{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:33:31Z","timestamp":1790512411256,"version":"4.1.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T00:00:00Z","timestamp":1607385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The activated G\u03b1 protein subunit (G\u03b1s) and the inhibitory G\u03b1 protein subunit (G\u03b1i) are involved in the signal transduction of G protein coupled receptors (GPCRs). Moreover, the conversion of G\u03b1i\/G\u03b1s can couple with sphingosine-1-phosphate receptors (S1PRs) and have a critical role in rheumatoid arthritis (RA). Through binding to S1PRs, sphingosine-1-phosphate (S1P) leads to activation of the pro-inflammatory signaling in rheumatoid arthritis synovial fibroblasts (RASFs). Geniposide (GE) can alleviate RASFs dysfunctions to against RA. However, its underlying mechanism of action in RA has not been elucidated so far. This study aimed to investigate whether GE could regulate the biological functions of MH7A cells by inhibiting S1PR1\/3 coupling G\u03b1i\/G\u03b1s conversion. We use RASFs cell line, namely MH7A cells, which were obtained from the patient with RA and considered to be the main effector cells in RA. The cells were stimulated with S1P (5\u00a0\u03bcmol\/L) and then were treated with or without different inhibitors: G\u03b1i inhibitor pertussis toxin (0.1\u00a0\u03bcg\/mL), S1PR1\/3 inhibitor VPC 23019 (5\u00a0\u03bcmol\/L), G\u03b1s activator cholera toxin (1\u00a0\u03bcg\/mL) and GE (25, 50, and 100\u00a0\u03bcmol\/L) for 24\u00a0h. The results showed that GE may inhibit the abnormal proliferation, migration and invasion by inhibiting the S1P-S1PR1\/3 signaling pathway and activating G\u03b1s or inhibiting G\u03b1i protein in MH7A cells. Additionally, GE could inhibit the release of inflammatory factors and suppress the expression of cAMP, which is the key factor of the conversion of G\u03b1i and G\u03b1s. GE could also restore the dynamic balance of G\u03b1i and G\u03b1s by suppressing S1PR1\/3 and inhibiting G\u03b1i\/G\u03b1s conversion, in a manner, we demonstrated that GE inhibited the activation of G\u03b1 downstream ERK protein as well. Taken together, our results indicated that down-regulation of S1PR1\/3-G\u03b1i\/G\u03b1s conversion may play a critical role in the effects of GE on RA and GE could be an effective therapeutic agent for RA.<\/jats:p>","DOI":"10.3389\/fphar.2020.584176","type":"journal-article","created":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T02:04:35Z","timestamp":1607393075000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Anti-Inflammatory Effect of Geniposide on Regulating the Functions of Rheumatoid Arthritis Synovial Fibroblasts via Inhibiting Sphingosine-1-Phosphate Receptors1\/3 Coupling G\u03b1i\/G\u03b1s Conversion"],"prefix":"10.3389","volume":"11","author":[{"given":"Rong-hui","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-jing","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-die","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-hong","family":"Bu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-hui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.molimm.2018.05.024","article-title":"A novel diindolylmethane analog, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane, inhibits the tumor necrosis factor-induced inflammatory response in primary murine synovial fibroblasts through a Nurr1-dependent mechanism","volume":"101","author":"Afzali","year":"2018","journal-title":"Mol. 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