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International Journal of... Sep 2016Diethylnitrosamine (DEN)-induced liver cancer normally develops in stages that progress from cirrhosis and carcinoma. Increased oxidative stress is suggested to play a...
Diethylnitrosamine (DEN)-induced liver cancer normally develops in stages that progress from cirrhosis and carcinoma. Increased oxidative stress is suggested to play a role in DEN-induced carcinogenicity. Blueberries (BB) contain high antioxidant capacity. We investigated the effect of BB supplementation on development of DEN-induced cirrhosis and neoplastic lesions in the liver. Rats were injected with DEN (200 mg/kg; i.p.) three times with an interval of 15 days at 4, 6, and 8 weeks and sacrificed 8 weeks after the last DEN injection. They were also fed on 8% BB (w/w) containing chow for 16 weeks. Hepatic damage markers in serum were determined together with hepatic histopathological examinations. Hydroxyproline (HYP), malondialdehyde (MDA), diene conjugate (DC), protein carbonyl (PC), and glutathione (GSH) levels, and CuZn-superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, and their mRNA expressions were measured. Protein and mRNA expressions of glutathione transferase-pi (GST-pi) were evaluated as a marker of preneoplastic lesions. BB supplementation decreased hepatic damage markers in serum and hepatic MDA, DC, and PC levels, but SOD, CAT, and GSH-Px activities and their mRNA expressions remained unchanged in DEN-treated rats. BB attenuated cirrhotic changes and decreased hepatic HYP levels and GST-pi expressions. Our results indicate that BB is effective in decreasing development of DEN-induced hepatic cirrhosis and preneoplastic lesions by acting as an antioxidant (radical scavenger) itself without affecting activities and mRNA expressions of antioxidant enzymes.
Topics: Animals; Antioxidants; Blueberry Plants; Catalase; Diethylnitrosamine; Glutathione; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; Malondialdehyde; Oxidative Stress; Plant Extracts; Precancerous Conditions; Rats; Rats, Wistar; Superoxide Dismutase
PubMed: 26684621
DOI: 10.1177/0394632015621319 -
International Journal of Molecular... May 2022Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably,...
Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably, recent studies have demonstrated that aberrant activation of NRF2 accelerates the proliferation and progression of cancer cells. The differential effects of NRF2 on multi-stage carcinogenesis have raised a concern about the validity of NRF2 activators for chemoprevention. This prompted us to assess the effects of sulforaphane (SFN), a prototypic NRF2 activating chemopreventive phytochemical, on experimentally induced carcinogenesis. In the present study, SFN was daily injected intraperitoneally (25 mg/kg) for 3 months to male C57BL/6 mice at 6 months after single intraperitoneal administration of a hepatocarcinogen, diethylnitrosamine (DEN). The liver to body weight ratio, tumor growth, and the number and the size of hepatomas measured at 9 months after DEN administration were significantly higher in SFN-treated mice than those in vehicle-treated mice. Moreover, the expression of NRF2, its target protein NAD(P)H:quinone oxidoreductase 1, and the cell proliferation marker, proliferating cell nuclear antigen was further elevated in DEN plus SFN-treated mice. These results suggest that once hepatocarcinogenesis is initiated, SFN may stimulate tumor progression.
Topics: Animals; Carcinogenesis; Diethylnitrosamine; Isothiocyanates; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Sulfoxides
PubMed: 35628208
DOI: 10.3390/ijms23105397 -
Basic & Clinical Pharmacology &... Nov 2020Alcoholic liver disease (ALD) may be attributed to multiple hits driving several alterations. The aim of this work was to determine whether nucleoredoxin (NXN) interacts...
Alcoholic liver disease (ALD) may be attributed to multiple hits driving several alterations. The aim of this work was to determine whether nucleoredoxin (NXN) interacts with flightless-I (FLII)/actin complex and how this ternary complex is altered during ALD progression induced by different ALD models. ALD was recapitulated in C57BL/6J female mice by the well-known ALD Lieber-DeCarli model, and by an in vitro human co-culture system overexpressing NXN. The effects of ethanol and low doses of lipopolysaccharides (LPS) and diethylnitrosamine (DEN) were also evaluated in vivo as a first approach of an ALD multi-hit protocol. We demonstrated that NXN interacts with FLII/actin complex. This complex was differentially altered in ALD in vivo and in vitro, and NXN overexpression partially reverted this alteration. We also showed that ethanol, LPS and DEN synergistically induced liver structural disarrangement, steatosis and inflammatory infiltration accompanied by increased levels of proliferation (Ki67), ethanol metabolism (CYP2E1), hepatocarcinogenesis (GSTP1) and LPS-inducible (MYD88 and TLR4) markers. In summary, we provide evidence showing that NXN/FLII/actin complex is involved in ALD progression and that NXN might be involved in the regulation of FLII/actin-dependent cellular functions. Moreover, we present a promising first approach of a multi-hit protocol to better recapitulate ALD pathogenesis.
