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Human & Experimental Toxicology 2023Diethylnitrosamine (DEN), a hepatocarcinogen, is found in a variety of smoked and fried foods and was reported to be hepatotoxic in mice. Butylated hydroxytoluene (BHT)...
Diethylnitrosamine (DEN), a hepatocarcinogen, is found in a variety of smoked and fried foods and was reported to be hepatotoxic in mice. Butylated hydroxytoluene (BHT) is a potent antioxidant used in cosmetic formulations and as a food additive and preservative. As a result, BHT was studied as a potential inhibitor in the early stages of diethylnitrosamine (DEN)-induced HCC. Male Wistar albino rats ( = 24) were equally subdivided. Group 1 was the negative control; Group 2 and 3 administered BHT and DEN, respectively; Group 4 received BHT followed by DEN. Blood samples and rat livers were taken for biochemical and histological investigation. Hepatotoxicity was assessed by increased liver enzymes and HCC indicators, along with reduced antioxidant and pro-apoptotic factors. AFP, AFPL3, GPC3, GSH, SOD, MDA, CASP3 and BAX expression increased significantly after DEN treatment. DEN also reduced GPx, CAT, and CYP2E1 activity, and BCl-2 expression. Moreover, in the hepatic parenchyma, the DEN caused histological alterations. Pretreatment with BHT enhanced antioxidant status while preventing histopathological and most biochemical alterations. BHT pretreatment suppresses DEN-initiated HCC by decreasing oxidative stress, triggering intrinsic mitotic apoptosis, and preventing histopathological changes in liver tissue.
Topics: Rats; Male; Animals; Mice; Carcinoma, Hepatocellular; Antioxidants; Diethylnitrosamine; Butylated Hydroxytoluene; Liver Neoplasms; Rats, Wistar; Liver
PubMed: 36943693
DOI: 10.1177/09603271231165664 -
Scientific Reports Jul 2022Several fractions of Calotropis gigantea extracts have been proposed to have potential anticancer activity in many cancer models. The present study evaluated the...
Several fractions of Calotropis gigantea extracts have been proposed to have potential anticancer activity in many cancer models. The present study evaluated the anticancer activity of C. gigantea stem bark extracts in liver cancer HepG2 cells and diethylnitrosamine (DEN)-induced primary liver cancer in rats. The carcinogenesis model induced by DEN administration has been widely used to study pathophysiological features and responses in rats that are comparable to those seen in cancer patients. The dichloromethane (CGDCM), ethyl acetate, and water fractions obtained from partitioning crude ethanolic extract were quantitatively analyzed for several groups of secondary metabolites and calactin contents. A combination of C. gigantea stem bark extracts with doxorubicin (DOX) was assessed in this study to demonstrate the enhanced cytotoxic effect to cancer compared to the single administration. The combination of DOX and CGDCM, which had the most potential cytotoxic effect in HepG2 cells when compared to the other three fractions, significantly increased cytotoxicity through the apoptotic effect with increased caspase-3 expression. This combination treatment also reduced ATP levels, implying a correlation between ATP and apoptosis induction. In a rat model of DEN-induced liver cancer, treatment with DOX, C. gigantea at low (CGDCM-L) and high (CGDCM-H) doses, and DOX + CGDCM-H for 4 weeks decreased the progression of liver cancer by lowering the liver weight/body weight ratio and the occurrence of liver hyperplastic nodules, fibrosis, and proliferative cells. The therapeutic applications lowered TNF-α, IL-6, TGF-β, and α-SMA inflammatory cytokines in a similar way, implying that CGDCM had a curative effect against the inflammation-induced liver carcinogenesis produced by DEN exposure. Furthermore, CGDCM and DOX therapy decreased ATP and fatty acid synthesis in rat liver cancer, which was correlated with apoptosis inhibition. CGDCM reduced cleaved caspase-3 expression in liver cancer rats when used alone or in combination with DOX, implying that apoptosis-inducing hepatic carcinogenesis was suppressed. Our results also verified the low toxicity of CGDCM injection on the internal organs of rats. Thus, this research clearly demonstrated a promising, novel anticancer approach that could be applied in future clinical studies of CGDCM and combination therapy.
Topics: Adenosine Triphosphate; Animals; Calotropis; Carcinogenesis; Caspase 3; Diethylnitrosamine; Doxorubicin; Liver; Liver Neoplasms; Plant Bark; Plant Extracts; Rats
PubMed: 35840761
DOI: 10.1038/s41598-022-16321-0 -
Proceedings of the National Academy of... Mar 2021The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated...
