Abstract
Dangguiliuhuang decoction (DGLHD) has been demonstrated to be effective in treating inflammatory, hepatic steatosis, and insulin resistance. In the study, we tried to elucidate the pharmacological efficacy and mechanism of DGLHD against liver fibrosis and predicate potential active ingredients and targets via network analysis and experimental validation. In the formula, we totally discovered 76 potential active ingredients like baicalein, berberine, and wogonin, and 286 corresponding targets including PTGS (prostaglandin-endoperoxide synthase) 2, PPAR (peroxisome proliferator-activated receptors) -γ, and NF-κB (nuclear factor-κB). Pathway and functional enrichment analysis of these putative targets indicated that DGLHD obviously influenced NF-κB and PPAR signaling pathway. Consistently, DGLHD downregulated levels of ALT (alanine transaminase) and AST (aspartate transaminase), reduced production of proinflammatory cytokines-TNF (tumor necrosis factor) -α and IL (Interleukin) -1β in serum and liver from mice with hepatic fibrosis, and inhibited hepatic stellate cell (HSC)-T6 cells proliferation. DGLHD decreased TGF (transforming growth factor) -β1 and α-SMA (smooth muscle actin) expression as well, maintained MMP (matrix metalloprotein) 13-TIMP (tissue inhibitor of metalloproteinases) 1 balance, leading to mitigated ECM (extracellular matrix) deposition in vivo and in vitro. Moreover, our experimental data confirmed that the alleviated inflammation and ECM accumulation were pertinent to NF-κB inhibition and PPAR-γ activation. Overall, our results suggest that DGLHD aims at multiply targets and impedes the progression of hepatic fibrosis by ameliorating abnormal inflammation and ECM deposition, thereby serving as a novel regimen for treating hepatic fibrosis in clinic.
Highlights
Hepatic fibrosis is well recognized as a wound-healing response that occurs in liver following any type of acute or chronic injury, which is characterized by excessive accumulation of extracellular matrix (ECM) caused by both increased synthesis and deposition of newly formed components, and decreased or unbalanced degradation of ECM (Liu et al, 2006; Friedman, 2015)
For the primary herbs – AG, radix rehmanniae (RR), rehmanniae praeparata (RRP): AG is obviously distinguished from RR and RRP at the six aspects while the values of oral bioavailability (OB), DL, and MLogP in RR and RRP are similar; For the ministerial herbs – golden cypress (GC), coptis chinensis (CC), scutellaria baicalensis (SB): the molecular characteristics of GC is alike with CC or SB, whereas CC is differ from SB in the aspects of molecular weight (MW), MLogP, HAcc, and DL
As described above in the methods section, we discovered 76 potential active compounds in Dangguiliuhuang decoction (DGLHD) after deleting redundancy (Supplementary Table 5), such as baicalein, berberine, quercetin, wogonin, and catapol, which was in line with our prior studies that these compounds are the major agents of DGLHD playing anti-inflammatory, immunosuppressive, anti-steatotic and anti-diabetic effects (Cao et al, 2017)
Summary
Hepatic fibrosis is well recognized as a wound-healing response that occurs in liver following any type of acute or chronic injury, which is characterized by excessive accumulation of extracellular matrix (ECM) caused by both increased synthesis and deposition of newly formed components, and decreased or unbalanced degradation of ECM (Liu et al, 2006; Friedman, 2015). A limitation of the current antifibrotic approaches is that they are inefficiently taken up by activated hepatic stellate cells (HSCs) and may produce unwanted side effects, such as liver toxicity and promoting cancer development (Bataller and Brenner, 2005). There are many TCM-based formulas and extracts of herbs that have been proved to be effective for alleviating liver fibrosis by suppressing inflammation, enhancing ECM degradation, and inhibiting HSCs activation, such as silymarin, emodin, tetrandrine, and ginkgo biloba extract (Xu and Lin, 2008; Federico et al, 2017)
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