背景:巴林达如何。是一种常用的传统中草药,具有补肝补肾的药理特性,增强骨骼和肌肉。环烯醚苷是这种植物的主要成分,包括单曲霉素,asperuloside,脱乙酰天花苷和脱乙酰天花苷酸,含量达到2%以上。甲氨蝶呤(MTX)是治疗类风湿性关节炎(RA)的首选药物,但是MTX引起的肝损伤限制了其在RA中的广泛使用。据报道,M.officinalis环烯醚萜苷(MOIG)具有抗RA和保肝作用,但对MTX诱导的肝损伤的确切疗效和潜在的分子机制仍不清楚。
目的:为了阐明MOIG对MTX治疗RA大鼠肝损伤的缓解作用,并探讨其可能的机制。
方法:用MTX治疗Wistar大鼠胶原性关节炎(CIA),研究MOIG的作用和机制。和MTX诱导的体外肝细胞损伤。进行了网络药理学和转录组学分析,以预测MOIG减轻MTX诱导的肝损伤的可能机制。并进行脂质组学分析以进一步验证MOIG对脂质代谢的调节作用。BRL-3A肝细胞用于评估MOIG对MTX相关肝损伤的调节作用。
结果:MOIG治疗增强了MTX的抗RA作用,减轻氧化损伤,MTX治疗CIA大鼠肝组织的炎症和凋亡。网络药理学和转录组学分析表明,MOIG通过调节自噬和脂质代谢来减轻肝损伤。脂质组学分析结果表明,MOIG逆转了MTX治疗后CIA大鼠肝组织脂质代谢紊乱。此外,MOIG还抑制细胞凋亡,降低乳酸脱氢酶(LDH)的水平,谷草转氨酶(ALT)和丙氨酸转氨酶(AST),调节的氧化应激,并增加了自噬体的形成和LC3在细胞核中的易位以及自噬调节基因Beclin-1,ATG5,LC3Ⅱ的表达,受到MTX损伤的肝细胞中的ATG7和ATG12。
结论:我们的研究结果表明,MOIG可以通过增加肝细胞自噬和改善脂质代谢稳态来改善MTX引起的RA肝损伤。
BACKGROUND: Morinda officinalis How. is a commonly used traditional Chinese herb with the pharmacological properties of tonifying liver and kidney, and enhancing bone and muscle. Iridoid glycosides are the predominant components of this plant, including monotropein, asperuloside, deacetylasperuloside and deacetylasperulosidic acid with their contents reaching more than 2%.
Methotrexate (MTX) is the drug of choice for the treatment of rheumatoid arthritis (RA), but liver injury induced by MTX limits its wider use for RA. Morindaofficinalis iridoid glycoside (MOIG) is reported as having anti-RA and hepatoprotective effects, but the exact efficacy on MTX-induced liver injury and the underlying molecular mechanism remain unclear.
OBJECTIVE: To elucidate the mitigating effect of MOIG against liver injury in RA rats treated with MTX, and explore the possible mechanism.
METHODS: The effect and mechanism of MOIG were investigated in Wistar rats with collagen-induced arthritis (CIA) which were then treated with MTX, and MTX-induced hepatocyte injury in vitro. Network pharmacological and transcriptomic analyses were conducted to predict the possible mechanisms of MOIG in mitigating MTX-induced liver injury, and lipidomic analysis was performed to further verify the regulatory effects of MOIG on lipid metabolism. BRL-3A hepatocytes were used to evaluate the regulatory effects of MOIG against MTX-associated liver injury.
RESULTS: MOIG treatment enhanced the anti-RA effect of MTX, and mitigated oxidative damage, inflammation and apoptosis of liver tissues in CIA rats treated with MTX. Network pharmacological and transcriptomic analyses demonstrated that MOIG attenuated liver injury by regulating autophagy and lipid metabolism. The result of lipidomic analysis showed that MOIG reversed the disturbance of lipid metabolism of the liver tissue in CIA rats after MTX treatment. In addition, MOIG also inhibited the apoptosis, reduced the levels of lactate dehydrogenase (LDH), aspartate aminotransferase (ALT) and alanine aminotransferase (AST), regulated oxidative stress, and increased the formation of autophagosome and translocation of LC3 in the nucleus and expression of autophagy regulatory genes Beclin-1, ATG5, LC3Ⅱ, ATG7 and ATG12 in hepatocytes subjected to MTX damage.
CONCLUSIONS: Our findings demonstrated that MOIG could ameliorate MTX-induced liver injury in the treatment of RA through increasing hepatocyte autophagy and improving lipid metabolism homeostasis.