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Environmental Toxicology Sep 2019Hepatocellular carcinoma is considered one of the most prevalent and lethal malignancies worldwide. Chemotherapy with cytotoxic agents showed a low response rate with...
Hepatocellular carcinoma is considered one of the most prevalent and lethal malignancies worldwide. Chemotherapy with cytotoxic agents showed a low response rate with possible toxic effects. Recently, some emphases have been placed on the anticancer properties of bovine whey protein and its components, especially lactoferrin. The present study aimed to evaluate and compare the antihepatocarcinogenic activity of bovine whey protein concentrate (WPC, 300 and 600 mg/kg body weight) and lactoferrin (30 and 60 mg/kg body weight), orally and daily for 14 weeks, in the mice model of diethylnitrosamine (DEN)-induced hepatocarcinogenesis. The results showed that both WPC and lactoferrin (in a dose-dependent manner) alleviated significantly (P < .001) the elevation in serum markers of liver carcinoma and inflammation in the DEN-treated mice. Also, they exhibited a great amelioration in the livers' histological structure of the DEN-treated mice by 37.0% to 66.7%. In addition, they decreased significantly (P < .001) the hepatic DNA fragmentation in the DEN-treated mice by 23.1% to 32.7%. Only, the high doses of WPC and lactoferrin completely modulated the decrease in the activity of liver enzymic antioxidant defense system (catalase, glutathione peroxidase, and superoxide dismutase) and improved significantly (P < .01-.001) the concentration of hepatic reduced glutathione of the DEN-treated mice. Moreover, the high doses of WPC and lactoferrin reduced significantly (P < .05-.001) the elevation in the concentrations of hepatic active caspases 3, 8, and 9 of the DEN-treated mice. In conclusion, both WPC and lactoferrin were effective in inhibiting the hepatocarcinogenic activity of DEN in mice model through their ability to alleviate the hepatic inflammation and apoptosis.
Topics: Animals; Anticarcinogenic Agents; Antioxidants; Cattle; Diethylnitrosamine; Dose-Response Relationship, Drug; Lactoferrin; Liver; Liver Neoplasms, Experimental; Male; Mice; Whey Proteins
PubMed: 31087429
DOI: 10.1002/tox.22773 -
Bulletin of Experimental Biology and... Nov 2016The general toxic and hepatocarcinogenic effects of diethylnitrosamine after stimulation of its metabolism with 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP)...
The general toxic and hepatocarcinogenic effects of diethylnitrosamine after stimulation of its metabolism with 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) were studied. The hydroxylating activity of liver microsomes of C57Bl/6Mv mice towards p-nitrophenol increased more than 4-fold 3 days after injection of TCPOBOP. Injection of diethylnitrosamine 3 days after TCPOBOP caused a lesser body weight loss and decrease of food consumption in C57Bl/6Mv mice than in response to diethylnitrosamine without preinduction. Injection of diethylnitrosamine to suckling ICR mice after TCPOBOP induction of cytochrome P450 2e1 activity led to development of 2-fold lesser number of tumors and pretumorous nodes in the liver in comparison with animals injected with diethylnitrosamine without induction. These data indicated that metabolism stimulation reduced the general toxic and hepatocarcinogenic effects of diethylnitrosamine.
Topics: Animals; Animals, Suckling; Body Weight; Carcinogenesis; Cytochrome P-450 CYP2E1; Cytochrome P-450 Enzyme Inducers; Diethylnitrosamine; Inactivation, Metabolic; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Microsomes, Liver; Nitrophenols; Pyridines; Tumor Burden
PubMed: 27878498
DOI: 10.1007/s10517-016-3555-3 -
Current Molecular Pharmacology 2022Liver cancer ranks as the 7th and 5th leading cause of cancer morbidity worldwide in men and women, respectively. Hepatocellular Carcinoma (HCC) is the most common type...
The Protective Role of Etoricoxib Against Diethylnitrosamine/2-acetylaminofluorene- Induced Hepatocarcinogenesis in Wistar Rats: The Impact of NF-κB/COX-2/PGE2 Signaling.
BACKGROUND
Liver cancer ranks as the 7th and 5th leading cause of cancer morbidity worldwide in men and women, respectively. Hepatocellular Carcinoma (HCC) is the most common type of liver cancer and is associated with an increasing global burden of Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH).
OBJECTIVE
The present study aimed to investigate the possible chemopreventive effect of etoricoxib on diethylnitrosamine (DENA) and 2-acetylaminofluorene (2AAF)-induced HCC in male Wistar rats.
