Liver fibrosis, which means a sort of the excessive accumulation of extracellular matrices (ECMs) components through the liver tissue, is considered as tissue repair or wound-healing status. This pathological stage potentially leads to cirrhosis, if not controlled, it progressively results in hepatocellular carcinoma. Herein, we investigated the pharmacological properties and underlying mechanisms of Gardeniae Fructus (GF) against thioacetamide (TAA)-induced liver fibrosis of mice model. GF not only attenuated hepatic tissue oxidation but also improved hepatic inflammation. We further confirmed that GF led to ameliorating liver fibrosis by ECMs degradations. Regarding the possible underlying mechanism of GF, we observed GF regulated epigenetic regulator, Sirtuin 1 (SIRT1), in TAA-injected liver tissue. These alterations were well supported by SIRT1 related signaling pathways through regulations of its downstream proteins including, AMP-activated protein kinase (AMPK), p47phox, NADPH oxidase 2, nuclear factor erythroid 2–related factor 2 (Nrf2), and heme oxygenase-1, respectively. To validate the possible mechanism of GF, we used HepG2 cells with hydrogen peroxide treated oxidative stress and chronic exposure conditions via deteriorations of cellular SIRT1. Moreover, GF remarkably attenuated ECMs accumulations in transforming growth factor–β1-induced LX-2 cells relying on the SIRT1 existence. Taken together, GF attenuated liver fibrosis through AMPK/SIRT1 pathway as well as Nrf2 signaling cascades. Therefore, GF could be a clinical remedy for liver fibrosis patients in the future.
Gardeniae Fructus (GF, the dried ripe fruits of Gardenia jasminoides Ellis) has traditionally been used to treat various diseases in East Asian countries, such as liver disease. Silymarin is a well-known medicine used to treat numerous liver diseases globally. The present study was purposed to evaluate the synergistic effects of GF and silymarin on the thioacetamide (TAA)-induced liver fibrosis of a mouse model. Mice were orally administered with distilled water, GF (100 mg/kg, GF 100), silymarin (100 mg/kg, Sily 100), and GF and silymarin mixtures (50 and 100 mg/kg, GS 50 and 100). The GS group showed remarkable amelioration of liver injury in the serum levels and histopathology by observing the inflamed cell infiltrations and decreases in necrotic bodies through the liver tissue. TAA caused liver tissue oxidation, which was evidenced by the abnormal statuses of lipid peroxidation and deteriorations in the total glutathione in the hepatic protein levels; moreover, the immunohistochemistry supported the increases in the positive signals against 4-hydroxyneal and 8-OHdG through the liver tissue. These alterations corresponded well to hepatic inflammation by an increase in F4/80 positive cells and increases in pro-inflammatory cytokines in the hepatic protein levels; however, administration with GS, especially the high dose group, not only remarkably reduced oxidative stress and DNA damage in the liver cells but also considerably diminished pro-inflammatory cytokines, which were driven by Kupffer cell activations, as compared with each of the single treatment groups. The pharmacological properties of GS prolonged liver fibrosis by the amelioration of hepatic stellate cells’ (HSCs’) activation that is dominantly expressed by huge extracellular matrix (ECM) molecules including α-smooth muscle actin, and collagen type1 and 3, respectively. We further figured out that GS ameliorated HSCs activated by the regulation of Sirtuin 1 (Sirt1) activities in the hepatic protein levels, and this finding excellently reenacted the transforming growth factor-β-treated LX-2-cells-induced cell death signals depending on the Sirt1 activities. Future studies need to reveal the pharmacological roles of GS on the specific cell types during the liver fibrosis condition.
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