The Combination of Sinusoidal Perfusion Enhancement and Apoptosis Inhibition by Riociguat Plus a Galactose-PEGylated Bilirubin Multiplexing Nanomedicine Ameliorates Liver Fibrosis Progression.
Fenfen LiZhaoxia ChengJingyi SunXiaoyu ChengChen LiZhouliang WuFeilong QiYing ZhaoGuangjun NiePublished in: Nano letters (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.
Keyphrases
- liver fibrosis
- cell cycle arrest
- cell death
- oxidative stress
- endoplasmic reticulum stress
- liver injury
- reactive oxygen species
- extracellular matrix
- drug induced
- induced apoptosis
- mouse model
- dna damage
- pi k akt
- pulmonary hypertension
- cancer therapy
- contrast enhanced
- wound healing
- physical activity
- body mass index
- replacement therapy