Jinsen Lu1, Jiazhao Yang1, Yongshun Zheng1, Shiyuan Fang2, Xiaoyu Chen3. 1. Department of Orthopaedics, Anhui Provincial Hospital, Anhui Medical University, Lujiang Road No. 17, Hefei, 230001, Anhui, People's Republic of China. 2. Department of Orthopaedics, Anhui Provincial Hospital, Anhui Medical University, Lujiang Road No. 17, Hefei, 230001, Anhui, People's Republic of China. fangshiyuan2008@126.com. 3. Department of Histology and Embryology, Anhui Medical University, Meishan Road No. 81, Hefei, 230032, China.
Abstract
BACKGROUND: Resveratrol was reported to trigger the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats but the subcellular mechanism remains unclear. Since ER stress, mitochondrial dysfunction and oxidative stress were involved in the effects of resveratrol with imbalance of calcium bio-transmission, store operated calcium entry (SOCE), a novel intracellular calcium regulatory pathway, may also participate in this process. RESULTS: In the present study, Resveratrol was found to suppress ORAI1 expression of a dose dependent manner while have no evident effects on STIM1 expressive level. Besides, resveratrol had no effects on ATP or TG induced calcium depletion but present partly dose-dependent suppression of SOCE. On the one hand, microinjection of ORAI1 overexpressed vector in sick toe partly counteracted the therapeutic effects of resveratrol on adjuvant arthritis and serum inflammatory cytokine including IL-1, IL-6, IL-8, IL-10 and TNF-α. On the other hand, ORAI1 SiRNA injection provided slight relief to adjuvant arthritis in rats. In addition, ORAI1 overexpression partly diminished the alleviation of hemogram abnormality induced by adjuvant arthritis after resveratrol treatment while ORAI1 knockdown presented mild resveratrol-like effect on hemogram in rats model. CONCLUSION: These results indicated that resveratrol reduced store-operated Ca2+ entry and enhanced the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats model via targeting ORAI1-STIM1 complex, providing a theoretical basis for ORAI1 targeted therapy in future treatment with resveratrol on rheumatoid arthritis.
BACKGROUND:Resveratrol was reported to trigger the apoptosis of fibroblast-like synoviocytes in adjuvant arthritisrats but the subcellular mechanism remains unclear. Since ER stress, mitochondrial dysfunction and oxidative stress were involved in the effects of resveratrol with imbalance of calcium bio-transmission, store operated calcium entry (SOCE), a novel intracellular calcium regulatory pathway, may also participate in this process. RESULTS: In the present study, Resveratrol was found to suppress ORAI1 expression of a dose dependent manner while have no evident effects on STIM1 expressive level. Besides, resveratrol had no effects on ATP or TG induced calcium depletion but present partly dose-dependent suppression of SOCE. On the one hand, microinjection of ORAI1 overexpressed vector in sick toe partly counteracted the therapeutic effects of resveratrol on adjuvant arthritis and serum inflammatory cytokine including IL-1, IL-6, IL-8, IL-10 and TNF-α. On the other hand, ORAI1 SiRNA injection provided slight relief to adjuvant arthritis in rats. In addition, ORAI1 overexpression partly diminished the alleviation of hemogram abnormality induced by adjuvant arthritis after resveratrol treatment while ORAI1 knockdown presented mild resveratrol-like effect on hemogram in rats model. CONCLUSION: These results indicated that resveratrol reduced store-operated Ca2+ entry and enhanced the apoptosis of fibroblast-like synoviocytes in adjuvant arthritisrats model via targeting ORAI1-STIM1 complex, providing a theoretical basis for ORAI1 targeted therapy in future treatment with resveratrol on rheumatoid arthritis.
Authors: Francine C Paim; Marta M M F Duarte; Márcio M Costa; Aleksandro S Da Silva; Patrícia Wolkmer; Cássia B Silva; Carlos B V Paim; Raqueli T França; Cinthia M A Mazzanti; Silvia G Monteiro; Alexandre Krause; Sonia T A Lopes Journal: Exp Parasitol Date: 2011-05-01 Impact factor: 2.011
Authors: Niklas Beyersdorf; Attila Braun; Timo Vögtle; David Varga-Szabo; Ronmy Rivera Galdos; Stephan Kissler; Thomas Kerkau; Bernhard Nieswandt Journal: J Immunol Date: 2009-03-15 Impact factor: 5.422