Minghui Sun1, Ran Deng1, Yan Wang1, Hong Wu2, Zhengrong Zhang1, Yanhong Bu1, Heng Zhang1. 1. College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei 230012, China. 2. College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei 230012, China. Electronic address: hongw@ahtcm.edu.cn.
Abstract
OBJECTIVE: Rheumatoid arthritis (RA) is a common inflammatory autoimmune disease characterized by the formation of joint synovitis and pannus. Sphingosine 1-phosphate (S1P) is an important mediator related to angiogenesis, inflammation and autoimmunity. As Geniposide (GE) has potent immuno-modulation function, we investigated the effects on the dynamic balance of angiogenesis-related factors and Sphingosine kinase 1 (SphK1)-S1P-S1P receptor 1 (S1PR1) signal transduction in adjuvant-induced arthritis (AA) rats. METHOD: The model evaluation was performed from paw swelling degree, arthritis index and movement score. The immunohistochemistry and enzyme-linked immunosorbent assay were used to study the microvascular density (MVD) and pro/anti-angiogenic factors levels. The cell viability was examined by cell counting kit-8 assay. SphK1, S1PR1 mRNA and protein levels in fibroblast-like synoviocytes (FLSs) were detected by quantitative real-time polymerase chain reaction and Western blotting. RESULTS: The results showed that GE can apparently suppressed the inflammatory pathological status. The arthritis index, paw swelling and MVD of AA rats were decreased with dose dependence (⁎P < 0.05, ⁎⁎P < 0.01). In addition, GE can reduce the secretion of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), promote the secretion of endostatin (ES) and inhibit excessive proliferation of FLSs (⁎P < 0.05, ⁎⁎P < 0.01). Importantly, GE can significantly inhibit the activity of SphK1, the level of S1P and the expression of SphK1 and S1PR1 in FLSs (⁎P < 0.05, ⁎⁎P < 0.01). CONCLUSION: It indicated that GE reduces the activity of SphK1 by restoring the dynamic balance between pro/anti-angiogenic factors, thereby interfering with SphK1-S1P-S1PR1 signal transduction, reducing the formation of synovial microvessels and exerting anti-angiogenesis effect of RA.
OBJECTIVE:Rheumatoid arthritis (RA) is a common inflammatory autoimmune disease characterized by the formation of joint synovitis and pannus. Sphingosine 1-phosphate (S1P) is an important mediator related to angiogenesis, inflammation and autoimmunity. As Geniposide (GE) has potent immuno-modulation function, we investigated the effects on the dynamic balance of angiogenesis-related factors and Sphingosine kinase 1 (SphK1)-S1P-S1P receptor 1 (S1PR1) signal transduction in adjuvant-induced arthritis (AA) rats. METHOD: The model evaluation was performed from paw swelling degree, arthritis index and movement score. The immunohistochemistry and enzyme-linked immunosorbent assay were used to study the microvascular density (MVD) and pro/anti-angiogenic factors levels. The cell viability was examined by cell counting kit-8 assay. SphK1, S1PR1 mRNA and protein levels in fibroblast-like synoviocytes (FLSs) were detected by quantitative real-time polymerase chain reaction and Western blotting. RESULTS: The results showed that GE can apparently suppressed the inflammatory pathological status. The arthritis index, paw swelling and MVD of AA rats were decreased with dose dependence (⁎P < 0.05, ⁎⁎P < 0.01). In addition, GE can reduce the secretion of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), promote the secretion of endostatin (ES) and inhibit excessive proliferation of FLSs (⁎P < 0.05, ⁎⁎P < 0.01). Importantly, GE can significantly inhibit the activity of SphK1, the level of S1P and the expression of SphK1 and S1PR1 in FLSs (⁎P < 0.05, ⁎⁎P < 0.01). CONCLUSION: It indicated that GE reduces the activity of SphK1 by restoring the dynamic balance between pro/anti-angiogenic factors, thereby interfering with SphK1-S1P-S1PR1 signal transduction, reducing the formation of synovial microvessels and exerting anti-angiogenesis effect of RA.
Authors: Fatemeh Khodadust; Aiarpi Ezdoglian; Maarten M Steinz; Judy R van Beijnum; Gerben J C Zwezerijnen; Gerrit Jansen; Sander W Tas; Conny J van der Laken Journal: Int J Mol Sci Date: 2022-06-25 Impact factor: 6.208