Topics: Animals; Body Weight; Cell Proliferation; Cytochrome P-450 CYP2E1; Diethylnitrosamine; Ethanol; Fatty Liver; Female; Lipopolysaccharides; Liver; Liver Diseases, Alcoholic; Mice; Mice, Inbred C57BL; Microfilament Proteins; Oxidoreductases
PubMed: 32524749
DOI: 10.1111/bcpt.13451 -
Experimental and Clinical... Jan 2022Hepatocellular carcinoma is the fourth leading cause of cancer deaths in the world. Conven - tional methods of cancer therapy are either invasive or have undesirable...
OBJECTIVES
Hepatocellular carcinoma is the fourth leading cause of cancer deaths in the world. Conven - tional methods of cancer therapy are either invasive or have undesirable side effects. Therefore, exploring new therapeutic strategies to control the progression of hepatocellular carcinoma, such as cell-based therapies, is a key issue for prolonging patient survival. In this study, we aimed to evaluate tumor suppressive effects of mesenchymal stem cells on the in vivo pro - gression of hepatocellular carcinoma in murine model.
MATERIALS AND METHODS
Hepatocellular carcinoma was induced in 40 rats with diethylnitrosamine. Rats were divided into 4 groups: 1 group injected with diethylnitrosamine only, 1 group injected with diethylnitrosamine and 1 dose of rat bone marrowderived mesenchymal stem cells, 1 group injected with diethylnitrosamine and 2 doses of rat bone marrowderived mesenchymal stem cells, and 1 group was injected with diethylnitrosamine and 3 doses of rat bone marrow-derived mesenchymal stem cells. Rats were killed after 1 month of dose 3. Liver specimens were histopathologically examined, and serum samples were examined for liver function and cytokines.
RESULTS
Histopathological examination revealed that mesenchymal stem cell transplant induced liver regeneration. It also improved liver function as revealed by decreased levels of alanine and aspartate aminotransferase. Mesenchymal stem cells also repaired the immunopathology of the liver environment, as it decreased levels of interleukin 2 and 10, tumor necrosis factor α, and interferon γ.
CONCLUSIONS
Mesenchymal stem cell infusion significantly enhanced hepatic structure and function of livers in a rat hepatocellular carcinoma model.
Topics: Animals; Bone Marrow; Carcinoma, Hepatocellular; Diethylnitrosamine; Disease Models, Animal; Humans; Liver; Liver Neoplasms; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Prognosis; Rats; Treatment Outcome
PubMed: 33928878
DOI: 10.6002/ect.2020.0495 -
Journal of Biochemical and Molecular... Mar 2022The development of bioengineered nanoparticles has attracted considerable universal attention in the field of medical science and disease treatment. Current studies...
The development of bioengineered nanoparticles has attracted considerable universal attention in the field of medical science and disease treatment. Current studies were executed to evaluate the hepatoprotective activity of biosynthesized silver nanoparticles (AgNPs). Their characterization was performed by UV-Visible analysis, fourier transform infrared spectroscopy, transmission electron microscopy (TEM), scanning electron microscope (SEM), and Zeta analyses. In in vivo studies, albino rats (180 ± 10 g) were persuaded with model hepatic toxicant N-nitrosodiethylamine (NDEA) and subsequently cotreated with Morus multicaulis at 100 mg/kg and AgNPs at 100 µg/kg dose. NDEA administration elevates the levels of liver function test biomarkers, which were reinstated to normal by cotreatment of test drugs. The oxidative stress and concentration of drug-metabolizing enzyme increase after induction of toxicant (NDEA), these markers are restored toward normal after cotreatment of nano-drug. Treatments of M. multicaulis extract did not show such significant protection. The NDEA-treated groups showed a significant rise in the level of cytokines (interleukin [IL-6] and IL-10) and reached normal with subsequent treatment with AgNPs. Histopathological studies also exhibited the curative effect of AgNPs in the same manner. Thus current results strongly suggest that biomimetic AgNPs could be used as an effective drug against hepatic alteration.
Topics: Animals; Biomimetic Materials; Chemical and Drug Induced Liver Injury; Diethylnitrosamine; Male; Metal Nanoparticles; Rats; Rats, Wistar; Silver
PubMed: 34820934
DOI: 10.1002/jbt.22968 -
Journal of Environmental Pathology,... 2022Liver cancer is the third most common cancer, with increasing morbidity and mortality rates worldwide. Despite the increasing occurrence of liver cancer, it has a poor...
