Phloridzin reduces synovial hyperplasia and inflammation in rheumatoid arthritis rat by modulating mTOR pathway.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease and management of it still a challenge. Given report evaluates protective effect of phlorizin on RA and also postulates the molecular mechanism of its action. Bovine type II collagen (CIA) and Freund's incomplete adjuvant (1:1 and 1 mg/ml) was administered on 1st and 8th day of protocol to induce RA in rats and treatment with phlorizin 60 and 120 mg/kg was started after 4th week of protocol. Level of inflammatory cytokines and expression of proteins were estimated in phlorizin treated RA rats. Moreover in-vitro study was performed on Fibroblast-like synoviocytes (FLSs) and effect of phlorizin was estimated on proliferation, apoptosis and expression of mTOR pathway protein after stimulating these cell lines with Tumour Necrosis Factor alpha (TNF-α). Data of study suggest that phlorizin reduces inflammation and improves weight in CIA induced RA rats. Level of inflammatory cytokines in the serum and expression of Akt/PI3K/mTOR proteins in the join tissue was reduced in phlorizin treated RA rats. Phlorizin also reported to reverse the histopathological changes in the joint tissue of RA rats. In-vitro study supports that phlorizin reduces proliferation and no apoptotic effect on TNF-α stimulated FLSs. Expression of Akt/PI3K/mTOR proteins also downregulated in phlorizin treated TNF-α stimulated FLSs. In conclusion, phlorizin protects inflammation and reduces injury to the synovial tissues in RA, as it reduces autophagy by regulating Akt/PI3K/mTOR pathway.

Wang L ，Wu X ，Wan Q ，Yang Y ，Gao C ... -  《-》

Phlorizin Regulates Synovial Hyperplasia and Inflammation in Rats With Rheumatoid Arthritis by Regulating the mTOR Pathway.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, and management of it is still a challenge. The present investigation assessed the potential preventive effect of phlorizin on rats with RA. A total of 40 healthy Wistar rats were used for this study. Bovine type II collagen and Freund's incomplete adjuvant (1:1 and 1 mg/ml) were administered on days 1 and 8 of the protocol to induce RA in rats; treatment with phlorizin at 60 or 120 mg/kg was started after the 4th week of the protocol, and its effect on inflammation, level of inflammatory cytokines, and expression of proteins were estimated in RA rats. Moreover, an in vitro study was performed on fibroblast-like synoviocytes (FLSs), and the effects of phlorizin on proliferation, apoptosis, and expression of the mechanistic target of rapamycin kinase pathway protein after stimulating these cells with tumor necrosis factor α (TNF-α) were estimated. The data obtained from the study indicate that phlorizin has the potential to mitigate inflammation and enhance weight management in rats with RA induced by bovine type II collagen (CII). The level of inflammatory cytokines in the serum and the expression of protein kinase B (AKT), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and mechanistic target of rapamycin kinase (mTOR) proteins in the joint tissue were reduced in phlorizin-treated rats with RA. In this investigation, phlorizin was shown to reverse the histological abnormalities in the joint tissue of rats with RA. The in-vitro study showed that phlorizin reduced proliferation and had no apoptotic effect on TNF-α-stimulated FLSs. Expression of AKT, PI3K, and mTOR proteins was also down-regulated in phlorizin-treated TNF-α-stimulated FLSs. Phlorizin protects against inflammation and reduces injury to synovial tissues in RA by modulating the AKT/PI3K/mTOR pathway.

Wang L ，Wu X ，Wan Q ，Yang Y ，Gao C ... -  《-》

Astragalus polysaccharides inhibits cell growth and pro-inflammatory response in IL-1β-stimulated fibroblast-like synoviocytes by enhancement of autophagy via PI3K/AKT/mTOR inhibition.

Meng Q ，Du X ，Wang H ，Gu H ，Zhan J ，Zhou Z ... -  《-》

Curcumin alleviates rheumatoid arthritis-induced inflammation and synovial hyperplasia by targeting mTOR pathway in rats.

Dai Q ，Zhou D ，Xu L ，Song X ... -  《Drug Design Development and Therapy》

Celastrol inhibits rheumatoid arthritis by inducing autophagy via inhibition of the PI3K/AKT/mTOR signaling pathway.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder of the synovial joints. Celastrol (Cel) is a quinone-methylated triterpenoid extracted from Tripterygium wilfordii Hook F (TwHF) that has been proven to be effective in treating RA. However, the underlying molecular mechanism of celastrol in the treatment of RA remains unknown. This study explored the protective effect of celastrol against RA and the specific mechanisms of celastrol in vitro and in vivo. A chicken type II collagen (CII)-induced arthritis (CIA) mouse model was used to explore the anti-arthritic effects of celastrol, and paw swelling degree, the poly-arthritis index score and serum cytokine levels were determined. Pathological morphology was observed using hematoxylin and eosin (H&E) staining. The influences of celastrol on the proliferation of tumor necrosis factor-α (TNF-α)-induced fibroblast-like synoviocytes (FLSs) were tested by Cell Counting Kit-8 (CCK-8) assays and5-ethynyl-2'-deoxyuridine (EdU) staining assays. The level of autophagy was detected by transmission electron microscopy (TEM). Furthermore, the PI3K/AKT/mTOR pathway and the status of autophagy in the CIA model and FLSs were also detected by western blot and immunofluorescence staining. The results showed that celastrol decreased arthritis severity and inhibited TNF-α-induced FLSs proliferation. Additionally, celastrol decreased the secretion of pro-inflammatory cytokines. Moreover, celastrol increased autophagosome levels and LC3B protein expression in TNF-α-treated FLSs. Furthermore, celastrol increased the protein expression of LC3-II and Beclin-1 and decreased the phosphorylation degree of mTOR and AKT. In conclusion, our findings confirmed that celastrol ameliorates RA via the up-regulation of autophagy by inhibiting the PI3K/AKT/mTOR axis.

Yang J ，Liu J ，Li J ，Jing M ，Zhang L ，Sun M ，Wang Q ，Sun H ，Hou G ，Wang C ，Xin W ... -  《-》