Chinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats via inhibiting MMP2/9, TIMP1/2 and the TGF-β/Smad signaling pathways

Environmental Toxicology

et al. 2019

Nickel oxide nanoparticles (Nano NiO) bears hepatotoxicity, while whether it leads to liver fibrosis remains unclear. The aim of this study was to establish the Nano NiO‐induced hepatic fibrosis model in vivo and investigate the roles of transforming growth factor β1 (TGF‐β1) in Smad pathway activation, epithelial‐mesenchymal transition (EMT) occurrence, and extracellular matrix (ECM) deposition in vitro. Male Wistar rats were exposed to 0.015, 0.06, and 0.24 mg/kg Nano NiO by intratracheal instilling twice a week for 9 weeks. HepG2 cells were treated with 100 μg/mL Nano NiO and TGF‐β1 inhibitor (SB431542) to explore the mechanism of collagen formation. Results of Masson staining as well as the elevated levels of type I collagen (Col‐I) and Col‐III suggested that Nano NiO resulted in hepatic fibrosis in rats. Furthermore, Nano NiO increased the protein expression of TGF‐β1, p‐Smad2, p‐Smad3, alpha‐smooth muscle actin (α‐SMA), matrix metalloproteinase9 (MMP9), and tissue inhibitors of metalloproteinase1 (TIMP1), while decreased the protein content of E‐cadherin and Smad7 in rat liver and HepG2 cells. Most importantly, Nano NiO‐triggered the abnormal expression of the abovementioned proteins were all alleviated by co‐treatment with SB431542, implying that TGF‐β1‐mediated Smad pathway, EMT and MMP9/TIMP1 imbalance were involved in overproduction of collagen in HepG2 cells. In conclusion, these findings indicated that Nano NiO induced hepatic fibrosis via TGF‐β1‐mediated Smad pathway activation, EMT occurrence, and ECM deposition.

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Nano Nio On Tgf-β1 Smad Pathway Emt and Mmp9mentioning

confidence: 99%

TGF‐β1 mediated Smad signaling pathway and EMT in hepatic fibrosis induced by Nano NiO in vivo and in vitro

Zhang

Chang

Environmental Toxicology

et al. 2019

“…MMP2 is important in the formation of hepatic fibrosis, degrading certain kinds of extra cellular matrix (ECM) such as collagens and proteoglycans. Downregulation of MMP2 expression and the TGF-β1/Smad signaling pathways can relieve liver fibrosis in rats [44]. MMP2 activity is also critical for TGFβ2-induced matrix contraction, which may promote fibrosis in vitro [45].…”

Section: Discussionmentioning

confidence: 99%

“…The integrative efficacy of the ingredients in Danshen was determined by analyzing the compounds and targets interactions obtained from the Search Tool for Interactions of Chemicals and Proteins (STITCH) database(Available online: ) [44], HIT (Herbal Ingredients’ Targets) Database (Available online: ) [45] and omics-based Ligand-Target Chemogenomic model (LTC) [46], respectively. Then, for better defining the role of Danshen in hepatoprotective potentials, these targets were mapped to the Therapeutic Target Database (TTD, Available online: ) [47], PharmGKB (Available online: ) [48], and the Comparative Toxicogenomics Database (CTD, Available online: ) [49] to eliminate the unrelated target protein and provide a more complete and accuracy view on compound-hepatoprotective target associations.…”

Section: Methodsmentioning

confidence: 99%

A Biomedical Investigation of the Hepatoprotective Effect of Radix salviae miltiorrhizae and Network Pharmacology-Based Prediction of the Active Compounds and Molecular Targets

Hong

et al. 2017

IJMS

Radix salviae miltiorrhizae (Danshen in Chinese), a classic traditional Chinese medicine (TCM) herb, has been used for centuries to treat liver diseases. In this study, the preventive and curative potential of Danshen aqueous extract on acute/chronic alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) was studied. The in vivo results indicated that Danshen could alleviate hepatic inflammation, fatty degeneration, and haptic fibrogenesis in ALD and NAFLD models. In the aspect of mechanism of action, the significant reduction in MDA levels in both ALD and NAFLD models implies the decreased levels of oxidative stress by Danshen. However, Danshen treatment could not activate the internal enzymatic antioxidant system in ALD and NAFLD models. To further explore the hepatoprotective mechanism of Danshen, an in silico-based network pharmacology approach was employed in the present study. The pharmacological network analysis result revealed that six potential active ingredients such as tanshinone iia, salvianolic acid b, and Danshensu may contribute to the hepatoprotective effects of Danshen on ALD and NAFLD. The action mechanism may relate with regulating the intracellular molecular targets such as PPARα, CYP1A2, and MMP2 for regulation of lipid metabolism, antioxidant and anti-fibrogenesis by these potential active ingredients. Our studies suggest that the combination of network pharmacology strategy with in vivo experimental study may provide a forceful tool for exploring the mechanism of action of traditional Chinese medicine (TCM) herb and developing novel bioactive ingredients.

“…MMP9 is a multifunctional protein, including mediating leukocyte traffic in hepatic ischemia and reperfusion injury[26], aggravating drug associated acute liver injury[27], regulating hepatic regeneration[28] and liver fibrosis[29]. It has been reported that MMP9 expression is observed in the early stages of liver fibrogenesis and MMP9 could activated latent transforming growth factor beta, a major profibrotic cytokine[30]. Ehling et al .…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Promotes Hepatic Stellate Cells Migration via Canonical NF-κB/MMP9 Pathway

Zhang

et al. 2016

PLoS ONE

In the liver, the signal and function of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) have mainly been assessed in association with liver regeneration.However, the effects of TWEAK on liver fibrosis have not been fully elucidated. To investigate the effects of TWEAK on human hepatic stellate cells (HSCs) and to explore the relevant potential mechanisms, human HSCs line—LX-2 were cultured with TWEAK. Cell migration was detected by transwell assay; cell viability was evaluated by Cell Counting Kit-8; the expression of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13 gene was identified by quantitative real-time polymerase chain reaction and western blotting; the activity of matrix metalloproteinases (MMPs) was tested by enzyme-linked immuno sorbent assay; small interfering RNA transfection was applied for depletion of MMP9 and p65. The result of transwell assay revealed that TWEAK promoted LX-2 migration. Subsequently, our data testified that the expression and activity of MMP9 was induced by TWEAK in LX-2 cells, which enhanced the migration. Furthermore, our findings showed that TWEAK upregulated the phosphorylation of IκBα and p65 protein to increase MMP9 expression in LX-2 cells. Meanwhile, the alpha-smooth muscle actin, vimentin and desmin expression were upregulated following TWEAK treatment. The results in the present study revealed that TWEAK promotes HSCs migration via canonical NF-κB/MMP9 pathway, which possibly provides a molecular basis targeting TWEAK for the therapy of liver fibrosis.