The Combination of Sinusoidal Perfusion Enhancement and Apoptosis Inhibition by Riociguat Plus a Galactose-PEGylated Bilirubin Multiplexing Nanomedicine Ameliorates Liver Fibrosis Progression

by Selleckchem | Jul 27 2023

Chronic liver injury and continuous wound healing lead to extracellular matrix (ECM) deposition and liver fibrosis. The elevated production of reactive oxygen species (ROS) in the liver leads to the apoptosis of hepatocytes and the activation of hepatic stellate cells (HSCs). In the current study, we describe a combination strategy of sinusoidal perfusion enhancement and apoptosis inhibition enabled by riociguat together with a tailor-designed galactose-PEGylated bilirubin nanomedicine (Sel@GBRNPs). Riociguat enhanced sinusoidal perfusion and decreased the associated ROS accumulation and inflammatory state of the fibrotic liver. Concurrently, hepatocyte-targeting galactose-PEGylated bilirubin scavenged excessive ROS and released encapsulated selonsertib. The released selonsertib inhibited apoptosis signal-regulating kinase 1 (ASK1) phosphorylation to alleviate apoptosis in hepatocytes. The combined effects on ROS and hepatocyte apoptosis attenuated the stimulation of HSC activation and ECM deposition in a mouse model of liver fibrosis. This work provides a novel strategy for liver fibrosis treatment based on sinusoidal perfusion enhancement and apoptosis inhibition.

Comments:

The study you described focuses on developing a combination strategy for the treatment of liver fibrosis. Chronic liver injury and continuous wound healing can result in liver fibrosis, characterized by excessive deposition of extracellular matrix (ECM). The process involves the production of reactive oxygen species (ROS), which leads to hepatocyte apoptosis and activation of hepatic stellate cells (HSCs).

The researchers employed two key components in their strategy: riociguat and a galactose-PEGylated bilirubin nanomedicine (Sel@GBRNPs). Riociguat is known to enhance sinusoidal perfusion, which refers to the blood flow within the liver's sinusoids. By improving perfusion, riociguat helps to reduce ROS accumulation and alleviate the inflammatory state associated with liver fibrosis.

The nanomedicine, Sel@GBRNPs, was specifically designed to target hepatocytes. It consists of galactose-PEGylated bilirubin, which serves as a scavenger of excessive ROS. Additionally, the nanomedicine encapsulates selonsertib, a drug that inhibits apoptosis signal-regulating kinase 1 (ASK1) phosphorylation. By releasing selonsertib within hepatocytes, the nanomedicine aims to prevent apoptosis and promote cell survival.

In the mouse model of liver fibrosis used in the study, the combined effects of riociguat and Sel@GBRNPs were observed. The enhanced sinusoidal perfusion, along with the scavenging of ROS and inhibition of hepatocyte apoptosis, resulted in reduced stimulation of HSC activation and ECM deposition. These findings suggest that the combination strategy has the potential to attenuate liver fibrosis.

Overall, this study presents a novel approach for the treatment of liver fibrosis by targeting multiple aspects of the disease, including sinusoidal perfusion, ROS accumulation, apoptosis, HSC activation, and ECM deposition. However, it's important to note that this description is based on the information provided, and further research and clinical trials would be needed to validate the effectiveness and safety of this strategy in human patients.