Motegi Satoko, Tsuchiya Atsunori, Iwasawa Takahiro, Sato Takeki, Kumagai Masaru, Natsui Kazuki, Nojiri Shunsuke, Ogawa Masahiro, Takeuchi Suguru, Sakai Yosiki, Miyagawa Shigeru, Sawa Yoshiki, Terai Shuji
Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan.
Inflamm Regen. 2022 Feb 1;42(1):3. doi: 10.1186/s41232-021-00191-6.
ONO-1301 is a novel long-lasting prostaglandin (PG) I mimetic with inhibitory activity on thromboxane (TX) A 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).
The 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.
ONO-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.
The 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.
ONO - 1301是一种新型长效前列腺素（PG）I模拟物，对血栓素（TX）A合酶具有抑制活性。该药物还可诱导内源性前列腺素（PG）I2和PGE2水平。此外，ONO - 1301作为一种细胞因子诱导剂，可在多种疾病中启动组织修复，如肺动脉高压、肺纤维化、心肌梗死和梗阻性肾病。在本研究中，我们的目的是评估ONO - 1301在非酒精性脂肪性肝炎（NASH）小鼠模型中对肝脏炎症和纤维化的影响。
使用促黑素皮质素4受体缺陷（Mc4r - KO）NASH模型小鼠评估ONO - 1301对肝损伤、纤维化和肝肿瘤发生的治疗效果。还在体外评估了ONO - 1301对巨噬细胞、肝星状细胞和内皮细胞的作用。
ONO - 1301改善了肝损伤和纤维化进展，无论NASH状态如何均有效，并抑制了Mc4r - KO NASH模型小鼠肝肿瘤的发生。在体外研究中，ONO - 1301抑制培养巨噬细胞中脂多糖诱导的炎症反应，抑制肝星状细胞（HSC）活化，上调HSC中血管内皮生长因子（VEGF）表达，并上调内皮细胞中肝细胞生长因子（HGF）和VEGF表达。
我们的研究结果突出了ONO - 1301在体内和体外模型中逆转NASH进展并预防肝肿瘤发生的潜力。ONO - 1301是一种多向性药物，可在多种途径中发挥关键作用，可进一步分析用作抗NASH的新药候选物。
