Guizhi Fuling pill attenuates liver fibrosisin vitroandin vivovia inhibiting TGF-β1/Smad2/3 and activating IFN-γ/Smad7 signaling pathways

Abstract

Liver fibrosis resulting from chronic liver injuries (CLI) is a common health problem globally. Guizhi Fuling pill (GZFL), a modern preparation from traditional Chinese medicine, exhibited anti-dysmenorrhea, anti-inflammatory, and immune-regulative effects. However, the effect of GZFL on liver fibrosis remains unknown. In this research, LX-2 cells were stimulated with acetaldehyde for mimicking liver fibrosis progression in vitro . In addition, carbon tetrachloride (CCl 4 )-induced mouse model of liver fibrosis was established as well. The data revealed GZFL obviously suppressed the proliferation and triggered the apoptosis of acetaldehyde-stimulated LX-2 cells. In addition, GZFL prevented acetaldehyde-induced activation of LX-2 cells via downregulation of TGF-β1, p-Smad2, p-Smad3, CUGBP1, and upregulation of p-STAT1 and Smad7. Meanwhile, GZFL significantly alleviated CCl 4 ‑induced liver fibrosis, as evidenced by the decrease of ALT and AST levels. Moreover, GZFL downregulated the expressions of TGF-β1, p-Smad2, p-Smad3, and CUGBP1 in CCl 4 -treated mice. Furthermore, GZFL remarkably elevated the levels of IFN-γ, p-STAT1, and Smad7 in CCl 4 -treated mice. To sum up, GZFL was able to inhibit liver fibrosis in vitro and in vivo through suppressing TGF-β1/Smad2/3-CUGBP1 signaling and activating IFN-γ/STAT1/Smad7 signaling. Thus, GZFL might have a potential to act as a therapeutic agent for anti-fibrotic therapy.

High level of C3 is associated with Th2 immune response and liver fibrosis in patients with schistosomiasis

“…As an immunomodulatory and anti-fibrosis Th1-type cytokine, IFN-γ can significantly inhibit the growth of HSC and downregulate the expression of fibro-related proteins such as IV-C and α-SMA in cells 36 which may be related to the promotion of Smad2 phosphorylation and the antagonism of TGF-β. 37 Anti-IFN-γ antibodies have demonstrated significant anti-fibrosis effects on liver injury models. 38 Studies on schistosomiasis confirmed that IFN-γ could reduce liver fibrosis in mice infected with schistosomiasis through regulating Th cell subsets.…”

“…We found that the addition of exogenous C3 induced collagen deposition in the liver tissues of mice, the hepatic fibrosis protein and the serum collagen level were upregulated, while IFN‐γ treatment could reverse such a pro‐fibrosis effect. As an immunomodulatory and anti‐fibrosis Th1‐type cytokine, IFN‐γ can significantly inhibit the growth of HSC and downregulate the expression of fibro‐related proteins such as IV‐C and α‐SMA in cells 36 which may be related to the promotion of Smad2 phosphorylation and the antagonism of TGF‐β 37 . Anti‐IFN‐γ antibodies have demonstrated significant anti‐fibrosis effects on liver injury models 38 .…”

ZNF165 Is Involved in the Regulation of Immune Microenvironment and Promoting the Proliferation and Migration of Hepatocellular Carcinoma by AhR/CYP1A1

“…Previously, frequent expression of ZNF165 has been reported in various cells [ 3 , 5 , 6 , 8 , 9 ]. The ZNF165, by directly inactivating the expression of negative feedback pathway regulators: SMURF2 [ 13 ], SMAD7 [ 14 ], and PMEPA1 [ 15 ], promotes the unrestrained activation of transforming growth factor β (TGF β ) signaling, which is required for the survival of triple-negative breast cancer cells in vitro and in vivo [ 7 , 8 ]. In this study, possible downstream pathways and factors that might be affected by ZNF165 were first analyzed; the tryptophan signaling pathway factors particularly CYP1A1 were downregulated after knocking down ZNF165 in HCC cells.…”

The Role of TGF-β/SMAD Signaling in Hepatocellular Carcinoma: from Mechanism to Therapy and Prognosis

“…SMAD2/3 are two important downstream genes of the TGF-β signaling pathway that are associated with liver fibrosis and carcinogenesis 66 . The phosphorylation of SMAD2/3 different domains results in different effects in normal and cancer cells.…”