Tumor necrosis factor-α(TNF-α)is a key player in the pathogenesis of rheumatoid arthritis(RA)and considered a promising target for therapeutic drug development.Activation of the nuclear factor-kappa B(NF-κB)pathway...Tumor necrosis factor-α(TNF-α)is a key player in the pathogenesis of rheumatoid arthritis(RA)and considered a promising target for therapeutic drug development.Activation of the nuclear factor-kappa B(NF-κB)pathway upon TNF-αbinding to its receptor is crucial for progression of RA.Stephanine(SA),an isoquinoline aporphine-type alkaloid recently identified in Stephania plants,exhibits anti-inflammatory properties,but its underlying mechanisms of action are unknown at present.In this study,we explored whether SA could ameliorate RA through inhibition of the NF-κB signaling pathway in association with TNF-αactivity.Our experiments revealed a binding affinity(K_(D))of SA for TNF-αof 2.934×10^(-6)mol/L.Additionally,SA at a concentration of 10μmol/L effectively hindered the binding of TNF-αto its receptors tumor necrosis factor receptor 1(TNFR1)and TNFR2.In vitro,SA prevented TNF-α-induced death of L929 cells and blocked NF-κB activation triggered by TNF-αin 293-TNF-αresponsive,as well as human fibroblast-like synoviocytes(HFLS)and human RA fibroblast-like synoviocytes(MH7A)cell lines.Furthermore,in a collagen-induced arthritis(CIA)mouse model,SA alleviated the symptoms of RA through suppression of NF-κB signaling.Our collective findings support the therapeutic efficacy of SA,a natural compound targeting TNF-α,in the management of RA.展开更多
基金supported by the grants from the National Natural Science Foundation of China(82404638)the Xingdian Talent Plan of Yunnan Province(XDYC-QNRC-2023-0427 and XDYC-YLXZ-2022-0025)the Natural Science Foundation of Yunnan Province(202101BD070001-034,202101BD070001-049,202201AT070267,and 202201AU070183).
文摘Tumor necrosis factor-α(TNF-α)is a key player in the pathogenesis of rheumatoid arthritis(RA)and considered a promising target for therapeutic drug development.Activation of the nuclear factor-kappa B(NF-κB)pathway upon TNF-αbinding to its receptor is crucial for progression of RA.Stephanine(SA),an isoquinoline aporphine-type alkaloid recently identified in Stephania plants,exhibits anti-inflammatory properties,but its underlying mechanisms of action are unknown at present.In this study,we explored whether SA could ameliorate RA through inhibition of the NF-κB signaling pathway in association with TNF-αactivity.Our experiments revealed a binding affinity(K_(D))of SA for TNF-αof 2.934×10^(-6)mol/L.Additionally,SA at a concentration of 10μmol/L effectively hindered the binding of TNF-αto its receptors tumor necrosis factor receptor 1(TNFR1)and TNFR2.In vitro,SA prevented TNF-α-induced death of L929 cells and blocked NF-κB activation triggered by TNF-αin 293-TNF-αresponsive,as well as human fibroblast-like synoviocytes(HFLS)and human RA fibroblast-like synoviocytes(MH7A)cell lines.Furthermore,in a collagen-induced arthritis(CIA)mouse model,SA alleviated the symptoms of RA through suppression of NF-κB signaling.Our collective findings support the therapeutic efficacy of SA,a natural compound targeting TNF-α,in the management of RA.