The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti-PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Line, Tumor; Diethylnitrosamine; Drug Synergism; Humans; Liver Neoplasms; Liver Neoplasms, Experimental; Lymphocytes, Tumor-Infiltrating; Male; Mice; Molecular Docking Simulation; Rats; Receptors, CXCR4; Signal Transduction; Sorafenib; T-Lymphocytes, Cytotoxic; Tumor Microenvironment; Tumor-Associated Macrophages; Xenograft Model Antitumor Assays
PubMed: 33753481
DOI: 10.1073/pnas.2015433118 -
European Review For Medical and... Jan 2021To study the association of inflammatory factors and hepatocarcinoma stem cells of induced liver cancer rats.
OBJECTIVE
To study the association of inflammatory factors and hepatocarcinoma stem cells of induced liver cancer rats.
MATERIALS AND METHODS
30 SD male healthy rats were selected. 10 rats were given water as normal control group. 10 rats only were implemented laparotomy as sham operation group. The remaining 10 rats were the liver cancer model group and treated with diethylnitrosamine (DEN) to induce liver cancer. Real-time quantitative PCR was used to detect the related inflammatory factors in HCC tissues, including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-β1 (TGF-β), human interleukin-1α (IL-1α), human interleukin 1β (IL-1β) and levels of hepatocarcinoma stem cells indicators CD90, CD133, Alpha-fetoprotein (AFP). Correlation analysis was used to analyze the correlation between inflammatory factors and hepatocarcinoma stem cells markers CD90 and CD133.
RESULTS
The expression levels of IL-6, MCP-1 and TGF-β of HCC tissues in liver cancer model group were significantly higher than those in the control group and the sham operation group. The expression levels of CD90 and CD133 of tissues in the liver cancer model group were significantly higher than those in the control group and the sham operation group. The differences were statistically significant (p<0.001). By inhibiting related inflammatory factors, the growth, migration and invasion of liver cancer cells were significantly inhibited, and apoptosis was promoted. Correlation analysis results showed that the expression changes of IL-6, MCP-1 and TGF-β were significantly positively correlated with CD90 up-regulation (p<0.05), while the expression changes of IL-6, MCP-1 and TGF-β were significantly positively correlated with CD133 up-regulation (p<0.05).
CONCLUSIONS
The inflammatory factors IL-6, MCP-1 and TGF-β are closely related to hepatocarcinoma stem cells, which play an important role in promoting the occurrence and deterioration of liver cancer.
Topics: Administration, Oral; Animals; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Chemokine CCL2; Diethylnitrosamine; Disease Models, Animal; Interleukin-6; Liver Neoplasms; Male; Neoplastic Stem Cells; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1
PubMed: 33577025
DOI: 10.26355/eurrev_202101_24632 -
Scientific Reports Mar 2023In the present study, the hepatoprotective effect of 5-benzylidine-2-thiohydantoin (5B2T), a unique derivative of the thiohydantoin group, on liver injury induced by...
In the present study, the hepatoprotective effect of 5-benzylidine-2-thiohydantoin (5B2T), a unique derivative of the thiohydantoin group, on liver injury induced by diethylnitrosamine (DEN) in male rats was investigated. The experimental animals were divided into three groups, each with 14 rats. Rats in group I were considered to be controls and received only 10% Tween 80. Rats in group II were injected with 200 mg/kg DEN intraperitoneally. Rats in group III were injected with a single dose of DEN 200 mg/kg intraperitoneally and received the treatment orally (50 mg/kg, 5B2T) for two durations, 3 and 6 weeks. At the end of the experiment, blood was collected for the analysis of liver function and pro-inflammatory cytokine IL-6 and tumor necrosis factor α (TNF-α) levels. Additionally, liver specimens were used for histopathological examination and immunohistochemistry. The single intraperitoneal injection of 200 mg/kg DEN into rats resulted in significant elevation of serum enzyme levels of AST, ALT and ALP, which are indicators of hepatocellular damage, along with elevation in TNF-α and IL-6 in the DEN group. The results of both LFTs and ELISA in the treatment group showed improvements and a decline in the levels of the markers. Histopathological examination showed fibrosis, necrosis and infiltration of inflammatory cells in the DEN group, with lower intensity in the treatment group. The results of immunohistochemical staining revealed strong positive staining of both HSA and Ki-67 antibodies in the DEN group, with much lower intensity in the treatment group. The results of the docking study indicated that 5B2T has a remarkable interaction with TNF-α (PDB ID: 1TNF) and human IL-6 (PDB ID: 1IL6) with binding site energies of - 7.1 and - 6.1 (kcal/mol), respectively. The correct absorption and binding between the drug and the receptor was evaluated through computerized molecular docking by using the AutoDock program. The conclusion of the results from the current study reflected the interesting hepatoprotective abilities of 5B2T against DEN-induced hepatocellular damage and cancer in experimental rats.