Liver cancer is the third most common cancer, with increasing morbidity and mortality rates worldwide. Despite the increasing occurrence of liver cancer, it has a poor prognosis and potential treatment options are still lacking. The current study aimed to explore the anticancer potential of arbutin against diethylnitrosamine (DEN)-triggered liver carcinogenesis in rats. Liver cancer was initiated in rats via the administration of DEN (200 mg/kg) and then treated with 30 mg/kg of arbutin. Albumin, globulin, and total protein were quantified using kits. Antioxidant, liver injury marker, and tumor biomarker contents were quantified using marker-specific assay kits. The inflammatory markers c-JNK, TRAIL, caspase-8, and p53 contents were also detected using kits. Reverse transcription PCR analysis was used to study the expression of chaperones GRP78, GRP94, and PDIA4 as well as ERDJ4, ATF4, and GADD34. Liver histology was studied microscopically. The arbutin treatment effectively improved body weight and reduced liver weight in animals with DEN-provoked liver cancer. The treatment also improved the albumin, globulin, and total protein contents and antioxidants. In addition, arbutin reduced liver injury marker enzyme function and improved c-JNK, TRAIL, caspase-8, and p53 contents. Arbutin supplementation also decreased the expression of GRP78, PDIA4, GRP94, ERDJ4, ATF4, and GADD34 in the liver tissues of DEN-provoked animals. Arbutin effectively ameliorated the DEN-provoked histological alterations. Altogether, our findings show that arbutin has anti-inflammatory, antioxidant, and anticarcinogenic activities against DEN-provoked liver cancer in rats.
Topics: Animals; Arbutin; Carcinoma, Hepatocellular; Diethylnitrosamine; Liver Neoplasms; Rats
PubMed: 35378001
DOI: 10.1615/JEnvironPatholToxicolOncol.2021039772 -
Biochimica Et Biophysica Acta.... May 2022The activation of Nuclear Factor, Erythroid 2 Like 2 - Kelch Like ECH Associated Protein 1 (NRF2-KEAP1) signaling pathway plays a critical dual role by either protecting...
The activation of Nuclear Factor, Erythroid 2 Like 2 - Kelch Like ECH Associated Protein 1 (NRF2-KEAP1) signaling pathway plays a critical dual role by either protecting or promoting the carcinogenesis process. However, its activation or nuclear translocation during hepatocellular carcinoma (HCC) progression has not been addressed yet. This study characterizes the subcellular localization of both NRF2 and KEAP1 during diethylnitrosamine-induced hepatocarcinogenesis in the rat. NRF2-KEAP1 pathway was continuously activated along with the increased expression of its target genes, namely Nqo1, Hmox1, Gclc, and Ptgr1. Similarly, the nuclear translocation of NRF2, MAF, and KEAP1 increased in HCC cells from weeks 12 to 22 during HCC progression. Likewise, colocalization of NRF2 with KEAP1 was higher in the cell nuclei of HCC neoplastic nodules than in surrounding cells. Moreover, immunofluorescence analyses revealed that the interaction of KEAP1 with filamentous Actin was disrupted in HCC cells. This disruption may be contributing to the release and nuclear translocation of NRF2 since the cortical actin cytoskeleton serves as anchoring of KEAP1. In conclusion, this evidence indicates that NRF2 is progressively activated and promotes the progression of experimental HCC.
Topics: Actin Cytoskeleton; Animals; Carcinoma, Hepatocellular; Cell Nucleus; Cyclooxygenase 1; Diethylnitrosamine; Disease Progression; Kelch-Like ECH-Associated Protein 1; Liver Neoplasms; Membrane Proteins; NF-E2-Related Factor 2; Proto-Oncogene Proteins c-maf; Rats; Rats, Inbred F344
PubMed: 35093454
DOI: 10.1016/j.bbamcr.2022.119222 -
Journal of Gastrointestinal Cancer Dec 2022Chromenes are a wide group of natural compounds that can be synthesized chemically. The chromen-4-one nucleus acts as a skeleton for varieties of additional active...
