Oxidative stress and cell damage in a model of precancerous lesions and advanced hepatocellular carcinoma in rats

Moreira, Adriana Aparecida; Rodrigues, Graziella; Bona, Silvia Regina; Cerski, Carlos Thadeu Schmidt; Marroni, Cláudio Augusto; Mauriz, José L.; González‐Gallego, Javier; Marroni, Norma Possa

doi:10.1016/j.toxrep.2014.11.015

Cited by 22 publications

(26 citation statements)

References 62 publications

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“…Increased serum levels of γGT and AP indicate cholestasis and cholangitis, potentially associated with mechanical biliary obstruction. In this study, the nodule size observed on histological analysis suggests that tumor nodules compressed bile ducts, thus producing mechanical obstruction to bile flow (Moreira et al 2015).…”

Section: Discussionmentioning

confidence: 58%

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Ductular reaction, cytokeratin 7 positivity, and gamma-glutamyl transferase in multistage hepatocarcinogenesis in rats

et al. 2016

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Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is characterized by multistage formation. The presence of ductular reaction, cytokeratin 7 positivity (PCK7), and increased levels of gamma glutamyltransferase (γGT) has been observed during liver carcinogenesis and contribute to tumor progression. Our goal was to evaluate the ductular reaction in multistage carcinogenesis and to correlate PCK7 and γGT levels with tumor incidence, histological characteristics, liver DNA damage index, and the expression of oxidative stress proteins. HCC was induced in 24 male Wistar rats weighing 145-150 g by chronic and intermittent exposure to 50 or 100 mg/kg diethylnitrosamine (DEN). Six control animals received only vehicle. Blood was collected to determine hepatic enzyme levels. Animals were divided into three groups: control (CO), precancerous lesions (PL), and advanced HCC. Liver samples were obtained for immunohistochemical analyses and the measurement of protein expression. Statistical analyses included Tukey's test and Pearson's correlation analyses. We observed an extensive ductular reaction in advanced HCC and a strong correlation between PCK7 and levels of γGT and the poor prognosis and aggressiveness of HCC. The extent of PCK7 and high γGT levels were associated with overexpression of inducible nitric oxide synthase (iNOS) and heat shock factor protein 1 (HSF-1). However, PCK7 and γGT levels were negatively correlated with protein expression of nuclear factor erythroid 2-related factor 2 (NRF2) and inducible heat shock protein 70 (iHSP70). These findings suggest that ductular reaction is involved in the progression of multistage hepatocarcinogenesis.

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Section: Discussionmentioning

confidence: 58%

“…twice a week for the first 3 weeks and once per week from weeks 4 to 6 and 11 to 13 weeks. A single dose of 2acetylaminofluorene (2-AAF, 100 mg/ kg, Sigma-Aldrich, St. Louis, MO) was administered in week 4 to both DEN groups (Moreira et al 2015).…”

Section: Animals and Protocolmentioning

confidence: 99%

Ductular reaction, cytokeratin 7 positivity, and gamma-glutamyl transferase in multistage hepatocarcinogenesis in rats

et al. 2016

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“…twice a week for the first three weeks and once a week from weeks 4 to 6 and 11 to 13 up to 19 weeks. A single dose of 2-acetylaminofluorene (2-AAF, 100 mg/ kg, Sigma Aldrich, St. Louis, MO) was administered in week 4 [ 27 ]. The animals were divided into five groups (n = 12): Control (CO); Control+melatonin (CO+MEL); DEN; DEN+melatonin from the 5th to the 19th week (DEN+MEL5) and (V) DEN+melatonin from the 12th to the 19th week (DEN+MEL12).…”

Section: Methodsmentioning

confidence: 99%

Melatonin Activates Endoplasmic Reticulum Stress and Apoptosis in Rats with Diethylnitrosamine-Induced Hepatocarcinogenesis

