Abstract
BackgroundONO-1301 is a novel long-lasting prostaglandin (PG) I2 mimetic with inhibitory activity on thromboxane (TX) A2 synthase. This drug can also induce endogenous prostaglandin (PG)I2 and PGE2 levels. Furthermore, ONO-1301 acts as a cytokine inducer and can initiate tissue repair in a variety of diseases, such as pulmonary hypertension, pulmonary fibrosis, cardiac infarction, and obstructive nephropathy. In this study, our aim was to evaluate the effect of ONO-1301 on liver inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH).MethodsThe therapeutic effects of ONO-1301 against liver damage, fibrosis, and occurrence of liver tumors were evaluated using melanocortin 4 receptor-deficient (Mc4r-KO) NASH model mice. The effects of ONO-1301 against macrophages, hepatic stellate cells, and endothelial cells were also evaluated in vitro.ResultsONO-1301 ameliorated liver damage and fibrosis progression, was effective regardless of NASH status, and suppressed the occurrence of liver tumors in Mc4r-KO NASH model mice. In the in vitro study, ONO-1301 suppressed LPS-induced inflammatory responses in cultured macrophages, suppressed hepatic stellate cell (HSC) activation, upregulated vascular endothelial growth factor (VEGF) expression in HSCs, and upregulated hepatocyte growth factor (HGF) and VEGF expression in endothelial cells.ConclusionsThe results of our study highlight the potential of ONO-1301 to reverse the progression and prevent the occurrence of liver tumors in NASH using in vivo and in vitro models. ONO-1301 is a multidirectional drug that can play a key role in various pathways and can be further analyzed for use as a new drug candidate against NASH.
Highlights
ONO-1301 is a novel long-lasting prostaglandin (PG) I2 mimetic with inhibitory activity on thromboxane (TX) A2 synthase
ONO-1301 ameliorates liver damage and fibrosis progression in non-alcoholic steatohepatitis (NASH) model mice To evaluate the therapeutic effects of ONO-1301, it was mixed into mice feed and administered to Mc4r-KO NASH model mice from 8 weeks after birth (ONO group)
Evaluation of fibrosis demonstrated that the Sirius Red stained area (Ctl group: 3.10% ± 2.59%, ONO group: 1.12% ± 1.01%, p < 0.0001; Fig. 1c) and hydroxyproline levels (Ctl group: 5.61 ± 1.15 nmol/mg, ONO group: 4.71 ± 0.86 nmol/mg, p = 0.0008; Fig. 1d) were significantly decreased in the ONO-1301 feeding group compared to those in the control group
Summary
ONO-1301 is a novel long-lasting prostaglandin (PG) I2 mimetic with inhibitory activity on thromboxane (TX) A2 synthase. This drug can induce endogenous prostaglandin (PG)I2 and PGE2 levels. Our aim was to evaluate the effect of ONO-1301 on liver inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH). Non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are among the most important causes of chronic liver disease and cirrhosis, mainly in South America and the Middle East, followed by the rest of Asia, the USA, and Europe. To evaluate the effects of cell therapy and drugs in NASH, appropriate animal models that reflect symptoms in humans, such as obesity, insulin resistance, and liver steatosis, are needed
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
