into a more effective dosage form or new drugs for OA treatment.<\/jats:p>","DOI":"10.1155\/2021\/4190098","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T02:20:51Z","timestamp":1634869251000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Shenjinhuoxue Mixture Attenuates Inflammation, Pain, and Cartilage Degeneration by Inhibiting TLR\u20104 and NF\u2010<i>\u03ba<\/i>B Activation in Rats with Osteoarthritis: A Synergistic Combination of Multitarget Active 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