Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Naples, Italy.
Gastroenterology Unit, Department of Clinical Medicine and Surgery, School of Medicine, Federico II University, Naples, Italy.
Oxid Med Cell Longev. 2018 Dec 17;2018:5045734. doi: 10.1155/2018/5045734. eCollection 2018.
Liver fibrosis is a complex process caused by chronic hepatic injury, which leads to an excessive increase in extracellular matrix protein accumulation and fibrogenesis. Several natural products, including sulfur-containing compounds, have been investigated for their antifibrotic effects; however, the molecular mechanisms underpinning their action are partially still obscure. In this study, we have investigated for the first time the effect of ovothiol A, -methyl-5-thiohistidine, isolated from sea urchin eggs on an murine model of liver fibrosis. Mice were intraperitoneally injected with carbon tetrachloride (CCl) to induce liver fibrosis and treated with ovothiol A at the dose of 50 mg/kg 3 times a week for 2 months. Treatment with ovothiol A caused a significant reduction of collagen fibers as observed by histopathological changes and serum parameters compared to mice treated with control solution. This antifibrotic effect was associated to the decrease of fibrogenic markers involved in liver fibrosis progression, such as the transforming growth factor (TGF-), the -smooth muscle actin (α-SMA), and the tissue metalloproteinases inhibitor (TIMP-1). Finally, we provided evidence that the attenuation of liver fibrosis by ovothiol A treatment can be regulated by the expression and activity of the membrane-bound -glutamyl-transpeptidase (GGT), which is a key player in maintaining intracellular redox homoeostasis. Overall, these findings indicate that ovothiol A has significant antifibrotic properties and can be considered as a new marine drug or dietary supplement in potential therapeutic strategies for the treatment of liver fibrosis.
肝纤维化是由慢性肝损伤引起的一种复杂过程，导致细胞外基质蛋白积累和纤维发生过度增加。已经研究了几种天然产物，包括含硫化合物，以研究其抗纤维化作用；然而，其作用的分子机制部分仍不清楚。在这项研究中，我们首次研究了从海胆卵中分离出的卵硫醇 A 和 -甲基-5-硫代组氨酸对肝纤维化的小鼠模型的影响。通过腹腔注射四氯化碳（CCl）诱导肝纤维化，并用卵硫醇 A 以 50mg/kg 的剂量每周 3 次处理 2 个月。与用对照溶液处理的小鼠相比，卵硫醇 A 处理导致胶原纤维的明显减少，如组织病理学变化和血清参数所示。这种抗纤维化作用与肝纤维化进展中涉及的纤维生成标志物的减少有关，如转化生长因子 (TGF-)、-平滑肌肌动蛋白 (α-SMA) 和组织金属蛋白酶抑制剂 (TIMP-1)。最后，我们提供了证据表明，卵硫醇 A 治疗可以通过膜结合的 -谷氨酰转肽酶 (GGT) 的表达和活性来调节，GGT 是维持细胞内氧化还原平衡的关键因素。总体而言，这些发现表明卵硫醇 A 具有显著的抗纤维化特性，可被视为治疗肝纤维化的潜在治疗策略中的新型海洋药物或膳食补充剂。
