Fructose 1,6-bisphosphate reduced TNF-α-induced apoptosis in galactosamine sensitized rat hepatocytes through activation of nitric oxide and cGMP production
Fructose 1,6-bisphosphate reduced TNF-α-induced apoptosis in galactosamine sensitized rat hepatocytes through activation of nitric oxide and cGMP production
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DOI：
10.1016/j.ejphar.2009.03.044
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发表时间：
2009-05-21
影响因子：
5
通讯作者：
Bermudez, Jordi
中科院分区：
文献类型：
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作者：
Calafell, Roser;Boada, Jordi;Bermudez, Jordi
果糖1，6-P2（F1，6 BP）通过两种平行作用保护大鼠肝脏免受半乳糖胺（GalN）诱导的实验性肝炎：预防炎症和降低肝细胞对肿瘤坏死因子-α（TNF-α）的敏感性。在以前的论文中，我们报道了预防炎症的潜在机制。在本研究中，我们研究了F1，6 BP抑制GalN致敏大鼠肝实质细胞中TNF-α诱导的细胞凋亡的细胞内机制。我们推测F1，6 BP处理的大鼠肝脏中一氧化氮（NO）的产生增加介导了抗凋亡作用。在用GalN加肿瘤坏死因子-α（GalN+ TNF-α）激发的培养的原代大鼠肝细胞中评价了这一假设，以在体外重现与实验性肝炎相关的损伤。我们的研究结果表明，细胞凋亡减少伴随着NO的产生增加，并减少氧化应激。在这种情况下，鸟苷酸环化酶被激活，cGMP的增加减少了肝细胞中TNF-α诱导的细胞凋亡。这些结果为F1，6 BP激活的保护机制提供了新的见解，并证实了其作为肝保护剂的兴趣。(C)2009爱思唯尔有限公司版权所有。
Fructose 1,6-P2 (F1,6BP) protects rat liver against experimental hepatitis induced by galactosamine (GalN) by means of two parallel effects: prevention of inflammation, and reduction of hepatocyte sensitization to tumour necrosis factor-alpha (TNF-alpha). In a previous paper we reported the underlying mechanism involved in the prevention of inflammation. In the present study, we examined the intracellular mechanisms involved in the F1,6BP inhibition of the apoptosis induced by TNF-alpha in parenchyma cells of GalN-sensitized rat liver. We hypothesized that the increased nitric oxide (NO) production in livers of F1,6BP-treated rats mediates the antiapoptotic effect. This hypothesis was evaluated in cultured primary rat hepatocytes challenged by GalN plus tumour necrosis factor-alpha (GalN+TNF-alpha), to reproduce in vitro the injury associated with experimental hepatitis. Our results show a reduction in apoptosis concomitant with an increase in NO production and with a reduction in oxidative stress. In such conditions, guanylyl cyclase is activated and the increase in cGMP reduces the TNF-alpha-induced apoptosis in hepatocytes. These results provide new insights in the protective mechanism activated by F1,6BP and confirm its interest as a hepatoprotective agent. (C) 2009 Elsevier B.V. All rights reserved.