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.

中文翻译：

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白藜芦醇通过靶向ORAI1-STIM1复合体，在佐剂关节炎大鼠模型中减少了贮存操纵的Ca2 +进入并增强了成纤维样滑膜细胞的凋亡。

背景技术据报道白藜芦醇在佐剂性关节炎大鼠中触发成纤维样滑膜细胞凋亡，但亚细胞机制尚不清楚。由于内质网应激，线粒体功能障碍和氧化应激都参与了白藜芦醇与钙生物传输失衡的影响，因此，一种新型的细胞内钙调节途径-储钙操作性钙输入（SOCE）也可能参与了这一过程。结果在本研究中，发现白藜芦醇以剂量依赖性方式抑制ORAI1表达，而对STIM1表达水平没有明显影响。此外，白藜芦醇对ATP或TG诱导的钙耗竭没有影响，但对SOCE具有部分剂量依赖性抑制作用。一方面，在患病脚趾中微量注射ORAI1过表达的载体部分抵消了白藜芦醇对佐剂性关节炎和血清炎性细胞因子（包括IL-1，IL-6，IL-8，IL-10和TNF-α）的治疗作用。另一方面，ORAI1 SiRNA注射可轻微缓解大鼠佐剂性关节炎。此外，在大鼠模型中，ORAI1的过表达部分减轻了白藜芦醇治疗后佐剂性关节炎引起的血象异常的减轻，而ORAI1敲低对大鼠血象有轻微的白藜芦醇样作用。结论这些结果表明，白藜芦醇可通过靶向ORAI1-STIM1复合物减少佐剂关节炎大鼠模型中的贮藏操作性Ca2 +进入并增强成纤维样滑膜细胞的凋亡，