Topics: Humans; Rats; Male; Animals; Diethylnitrosamine; Tumor Necrosis Factor-alpha; Interleukin-6; Chemical and Drug Induced Liver Injury, Chronic; Molecular Docking Simulation; Liver; Liver Neoplasms, Experimental
PubMed: 36949140
DOI: 10.1038/s41598-023-27725-x -
Gamma-irradiated β-glucan modulates signaling molecular targets of hepatocellular carcinoma in rats.Tumour Biology : the Journal of the... Aug 2017β-glucans are one of the most abundant forms of polysaccharides known as biological response modifiers which influence host's biological response and stimulate immune...
β-glucans are one of the most abundant forms of polysaccharides known as biological response modifiers which influence host's biological response and stimulate immune system. Accordingly, this study was initiated to evaluate irradiated β-glucan as a modulator for cellular signaling growth factors involved in the pathogenesis of hepatocellular carcinoma in rats. Hepatocellular carcinoma was induced with 20 mg diethylnitrosamine/kg BW. Rats received daily by gastric gavage 65 mg irradiated β-glucan/kg BW. It was found that treatment of rats with diethylnitrosamine induced hepatic injury and caused significant increase in liver injury markers with a concomitant significant increase in both hepatic oxidative and inflammatory indices: alpha-fetoprotein, interferon gamma, and interleukin 6 in comparison with normal and irradiated β-glucan-treated groups. Western immunoblotting showed a significant increase in the signaling growth factors: extracellular signal-regulated kinase 1 and phosphoinositide 3-kinase proteins in a diethylnitrosamine-treated group while both preventive and therapeutic irradiated β-glucan treatments recorded significant improvement versus diethylnitrosamine group via the modulation of growth factors that encounters hepatic toxicity. The transcript levels of vascular endothelial growth factor A and inducible nitric oxide synthase genes were significantly higher in the diethylnitrosamine-treated group in comparison with controls. Preventive and therapeutic treatments with irradiated β-glucan demonstrated that the transcript level of these genes was significantly decreased which demonstrates the protective effect of β-glucan. Histological investigations revealed that diethylnitrosamine treatment affects the hepatic architecture throughout the significant severe appearance of inflammatory cell infiltration in the portal area and congestion in the portal vein in association with severe degeneration and dysplasia in hepatocytes all over hepatic parenchyma. The severity of hepatic architecture changes was significantly decreased with both β-glucan therapeutic and preventive treatments. In conclusion, irradiated β-glucan modulated signal growth factors, vascular endothelial growth factor A, extracellular signal-regulated kinase 1, and phosphatidylinositol-3-kinase, which contributed to experimental hepatocarcinogenesis.
Topics: Animals; Carcinoma, Hepatocellular; Diethylnitrosamine; Disease Models, Animal; Gamma Rays; Humans; Liver; Liver Neoplasms; Mitogen-Activated Protein Kinase 3; Phosphatidylinositol 3-Kinases; Rats; Signal Transduction; Vascular Endothelial Growth Factor A; beta-Glucans
PubMed: 28810822
DOI: 10.1177/1010428317708703 -
Hepatology Communications Nov 2022Phospholipase C gamma 1 (PLCγ1) plays an oncogenic role in several cancers, alongside its usual physiological roles. Despite studies aimed at identifying the effect of...
Phospholipase C gamma 1 (PLCγ1) plays an oncogenic role in several cancers, alongside its usual physiological roles. Despite studies aimed at identifying the effect of PLCγ1 on tumors, the pathogenic role of PLCγ1 in the tumorigenesis and development of hepatocellular carcinoma (HCC) remains unknown. To investigate the function of PLCγ1 in HCC, we generated hepatocyte-specific PLCγ1 conditional knockout (PLCγ1 ; Alb-Cre) mice and induced HCC with diethylnitrosamine (DEN). Here, we identified that hepatocyte-specific PLCγ1 deletion effectively prevented DEN-induced HCC in mice. PLCγ1 ; Alb-Cre mice showed reduced tumor burden and tumor progression, as well as a decreased incidence of HCC and less marked proliferative and inflammatory responses. We also showed that oncogenic phenotypes such as repressed apoptosis, and promoted proliferation, cell cycle progression and migration, were induced by PLCγ1. In terms of molecular mechanism, PLCγ1 regulated the activation of signal transducer and activator of transcription 3 (STAT3) signaling. Moreover, PLCγ1 expression is elevated in human HCC and correlates with a poor prognosis in patients with HCC. Our results suggest that PLCγ1 promotes the pathogenic progression of HCC, and PLCγ1/STAT3 axis was identified as a potential therapeutic target pathway for HCC.
Topics: Humans; Mice; Animals; STAT3 Transcription Factor; Carcinoma, Hepatocellular; Diethylnitrosamine; Liver Neoplasms; Phospholipase C gamma; Cell Proliferation; Carcinogenesis
PubMed: 36153805
DOI: 10.1002/hep4.2077 -
Japanese Journal of Cancer Research :... Jan 1996Modifying effects of taurine, a naturally occurring organosulfur compound, on diethylnitrosamine (DEN) and phenobarbital (PB)-induced hepatocarcinogenesis were examined...
