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Early Effects of Diethylnitrosamine Contributes to Hepatocarcinogenesis
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UPLOADED BY-ADMIN, OMAR M. M. MOHAFEZ, MEKKY M. M. ABOUZIED
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| Abstract:
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Diethylnitrosoamine (DENA) present in many products is one of the etiological factors responsible for induction of
Hepatocellular carcinoma. In this study, we injected rats with a single dose of DENA at a dose of 90 mg/kg. Rats were
sacrificed after 2, 4 and 6 days. RT-PCR was used to invistigate inositol requiring enzyme-1 (IRE-1), caspase-3, glutathione
reductase (GR) and TNF-a mRNA expression. We found overexpression of the endoplasmic reticulum stress sensor, IRE-1,
and glutathione reductase soon after the DENA injection. Conversely, there was a gradual decrease in the level of
glutathione in liver homogenates of treated animals. Moreover, The prolonged activation of the unfolded protein response
(UPR) led to an apoptotic cell death, that was manifested by a gradual increase in mRNA levels of the apoptotic marker,
caspase-3, and the inflammatory cytokine TNF-a starting from day four of DENA administration. On the other hand, the
gradually increasing levels of thiobarbituric acid reactive substance (TBARS) and alanine transamination point at prolonged
activation of UPR and liver cell injury. In consistence with the biochemical parameters, the histopathological examination
showed parenchymal cell damage as indicated by numerous necrotic hepatocytes with altered nuclei and eosinophilic
cytoplasm. The results indicate that ER stress is the first manifestation of DENA administration followed by apoptosis and
inflammation. These events can be considered as early steps responsible for initiation and promotion of
hepatocarcinogenesis.
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| Keyword:
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hepatocarcinogenesis, endoplasmic reticulum, apoptosis, inflammation, TNF-a, and caspase-3
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| DOI:
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