莱维斯蒂利德A通过抑制M1巨噬细胞中的NF-κB/iNOS/NO信号通路减轻四氯化碳（CCl）诱导的肝纤维化。
Levistilide A attenuates carbon tetrachloride (CCl)-induced liver fibrosis by inhibiting the NF-κB/iNOS/NO signalling pathway in M1 macrophages.
作者信息
Zeng Rui, Shen Liu, Ye Tingjie, Xu Wei, Huang Kai, Qiu Fengjun, Liu Chenghai, Hu Xudong
机构信息
Department of Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong New Area, Shanghai, 201203, China; Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New Area, Shanghai, 201203, China.
Department of Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong New Area, Shanghai, 201203, China.
出版信息
J Ethnopharmacol. 2025 Jul 24;351:120074. doi: 10.1016/j.jep.2025.120074. Epub 2025 Jun 4.
ETHNOPHARMACOLOGICAL RELEVANCE
Danggui (Angelica sinensis (Oliv.) Diels), a well-known traditional Chinese medicinal herb, has been extensively used for millennia due to its diverse pharmacological properties. It is commonly used to manage liver fibrosis (LF). However, the precise antifibrotic mechanism of levistilide A (LA), the major bioactive constituent of Danggui, remains largely unexplored.
AIM OF THE STUDY
To investigate the inhibitory effects of LA on nitric oxide (NO) production in M1 macrophages and to elucidate its anti-LF property.
MATERIALS AND METHODS
Using lipopolysaccharide/interferon-γ-activated RAW264.7 macrophages for in vitro studies to investigate LA's repressive effects on nuclear factor-κB (NF-κB)/inducible nitric oxide synthase (iNOS)/NO axis in M1 macrophages. Additionally, using CCl-induced LF mice for in vivo studies to explore LA's therapeutic mechanism on LF via restraining the NF-κB/iNOS/NO axis.
RESULTS
LA markedly attenuated p65 activation in M1 macrophages, leading to a dose-dependent suppression of iNOS expression, and a concomitant reduction in NO production. In CCl-induced fibrotic mice, LA administration resulted in a significant reduction in serum levels of alanine aminotransferase, aspartate aminotransferase and NO, mitigating hepatic tissue injury and collagen deposition. Furthermore, LA downregulated the hepatic expression of iNOS, tumour necrosis factor-α, interleukin-6, and tissue inhibitor of metalloproteinase-1, while upregulating interleukin-10 and matrix metalloproteinase-12. Additionally, LA significantly reduced the hepatic protein expression of α-smooth muscle actin, CD86, p65, p-p65 and iNOS, further supporting its antifibrotic efficacy.
CONCLUSIONS
LA exerts antifibrotic effects by suppressing NO overproduction through inhibition of the NF-κB/iNOS signalling pathway in M1 macrophages, thereby demonstrating therapeutic potential in CCl-induced liver fibrosis.
民族药理学相关性
当归（Angelica sinensis (Oliv.) Diels）是一种著名的传统中草药，因其多样的药理特性已被广泛使用了数千年。它常用于治疗肝纤维化（LF）。然而，当归的主要生物活性成分阿魏酸（LA）的确切抗纤维化机制在很大程度上仍未被探索。
研究目的
研究LA对M1巨噬细胞中一氧化氮（NO）产生的抑制作用，并阐明其抗肝纤维化特性。
材料与方法
使用脂多糖/干扰素-γ激活的RAW264.7巨噬细胞进行体外研究，以研究LA对M1巨噬细胞中核因子-κB（NF-κB）/诱导型一氧化氮合酶（iNOS）/NO轴的抑制作用。此外，使用四氯化碳诱导的肝纤维化小鼠进行体内研究，以探索LA通过抑制NF-κB/iNOS/NO轴对肝纤维化的治疗机制。
结果
LA显著减弱了M1巨噬细胞中p65的激活，导致iNOS表达呈剂量依赖性抑制，并伴随NO产生减少。在四氯化碳诱导的纤维化小鼠中，给予LA导致血清丙氨酸转氨酶、天冬氨酸转氨酶和NO水平显著降低，减轻了肝组织损伤和胶原沉积。此外LA下调了肝脏中iNOS、肿瘤坏死因子-α、白细胞介素-6和金属蛋白酶组织抑制剂-1的表达，同时上调了白细胞介素-10和基质金属蛋白酶-12的表达。此外，LA显著降低了肝脏中α-平滑肌肌动蛋白、CD86、p65、p-p65和iNOS的蛋白表达，进一步支持了其抗纤维化功效。
结论
LA通过抑制M1巨噬细胞中NF-κB/iNOS信号通路来抑制NO的过量产生，从而发挥抗纤维化作用，从而在四氯化碳诱导的肝纤维化中显示出治疗潜力。
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