Modifying effects of taurine, a naturally occurring organosulfur compound, on diethylnitrosamine (DEN) and phenobarbital (PB)-induced hepatocarcinogenesis were examined in rats. Male F344 rats, 5 weeks old, were divided into 8 groups. Rats of groups 1 through 5 were given i.p. injections of DEN (100 mg/kg body weight) once a week for 3 weeks from one week after the start of the experiment. Of them, animals of group 2 received taurine mixed in a basal diet at a concentration of 2000 ppm for the initial 4 weeks, and those of groups 3 and 5 were given the agent starting 4 weeks after the beginning of the experiment until the end (24 weeks). Rats in groups 1, 4, 7 and 8 were kept on the basal diet throughout the experiment (24 weeks). Group 6 was given taurine throughout the experiment and group 8 was treated as a vehicle control. Animals of groups 1,2, 3 and 7 received PB in drinking water at a dose of 500 ppm from one week after the end of carcinogen or vehicle treatment. Liver neoplasms were recognized only in DEN-treated groups. The incidence and average number of liver neoplasms of group 3 were significantly lower than those of group 1. The number of glutathione S-transferase placental form (GST-P)-positive foci of group 2 or 3 was significantly smaller than that of group 1 (P < 0.01 or P < 0.005). The average and unit areas of GST-P-positive foci in groups 2 and 3 were also significantly smaller than those in group 1 (P < 0.005 and P < 0.0001 and P < 0.0001, respectively). In this study, the level of ornithine decarboxylase activity in non-neoplastic liver tissue was reduced by taurine treatment in both the initiation and postinitiation phases. These results suggest that taurine could be a chemopreventive agent for liver neoplasia.
Topics: Animals; Anticarcinogenic Agents; Carcinogens; Diethylnitrosamine; Glutathione Transferase; Liver; Liver Neoplasms, Experimental; Male; Ornithine Decarboxylase; Phenobarbital; Placenta; Rats; Rats, Inbred F344; Taurine
PubMed: 8609045
DOI: 10.1111/j.1349-7006.1996.tb00196.x -
Oxidative Medicine and Cellular... 2021Maternal exposure to cadmium causes obesity and metabolic changes in the offspring, including nonalcoholic fatty liver disease-like pathology. However, whether maternal...
Maternal exposure to cadmium causes obesity and metabolic changes in the offspring, including nonalcoholic fatty liver disease-like pathology. However, whether maternal cadmium exposure accelerates liver cancer in the offspring is unknown. This study investigated the impact of early-life exposure to cadmium on the incidence and potential mechanisms of hepatocellular carcinoma (HCC) in offspring subjected to postweaning HCC induction. HCC in C57BL/6J mice was induced by diethylnitrosamine (DEN) injection at weaning, followed by a long-term high-fat choline-deficient (HFCD) diet. Before weaning, liver cadmium levels were significantly higher in mice with early-life cadmium exposure than in those without cadmium exposure. However, by 26 and 29 weeks of age, hepatic cadmium fell to control levels, while a significant decrease was observed in copper and iron in the liver. Both male and female cadmium-exposed mice showed increased body weight compared to non-cadmium-treated mice. For females, early-life cadmium exposure also worsened insulin intolerance but did not significantly promote DEN/HFCD diet-induced liver tumors. In contrast, in male mice, early-life cadmium exposure enhanced liver cancer induction by DEN/HFCD with high incidence and larger liver tumors. The liver peritumor tissue of early-life cadmium-exposed mice exhibited greater inflammation and disruption of fatty acid metabolism, accompanied by higher malondialdehyde and lower esterified triglyceride levels compared to mice without cadmium exposure. These findings suggest that early-life exposure to low-dose cadmium accelerates liver cancer development induced by a DEN/HFCD in male mice, probably due to chronic lipotoxicity and inflammation caused by increased uptake but decreased consumption of fatty acids.
Topics: Animals; Animals, Newborn; Cadmium; Choline; Diet, High-Fat; Diethylnitrosamine; Disease Models, Animal; Fatty Acids; Female; Liver; Liver Neoplasms; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Triglycerides
PubMed: 34876963
DOI: 10.1155/2021/1427787 -
The Journal of Experimental Medicine May 2017Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription...
Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos-expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.
Topics: Animals; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cholesterol; Diethylnitrosamine; Disease Models, Animal; Drosophila Proteins; Liver; Liver Neoplasms; Mice; Proto-Oncogene Proteins c-fos; Repressor Proteins
PubMed: 28356389
DOI: 10.1084/jem.20160935