Neoagarooligosaccharide Protects against Hepatic Fibrosis via Inhibition of TGF-β/Smad Signaling Pathway

Abstract

Hepatic fibrosis occurs when liver tissue becomes scarred from repetitive liver injury and inflammatory responses; it can progress to cirrhosis and eventually to hepatocellular carcinoma. Previously, we reported that neoagarooligosaccharides (NAOs), produced by the hydrolysis of agar by β-agarases, have hepatoprotective effects against acetaminophen overdose-induced acute liver injury. However, the effect of NAOs on chronic liver injury, including hepatic fibrosis, has not yet been elucidated. Therefore, we examined whether NAOs protect against fibrogenesis in vitro and in vivo. NAOs ameliorated PAI-1, -SMA, CTGF and fibronectin protein expression and decreased mRNA levels of fibrogenic genes in TGF-β-treated LX-2 cells. Furthermore, downstream of TGF-β, the Smad signaling pathway was inhibited by NAOs in LX-2 cells. Treatment with NAOs diminished the severity of hepatic injury, as evidenced by reduction in serum alanine aminotransferase and aspartate aminotransferase levels, in carbon tetrachloride (CCl4)-induced liver fibrosis mouse models. Moreover, NAOs markedly blocked histopathological changes and collagen accumulation, as shown by H&E and Sirius red staining, respectively. Finally, NAOs antagonized the CCl4-induced upregulation of the protein and mRNA levels of fibrogenic genes in the liver. In conclusion, our findings suggest that NAOs may be a promising candidate for the prevention and treatment of chronic liver injury via inhibition of the TGF-β/Smad signaling pathway.

Knocking out Fkbp51 decreases CCl4-induced liver injury through enhancement of mitochondrial function and Parkin activity

“…Male 8-week-old WT and Fkbp51 KO mice were randomly assigned into either olive oil injection control or CCl 4 injection treatment groups. Modified protocol was followed from previous publication [ 35 , 86 ]; specifically, mice were injected intraperitoneally (IP) three times weekly for 2 weeks with olive oil (vehicle, sigma-aldrich, MO, USA) or carbon tetrachloride (CCl 4 , sigma-aldrich, MO, USA) diluted 1:9 in olive oil at a dose of 5 μl/g of body weight (BW). A schematic diagram illustrating the injection procedure can be found in Additional file 2 : Fig.…”

Elimination of FKBP51 attenuates CCl4-induced liver injury via enhancement of mitochondrial function by increased Parkin activity

“…Male 8-week-old WT and Fkbp51 KO mice were randomly assigned into either olive oil injection control or CCl 4 injection treatment groups. Modi ed protocol was followed from previous publication (Boonying et al, 2019;Yang et al, 2021); speci cally, mice were injected intraperitoneally (IP) three times weekly for two weeks with olive oil (vehicle, sigma-aldrich, MO, USA) or carbon tetrachloride (CCl 4 , sigma-aldrich, MO, USA) diluted 1:9 in olive oil at a dose of 0.5 μl/g of body weight (BW). Mice were sacri ced 48 h after the last injection.…”

FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner

“…It is mainly provoked by hepatic stresses including viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), iron overload syndrome, hereditary haemochromatosis, and diabetes mellitus [2] , [3] . With persistent deterioration of liver fibrosis, chronic liver failure, cirrhosis, and hepatocellular carcinoma ensue, imposing a major threat for human health although little effective treatment remedy is readily available for patients with advanced liver fibrosis beyond liver transplantation due to its poorly defined underlying mechanism(s) [4] , [5] . In this context, it is imperative to seek novel antifibrotic therapeutic options to retard and prevent the onset and progression of liver fibrosis.…”