et al. 2015

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Hepatocellular carcinoma (HCC) is one of the most lethal human cancers worldwide because of its high incidence, its metastatic potential and the low efficacy of conventional treatment. Inactivation of apoptosis is implicated in tumour progression and chemotherapy resistance, and has been linked to the presence of endoplasmic reticulum stress. Melatonin, the main product of the pineal gland, exerts anti-proliferative, pro-apoptotic and anti-angiogenic effects in HCC cells, but these effects still need to be confirmed in animal models. Male Wistar rats in treatment groups received diethylnitrosamine (DEN) 50 mg/kg intraperitoneally twice/once a week for 18 weeks. Melatonin was given in drinking water at 1 mg/kg/d, beginning 5 or 12 weeks after the start of DEN administration. Melatonin improved survival rates and successfully attenuated liver injury, as shown by histopathology, decreased levels of serum transaminases and reduced expression of placental glutathione S-transferase. Furthermore, melatonin treatment resulted in a significant increase of caspase 3, 8 and 9 activities, polyadenosine diphosphate (ADP) ribose polymerase (PARP) cleavage, and Bcl-associated X protein (Bax)/Bcl-2 ratio. Cytochrome c, p53 and Fas-L protein concentration were also significantly enhanced by melatonin. Melatonin induced an increased expression of activating transcription factor 6 (ATF6), C/EBP-homologous protein (CHOP) and immunoglobulin heavy chain-binding protein (BiP), while cyclooxygenase (COX)-2 expression decreased. Data obtained suggest that induction of apoptosis and ER stress contribute to the beneficial effects of melatonin in rats with DEN-induced HCC.

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“…In this process, the development and progression of many chronic diseases, including liver diseases, the involvement of oxidative stress, was well described . LPO is one of the major consequences of oxidative damage and is suggested as a possible mediator of liver fibrosis, having a strong influence on the synthesis and expression of collagen . F2‐isoprostanes are produced from the oxidative degradation of arachidonic acid and released into the circulation.…”

Section: Discussionmentioning

confidence: 99%

“…11 LPO is one of the major consequences of oxidative damage and is suggested as a possible mediator of liver fibrosis, having a strong influence on the synthesis and expression of collagen. 3,11,12,[24][25][26][27][28][29] F2-isoprostanes are produced from the oxidative degradation of arachidonic acid and released into the circulation. Therefore, they can be easily measured in biological samples as a marker of LPO.…”

Section: Discussionmentioning

confidence: 99%

Antifibrogenic effect of melatonin in rats with experimental liver cirrhosis induced by carbon tetrachloride

et al. 2018

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Background and AimLiver diseases are a major public health problem, accounting for a significant number of hospital visits and admissions and an increasing mortality rate. Melatonin (MLT) is a powerful antioxidant molecule that has been shown to be beneficial under various conditions. The objective was to evaluate the effect of MLT on experimental liver cirrhosis induced by carbon tetrachloride (CCl4) in rats.MethodsTwenty male Wistar rats (230–250 g) were divided into four groups. I: control group (CO); II: CO + MLT; III: CCl4; and IV: CCl4 + MLT. CCl4 was administered intraperitoneally (i.p.) as follows: 10 doses every 5 days, 10 doses every 4 days, and 7 doses every 3 days. MLT was administered i.p. at a dose of 20 mg/kg from the 10th week to the end of the experiment (16th week).ResultsIn the CCl4 + MLT group, we found that MLT caused a decrease in the level of F2‐isoprostanes and NQO1 expression. We also found that MLT reduced the inflammatory process as shown by decreased expressions of NF‐KB/p65 and inducible nitric oxide synthase (iNOS) and a smaller amount of inflammatory infiltrate. MLT reduced the expression of transforming growth factor beta1 (TGF‐β1), alpha‐smooth muscle actin (α‐SMA), and vascular endothelial growth factor (VEGF). Picrosirius staining showed that MLT decreases fibrosis.ConclusionMLT has a potent antifibrogenic effect, modulating the parameters of oxidative stress, angiogenesis, and inflammation.

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Oxidative stress and cell damage in a model of precancerous lesions and advanced hepatocellular carcinoma in rats

Cited by 22 publications

References 62 publications

Ductular reaction, cytokeratin 7 positivity, and gamma-glutamyl transferase in multistage hepatocarcinogenesis in rats

Ductular reaction, cytokeratin 7 positivity, and gamma-glutamyl transferase in multistage hepatocarcinogenesis in rats

Melatonin Activates Endoplasmic Reticulum Stress and Apoptosis in Rats with Diethylnitrosamine-Induced Hepatocarcinogenesis

Antifibrogenic effect of melatonin in rats with experimental liver cirrhosis induced by carbon tetrachloride

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