Dissect the Anti- Fibrotic Efficacy and Its Microenvironment as Well as Associated Molecular Mechanisms of Sho-Saiko-To

Hepatic fibrosis is a wound-healing response to prolonged liver injury while untreated or uncontrolled fibrosis may progress to liver cirrhosis/hepatoma ultimately leading to organ failure and death. However, the current medicine for clinical treatment of hepatic fibrosis has been hindered by the limitation to confirm the efficacy and mechanisms of antifibrotic agents as well as the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of liver fibrosis progression in patients. Particularly, the assessment of hepatic fibrosis provides much information, not only for the diagnosis and prognosis of disease, but also for the therapeutic decision under treatment. In addition, most of therapeutic drugs for liver fibrosis appear to be effective only if given as a prophylactic or early treatment. Therefore, early diagnosis of liver fibrosis improves prognosis and survival. Moreover, critical to the progression of hepatic fibrosis, are the complex interactions between the hepatocytes and non-parenchymal cells including liver sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells (HSCs). Several inflammatory factors can stimulate HSCs, which in turn enhance secretion of large amounts of extra-cellular matrix (ECM) protein and continue the progression of liver fibrosis. Thus, study on cellular microenvironment would be helpful in removal of the aetiological agents and effective therapies that result in significant regression of hepatic fibrosis. Nowadays, lots of Chinese herbal formulae have been reported to exhibit therapeutic or protective functions against hepatic diseases. Of note, Sho-saiko-to is wildly used to relieve fever, pain and detoxify. It is also effective to modulate immune responses. Meanwhile, Sho-saiko-to has long been used as an important remedy in several to clinically treat chronic hepatic hepatitis and cirrhosis. Taken together, we attempt to reveal the efficacy, cellular microenvironment and molecular mechanisms associated with Sho-saiko-to-mediated reversal of liver fibrosis in proper cellular and rodent models with functional proteomic and bioinformatic tools. This proposal will especially address the specific goals as follows: 1. To systematically screen the active components derived from Sho-saiko-to for anti-liver fibrosis with in vitro model. 2. To establish the hepatic fibrosis rodent models induced by thioacetamide (TAA) and Pig serum (PS). Given the effective extracts of Sho-saiko-to and collect the plasma/liver samples at specific stages. 3. To characterize the differential protein profiles from plasma and liver tissues among the various stages during the progress of liver fibrosis with different treatments by proteome and microRNA analytic systems to expose the possible biomakers as well as the signaling pathways for fibrosis/antifibrosis. 4. To set up a cell co-culture systems and collect samples for microenvironment study upon interaction of molecules and secretion of exosomes. 5. To further confirm the potential markers and reveal the antifibrotic efficacy as well as the mechanisms of Sho-saiko-to with animal and cellular biology experiments. 6. Targeted therapy: molecular targets or pathways involved in antifibrosis. Bioinformatics will be applied to develop and improve in the targeted delivery to relevant liver cells. 7. Development of diagnostic and prognostic panel for translational medicine. The findings of this project not only provide solid evidence in therapy of liver fibrosis with traditional Chinese herbal formulae but also help to develop non-invasive liver fibrosis/ anti-fibrosis biomarkers, which will contribute to the clinical applications in diagnosis and treatment of hepatic fibrosis in future.

Project ID:PC10601-0588
External Project ID:MOST105-2320-B182-007-MY3