巴戟天中环烯醚萜苷通过抑制 MAPK 和 NF-κB 信号通路发挥抗炎和抗关节炎作用。
Iridoid glycosides from Morinda officinalis How. exert anti-inflammatory and anti-arthritic effects through inactivating MAPK and NF-κB signaling pathways.
机构信息
College of Pharmaceutical Sciences, Zhejiang University of Traditional Chinese Medicine, Gaoke Road, Fuyang District, Hangzhou, 310053, People's Republic of China.
School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China.
出版信息
BMC Complement Med Ther. 2020 Jun 5;20(1):172. doi: 10.1186/s12906-020-02895-7.
BACKGROUND
The root of Morinda officinalis How. (MO, the family of Rubiaceae) has long been used to treat inflammatory diseases in China and other eastern Asian countries, and iridoid glycosides extracted from MO (MOIG) are believed to contribute to this anti-inflammatory effect. However, the mechanism underlying the anti-inflammatory and anti-arthritic activities of MOIG has not been elucidated. The aim of the present study was to determine how MOIG exerted anti-inflammatory and anti-arthritic effects in vivo and in RAW 264.7 macrophages.
METHODS
MOIG were enriched by XDA-1 macroporous resin. The maximum feasible dose method was adopted to evaluate its acute toxicity. The analgesic effect of MOIG was evaluated by acetic acid writhing test and the anti-inflammatory effect was evaluated by cotton-pellet granuloma test in rats and air pouch granuloma test in mice. The anti-arthritic effect was evaluated by establishing an adjuvant arthritis model induced by Complete Freund's Adjuvant (CFA). The viability of the cultured RAW 264.7 macrophages was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The anti-inflammatory activity was evaluated by measuring NO, IL-1β, IL-6 and TNF-α levels in LPS-stimulated RAW 264.7 cells. The protein level of inflammatory responsive genes was evaluated by Western blot analysis.
RESULTS
MOIG had no significant toxicity at maximum feasible dose of 22.5 g/kg. MO extracts and MOIG (50,100 and 200 mg/kg) all evoked a significantly inhibitory effects on the frequency of twisting induced by acetic acid in mice compared with the model control group. Administration of MO extracts and MOIG markedly decreased the dry and wet weight of cotton pellet granuloma in rats and air pouch granuloma in mice. MOIG significantly attenuated the paw swelling and decreased the arthritic score, weight loss, spleen index, and the serum level of inflammatory factors IL-1β, IL-6 and IL-17a in CFA-induced arthritic rats. MOIG inhibited the production of inflammatory cytokines in LPS-stimulated RAW264.7 cells, and the expressions of iNOS, COX-2 and proteins related to MAPK and NF-κB signaling pathways in LPS-stimulated RAW 264.7 macrophages.
CONCLUSION
MOIG exerted anti-inflammatory and anti-arthritic activities through inactivating MAPK and NF-κB signaling pathways, and this finding may provide a sound experimental basis for the clinical treatment of rheumatoid arthritis with MOIG.
背景
桑科植物巴戟天（MO，茜草科）的根在中国和其他东亚国家长期以来一直被用于治疗炎症性疾病，从 MO 中提取的环烯醚萜苷（MOIG）被认为具有这种抗炎作用。然而，MOIG 的抗炎和抗关节炎活性的机制尚未阐明。本研究旨在确定 MOIG 体内和 RAW 264.7 巨噬细胞中发挥抗炎和抗关节炎作用的方式。
方法
通过 XDA-1 大孔树脂富集 MOIG。采用最大可行剂量法评价其急性毒性。采用醋酸扭体试验评价 MOIG 的镇痛作用，采用大鼠棉球肉芽肿试验和小鼠气囊肉芽肿试验评价其抗炎作用，采用完全弗氏佐剂（CFA）诱导的佐剂性关节炎模型评价其抗关节炎作用。采用 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐（MTT）比色法评估培养的 RAW 264.7 巨噬细胞的活力。通过测量 LPS 刺激的 RAW 264.7 细胞中 NO、IL-1β、IL-6 和 TNF-α 的水平来评估抗炎活性。通过 Western blot 分析评估炎症反应基因的蛋白水平。
结果
MOIG 在最大可行剂量 22.5g/kg 时无明显毒性。MO 提取物和 MOIG（50、100 和 200mg/kg）均能显著抑制醋酸诱导的小鼠扭体反应频率，与模型对照组相比。给予 MO 提取物和 MOIG 可显著减少大鼠棉球肉芽肿和小鼠气囊肉芽肿的干重和湿重。MOIG 显著减轻 CFA 诱导的关节炎大鼠的足肿胀，并降低关节炎评分、体重减轻、脾指数以及血清中炎症因子 IL-1β、IL-6 和 IL-17a 的水平。MOIG 抑制 LPS 刺激的 RAW264.7 细胞中炎症细胞因子的产生，并抑制 LPS 刺激的 RAW 264.7 巨噬细胞中 iNOS、COX-2 以及与 MAPK 和 NF-κB 信号通路相关的蛋白质的表达。
结论
MOIG 通过抑制 MAPK 和 NF-κB 信号通路发挥抗炎和抗关节炎活性，这一发现可能为 MOIG 临床治疗类风湿关节炎提供良好的实验基础。
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