This study aimed the integrative characterization of morphological, biochemical and molecular features of chemically-induced cirrhosis-associated hepatocarcinogenesis. Thus, male Wistar rats were submitted to a diethylnitrosamine (DEN)/thioacetamide (TAA)-induced model. Liver tissue was processed for global gene expression, histopathological and collagen evaluations; as well as immunohistochemical and oxidative stress analysis. Gene Ontology and functional analysis showed the upregulation of extracellular matrix deposition genes, such as collagen type I alpha 1 and 2 (Col1α1 and Col1α2) and tissue inhibitor of metalloproteinase 1 and 2 genes (Timp1 and Timp2). In agreement these findings, animals presented extensive liver cirrhosis with increased collagen deposition (Sirius red). Besides, the animals developed many glutathione S-transferase pi (GST-P)-positive preneoplastic lesions showing high cell proliferation (Ki-67), in keeping with the Gstp1 and Gstp2 increased gene expression. DEN/TAA-treated rats also showed the upregulation of tumorigenesis-related annexin A2 gene (Anxa2) and few neoplastic lesions (hepatocellular adenomas, carcinomas, and cholangiocarcinoma). In contrast, gene expression and activity of antioxidant enzymes were decreased (glutathione peroxidase, total glutathione-S-transferase, and catalase). The model featured remarkable similarities to human hepatocarcinogenesis. Our findings could bring up new molecular insights into cirrhosis-associated hepatocarcinogenesis, and provide a suitable animal model for the establishment of further diagnostic, preventive and therapeutic approaches.
Capsaicin (8-Methyl-N-vanillyl-(trans)-6-nonenamide) is the major pungent ingredient found in chili peppers consumed worldwide. Most reports on capsaicin potential carcinogenicity have yielded inconsistent findings. Some studies have shown that capsaicin exerts anti-proliferative and pro-apoptotic effects on different cancer cell lines, while others have reported an association between capsaicin at high doses with mutagenicity and carcinogenicity. Thus, this study aimed at assessing the effects of capsaicin administration on 1,2-dimethyl-hydrazine (DMH)-induced colon carcinogenesis in male Wistar rats. Our results show that capsaicin administration, before and during carcinogen exposure, modified DMH-induced cytotoxicity and genotoxicity, promoting anti-proliferative and pro-apoptotic responses through the expression of the genes involved in apoptosis, cell cycle suppression and cell/tissue differentiation. Furthermore, capsaicin reduced aberrant crypt foci (ACF) number and multiplicity, although there were no differences in tumor incidence and multiplicity among the groups. Taken together, the results suggest that capsaicin may have a preventive effect against DMH-induced colorectal carcinogenesis.
Background
The aim of this study was to investigate dose-response effects of vitamin D3 (VD3) supplementation on the early stages of diethylnitrosamine (DEN) and carbon tetrachloride (CCl4)-induced hepatocarcinogenesis in rats.
Methods
The animals were randomly allocated into six experimental groups (10 rats each) treated as follows: group 1: no treatment; groups 2–6: single intraperitoneal injection of N-diethylnitrosamine; groups 2–6: intragastric CCl4; groups 3–6: intragastric VD3 at 10,000, 20,000, 40,000, and 60,000 IU/kg b.w., respectively.
Results
Serum 25-hydroxyvitamin D (25-OHD) levels in the VD3-supplemented groups were significantly higher than those in the control groups (G1 and G2, p < 0.001). Serum levels of phosphate were higher in the groups supplemented with VD3 at 10,000 and 60,000 IU/kg (G3 and G6, p < 0.005). VD3 higher doses reduced cell proliferation and the number of larger placental glutathione S-transferase (GST-P)-positive hepatocellular preneoplastic lesions. Neither the DEN/CCl4 regimen nor the VD3 supplementation altered vitamin D receptor (VDR) protein expression in the liver.
Conclusion
The results indicate that high-dose VD3 supplementation reduced the development of DEN/CCl4-induced preneoplastic lesions in the liver.
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