BACKGROUND
Chromenes are a wide group of natural compounds that can be synthesized chemically. The chromen-4-one nucleus acts as a skeleton for varieties of additional active groups that makes the chromene activity vary between antioxidant and anti-inflammatory agents. In the present study, a newly synthesized chromene compound exhibits different behaviors other than anti-inflammatory and antioxidant activities that it is the first time that a member of chromen-4-one compound can control the cancer progress. Inflammation is the first step in tumor development where the severity grade can potentiate tumor growth and progression. In many tumors, pro-inflammatory genes record high expression level such as tumor necrosis factor (TNF-α) and vascular endothelial growth factors (VEGF). These pro-inflammatory factors act as rate limiting steps in tumor initiation, and controlling its expression acts as an early therapeutic way to control the tumor proliferation. The chromone derivatives have biological activities such as anti-inflammatory and anti-tumor activity.
METHODS
In the present study, hepatocellular cancer (HCC) induced by diethylnitrosamine (DEN) in rats and then treated with the new chromene derivative and the parameters TNF-α, VEGF, p53, Cyt C, MMP-9, Bcl2, and Bax were measured.
RESULTS
The treatment strategy Ch compound is to downregulate pro-inflammatory gene expression of early genes as TNF-α as well as VEGF and subsequently control other factors such as p53, Cyt C, and MMP-9. Also, retrieve the balance between Bcl2 and Bax proteins in DEN-induced HCC in rats.
CONCLUSION
The ability of the new Ch derivative to control the primary initiators of HCC such as TNF-α offers this derivative an anti-tumor activity and encourages further researches to follow and monitor its effect on the molecular level.
Topics: Animals; Humans; Rats; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; bcl-2-Associated X Protein; Benzopyrans; Carcinoma, Hepatocellular; Diethylnitrosamine; Liver Neoplasms; Matrix Metalloproteinase 9; Proto-Oncogene Proteins c-bcl-2; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A
PubMed: 34698995
DOI: 10.1007/s12029-021-00724-9 -
Carcinogenesis Jan 2018Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity, is an emerging risk factor for hepatocellular carcinoma (HCC). Accumulating evidence has...
Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity, is an emerging risk factor for hepatocellular carcinoma (HCC). Accumulating evidence has shown that chronic inflammation represents a plausible link between obesity and HCC and that the pro-inflammatory cytokine interleukin (IL)-6 contributes to the development of obesity-related HCC. In the present study, we aimed to examine the therapeutic potential of the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA), which exerts anti-inflammatory effects. The results showed that the development of carcinogen-induced HCC was significantly less in mice fed a high-fat diet (HFD) supplemented with EPA than in those fed HFD only, suggesting that EPA attenuates the development of obesity-related HCC. Although EPA did not appear to affect obesity-linked inflammation, it suppressed the activation of the pro-tumorigenic IL-6 effector STAT3, contributing to the inhibition of tumor growth. These findings suggest a clinical implication of EPA as a treatment for obesity-related HCC.
Topics: Animals; Carcinogenesis; Carcinogens; Carcinoma, Hepatocellular; Diet, High-Fat; Diethylnitrosamine; Eicosapentaenoic Acid; Liver Neoplasms; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; STAT3 Transcription Factor
PubMed: 29040439
DOI: 10.1093/carcin/bgx112 -
Cancer Prevention Research... Nov 2017Caloric restriction (CR) and endurance exercise elicit wide-ranging health benefits including reduced risk of select cancers. In addition, diet composition influences...
Caloric restriction (CR) and endurance exercise elicit wide-ranging health benefits including reduced risk of select cancers. In addition, diet composition influences oncogenesis, although its interactions with exercise and CR are not well understood. Therefore, to investigate the potential interactions between diet and lifestyle interventions on liver tumorigenesis, the carcinogen diethylnitrosamine was administered to 72 male C57Bl/6 mice that were subsequently fed diets enriched with lard (CTL) or olive oil and were further stratified to voluntary wheel running (Ex) or 30% CR for 49 weeks. Although Ex and diet composition did not influence liver oncogenesis, CR prevented hepatic tumor formation. In addition, CR reduced steatosis, hepatocyte ballooning, inflammation, and immune cell infiltration, all of which are hallmarks in the progression of nonalcoholic fatty liver disease to liver tumorigenesis. RNA sequencing of nontransformed liver tissues from CR mice revealed changes in metabolic pathways and reduced inflammation, cytokine production, stellate cell activation and migration, and genes associated with liver injury and oncogenesis. These data demonstrate that CR protects against steatosis, liver inflammation, and liver injury and is a robust deterrent of carcinogen-induced hepatic oncogenesis. .
Topics: Animals; Caloric Restriction; Carcinogenesis; Carcinogens; Chemical and Drug Induced Liver Injury; Dietary Fats; Diethylnitrosamine; Hepatitis; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Olive Oil; Physical Conditioning, Animal
PubMed: 28847977
DOI: 10.1158/1940-6207.CAPR-17-0174