Journal of ethnopharmacology · 2025
Levistilide A attenuates carbon tetrachloride (CCl4)-induced liver fibrosis by inhibiting the NF-κB/iNOS/NO signalling pathway in M1 macrophages.
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Zeng Rui, Shen Liu, Ye Tingjie, Xu Wei, Huang Kai, Qiu Fengjun, Liu Chenghai, Hu Xudong
Аннотация
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 CCl4-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 CCl4-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 CCl4-induced liver fibrosis.
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 CCl4-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 CCl4-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 CCl4-induced liver fibrosis.