Dynamic Changes in MMP1 and TIMP1 in the Antifibrotic Process of Dahuang Zhechong Pill in Rats with Liver Fibrosis

Abstract

On the basis of carbon tetrachloride (CCl4)induced liver fibrosis in rats, this study aims to investigate the dynamic changes in matrix metalloproteinase 1 (MMP1) and the tissue inhibitor of metalloproteinase 1 (TIMP1) in the antifibrotic process of Dahuang Zhechong Pill (DHZCP). A total of 50 male Sprague Dawley rats, aged 8 weeks, were randomly divided into 3 groups: the control group, the model group (the group treated with CCl4), and the treatment group (the group treated with CCl4 and DHZCP). Rats were sacrificed at Weeks 4 and 8. Liver tissues were separated for RNA sequencing and bioinformatics analysis. Real-time PCR, Western blot analysis, and histological staining were conducted to confirm the gene expression and pathological change in liver tissues. Compared with control group, rats in model group showed poor mental state and slow weight gain. The liver tissues of the rats in the model group exhibited a damaged hepatic lobule structure, fibrous connective tissue hyperplasia, and inflammatory cell infiltration among the hyperplastic tissues. DHZCP could significantly improve the appearance of rats and alleviate CCl4-induced fibrosis. Compared to model group, 798 differentially expressed mRNAs were found in the treatment group, of which 120 were up-regulated and 678 were down-regulated. Differentially expressed mRNAs between the CCl4-induced group and the DHZCP-treated group were mainly focused on the following KEGG pathways: focal adhesion, phagosome, tight junction, and ECM–receptor interactions. Relative to those in the control group, MMP1 was downregulated, whereas, TIMP1 and Col1A1 were upregulated in the CCl4-induced group at Weeks 4 and 8. DHZCP could reverse MMP1, TIMP1, and Col1A1 expression.DHZCP protects against liver injury and exerts an antifibrotic effect on liver fibrosis induced by CCl4 in rats. Its mechanism may be related to the upregulation of MMP1, downregulation of TIMP1, and promotion of collagen degradation.

Complexation with Random Methyl-β-Cyclodextrin and (2-Hidroxypropyl)-β-Cyclodextrin Enhances In Vivo Anti-Fibrotic and Anti-Inflammatory Effects of Chrysin via the Inhibition of NF-κB and TGF-β1/Smad Signaling Pathways and Modulation of Hepatic Pro/Anti-Fibrotic miRNA

“…This study found that chrysin/cyclodextrin complexes were able to upregulate MMP-1 gene expression and further stimulate cleavage of the native fibrillar collagens, especially Col I, by regulating the ECM balance via TIMP-1/MMP-1 components. MMP-1 was downregulated in fibrotic livers, but was expressed again during the resolution process, and may act through ECM degradation as well, confirmed by previous findings [ 30 , 46 , 47 ].…”

Ameliorative Effect of Pomegranate Peel Extract (PPE) on Hepatotoxicity Prompted by Iron Oxide Nanoparticles (Fe2O3-NPs) in Mice

“…Additionally, PPE clearly plays a part in modifying this hepatotoxicity, even though it has several benefits. However, a number of studies [ 45 ] found that the size and quality of nanoparticles could have negative effects on biological systems. Different nanoparticles could produce free radicals and cause oxidative damage, which altered how cells functioned [ 27 ].…”

“…Their levels are increased during numerous liver diseases [ 46 ], although cells have a powerful antioxidant defense system to intercept ROS. However, if the biological systems fail to nullify the overwhelming ROS, they will lead to the oxidation of biomolecules such as proteins, lipids, and DNA [ 45 ]. In our study, it was found that Fe 2 O 3 -NPs induced significant hepatotoxic effects through the generation of ROS, as evidenced by a significant reduction in TAC activities, and these ROS might be detoxified by CAT and SOD by accelerating the decomposition of superoxide radicals into H 2 O 2 , which had been degraded into H 2 O and O 2 by CAT.…”