Latha Paka, David E Smith, Dawoon Jung, Siobhan McCormack, Ping Zhou, Bin Duan, Jing-Song Li, Jiaqi Shi, Yong-Jie Hao, Kai Jiang, Michael Yamin, Itzhak D Goldberg, Prakash Narayan, Department of Research and Development, Angion Biomedica Corp., Uniondale, NY 11553, United States.
World J Gastroenterol. 2017 Jun 21;23(23):4181-4190. doi: 10.3748/wjg.v23.i23.4181.
To evaluate a calcium activated potassium channel (KCa3.1) inhibitor attenuates liver disease in models of non-alcoholic fatty liver disease (NAFLD).
We have performed a series of and studies using the KCa3.1 channel inhibitor, Senicapoc. Efficacy studies of Senicapoc were conducted in toxin-, thioacetamide (TAA) and high fat diet (HFD)-induced models of liver fibrosis in rats. Efficacy and pharmacodynamic effects of Senicapoc was determined through biomarkers of apoptosis, inflammation, steatosis and fibrosis.
Upregulation of KCa3.1 expression was recorded in TAA-induced and high fat diet-induced liver disease. Treatment with Senicapoc decreased palmitic acid-driven HepG2 cell death. ( < 0.05 control) supporting the finding that Senicapoc reduces lipid-driven apoptosis in HepG2 cell cultures. In animals fed a HFD for 6 wk, co-treatment with Senicapoc, (1) reduced non-alcoholic fatty liver disease (NAFLD) activity score (NAS) (0-8 scale), (2) decreased steatosis and (3) decreased hepatic lipid content (Oil Red O, < 0.05 vehicle). Randomization of TAA animals and HFD fed animals to Senicapoc was associated with a decrease in liver fibrosis as evidenced by hydroxyproline and Masson's trichrome staining ( < 0.05 vehicle). These results demonstrated that Senicapoc mitigates both steatosis and fibrosis in liver fibrosis models.
These data suggest that Senicapoc interrupts more than one node in progressive fatty liver disease by its anti-steatotic and anti-fibrotic activities, serving as a double-edged therapeutic sword.
评估钙激活钾通道（KCa3.1）抑制剂在非酒精性脂肪性肝病（NAFLD）模型中对肝脏疾病的作用。
我们使用 KCa3.1 通道抑制剂 Senicapoc 进行了一系列和研究。在毒素、硫代乙酰胺（TAA）和高脂肪饮食（HFD）诱导的大鼠肝纤维化模型中进行了 Senicapoc 的疗效研究。通过凋亡、炎症、脂肪变性和纤维化的生物标志物来确定 Senicapoc 的疗效和药效学作用。
在 TAA 诱导和高脂肪饮食诱导的肝病中记录到 KCa3.1 表达上调。Senicapoc 治疗可降低棕榈酸驱动的 HepG2 细胞死亡。（<0.05 对照）支持 Senicapoc 减少 HepG2 细胞培养物中脂质驱动的细胞凋亡的发现。在喂养 HFD 6 周的动物中，Senicapoc 联合治疗：（1）降低非酒精性脂肪性肝病（NAFLD）活动评分（NAS）（0-8 级），（2）减少脂肪变性，（3）降低肝脂质含量（油红 O，<0.05 载体）。TAA 动物和 HFD 喂养动物随机分组接受 Senicapoc 治疗与肝纤维化的减少有关，这表现为羟脯氨酸和 Masson 三色染色减少（<0.05 载体）。这些结果表明，Senicapoc 通过其抗脂肪变性和抗纤维化活性减轻了肝纤维化模型中的脂肪变性和纤维化。
这些数据表明，Senicapoc 通过其抗脂肪变性和抗纤维化活性阻断了进展性脂肪性肝病的多个节点，是一种双刃剑治疗方法。
