Polat Beyzagul, Halici Zekai, Cadirci Elif, Karakus Emre, Bayir Yasin, Albayrak Abdulmecit, Unal Deniz
Ataturk University, Faculty of Pharmacy, Department of Pharmacology, 25240 Erzurum, Turkey.
Ataturk University, Faculty of Medicine, Department of Pharmacology, 25240 Erzurum, Turkey.
Int Immunopharmacol. 2017 Feb;43:227-235. doi: 10.1016/j.intimp.2016.12.023. Epub 2016 Dec 30.
Hepatocellular cancer (HCC) is the sixth most common cancer and liver fibrosis is strongly associated with HCC. Treatment options are limited, and preventive strategies should be developed. An important step in the beginning of liver fibrosis is a strong inflammatory response. 5-HT7 is the last recognized member of the serotonin receptor family and is expressed in both central nerve system and peripheral system and have a lot of functions like learning, memory, smooth muscular relaxation, in the control of circadian rhythms and thermoregulation, pain and migraine, schizophrenia, anxiety, cognitive disturbances, and even inflammation.
We therefore examined the biochemical, histopathological and molecular effects of the 5-HT7 receptor agonist and antagonist on inflammatory liver fibrogenesis in animal models of progressive cirrhosis: a mouse model induced by carbon tetrachloride (CCl4) and in Hep3b cells.
5-HT7 expression was observed in the liver in vivo and in vitro in CCl4-induced damage. 5-HT7 receptor agonist but not the antagonist reduced liver markers in mice and in Hep3b cells in carbon tetrachloride (CCl4) induced damage. 5-HT7 agonist, but not antagonist, protected liver tissue from oxidative stress in fibrosis. 5-HT7 agonist but not antagonist induces anti-inflammatory, anti-fibrinotic and anti-cytokine features in liver fibrosis in vivo and in vitro.
5-HT7 receptors have modulatory function and are an up-and-coming pharmacological target in the inflammatory fibrotic process. 5-HT7 receptor agonist LP-44 showed significant hepatoprotective effects against liver fibrosis, and LP-44 might become a useful therapeutic target for chronic liver inflammation and fibrosis.
肝细胞癌（HCC）是第六大常见癌症，肝纤维化与HCC密切相关。治疗选择有限，因此应制定预防策略。肝纤维化起始的一个重要步骤是强烈的炎症反应。5-HT7是血清素受体家族中最后被确认的成员，在中枢神经系统和外周系统均有表达，具有多种功能，如学习、记忆、平滑肌舒张、昼夜节律和体温调节控制、疼痛与偏头痛、精神分裂症、焦虑、认知障碍，甚至炎症反应。
因此，我们在进行性肝硬化动物模型（四氯化碳（CCl4）诱导的小鼠模型）和Hep3b细胞中，研究了5-HT7受体激动剂和拮抗剂对炎症性肝纤维化形成的生化、组织病理学和分子效应。
在体内和体外CCl4诱导损伤的肝脏中均观察到5-HT7表达。在四氯化碳（CCl4）诱导损伤的小鼠和Hep3b细胞中，5-HT7受体激动剂而非拮抗剂降低了肝脏标志物水平。5-HT7激动剂而非拮抗剂在纤维化过程中保护肝脏组织免受氧化应激。5-HT7激动剂而非拮抗剂在体内和体外肝纤维化中诱导抗炎、抗纤维化和抗细胞因子特性。
5-HT7受体具有调节功能，是炎症性纤维化过程中一个新兴的药理学靶点。5-HT7受体激动剂LP-44对肝纤维化显示出显著的肝保护作用，LP-44可能成为慢性肝脏炎症和纤维化的一个有用治疗靶点。