METHODS
HCC was induced by DENA (150 mg/kg/week; i.p) for 2 weeks, then 2AAF (20 mg/kg; p.o) every other day for three successive weeks. Etoricoxib (0.6 mg/kg, p.o.) was given to DENA/ 2AAF-administered rats for 20 weeks.
RESULTS
Etoricoxib significantly suppressed alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19.9) as liver tumor biomarkers. It also decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin levels while increased serum albumin levels. Besides, it alleviated DENA/2AAF-induced histopathological abrasions and inflammatory cell infiltration. Furthermore, etoricoxib showed a potent antioxidant effect, supported by a significant lipid peroxide reduction and elevation in superoxide dismutase activity and GSH content. In addition, Etoricoxib significantly down-regulated the protein expression of interleukin 1 beta (IL-1β), tumor necrosis factor α (TNFα), nuclear Factor-kappa B (NF-κB), phosphorylated nuclear Factor-kappa B (p-NF-κB), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2).
CONCLUSION
In conclusion, the current results proved that etoricoxib possesses an anticarcinogenic effect via its antioxidant, anti-inflammatory, and modulation of NF-κB/COX-2/PGE2 signaling.
Topics: 2-Acetylaminofluorene; Animals; Carcinoma, Hepatocellular; Cyclooxygenase 2; Diethylnitrosamine; Dinoprostone; Etoricoxib; Female; Humans; Liver Neoplasms; Male; NF-kappa B; Rats; Rats, Wistar
PubMed: 34238176
DOI: 10.2174/1874467214666210708103752 -
Journal of Ethnopharmacology Mar 2022Fuzheng Xiaozheng prescription (FZXZP), a traditional Chinese medicine, which was derived from the famous decoction, Sanjiasan, in the book of "Wenyilun" in Ming...
ETHNOPHARMACOLOGICAL RELEVANCE
Fuzheng Xiaozheng prescription (FZXZP), a traditional Chinese medicine, which was derived from the famous decoction, Sanjiasan, in the book of "Wenyilun" in Ming dynasty. Due to its function of invigorating the circulation of blood in Chinese medicine, it was usually used for treating the liver cirrhosis, hepatocellular carcinoma (HCC), etc. Clinical application found that FZXZP exhibited satisfactory therapeutic effects in HCC treatments. However, we still know little about the underlying mechanisms.
AIM OF STUDY
In this study, we aim to gain a deeper insight into the inhibiting effects of FZXZP on HCC rats and preliminarily elucidate the underlying intervention effects.
MATERIALS AND METHODS
Two doses of FZXZP were adopted to evaluate the therapeutic effects on rat HCC, and then the intervention effects were evaluated from different aspects. High performance liquid chromatography (HPLC) was used for the active compounds prediction in FZXZP. Finally, the mRNA-Seq was conducted to reveal the intervention mechanisms and the mechanisms were further validated by quantitative Real-time PCR (qRT-PCR) and lipid contents analyses.
RESULTS
The results showed that FZXZP significantly alleviated the serum biochemical indicators and improved the pathological characteristics of HCC rats. Mechanistically, FZXZP could regulate some lipid related metabolisms, including arachidonic acid, linoleic acid and retinol, as well as improving the steroid hormone biosynthesis, to improve the inflammatory statuses and restoring ability of HCC livers, and these were further confirmed by our following analyses on serum lipid contents and cytokine expressions. In addition, FZXZP could also negatively regulate four extracellular growth factors which could result in the blocking of two cancer-related signaling pathways, Ras/MAPK and Ras/PI3K-Akt.
CONCLUSION
Our results suggested that FZXZP demonstrated significant inhibiting effects on rat HCC progresses, and these may be realized by improving the inflammatory statuses and blocking the Ras/MAPK and Ras/PI3K-Akt signaling pathways.
Topics: Animals; Rats; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Diethylnitrosamine; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Gene Expression Regulation, Neoplastic; Liver; Liver Neoplasms; Random Allocation; Rats, Sprague-Dawley; RNA, Messenger
PubMed: 34910953
DOI: 10.1016/j.jep.2021.114913 -
Free Radical Biology & Medicine May 2019Oxidative stress and mitochondrial dysfunction play a significant role in hepatocarcinogenesis. Mitochondria are source organelle as well as target for free radicals....
BACKGROUND
Oxidative stress and mitochondrial dysfunction play a significant role in hepatocarcinogenesis. Mitochondria are source organelle as well as target for free radicals. The oxidative damage to mitochondria can be prevented by mitochondria-targeted antioxidant, mito-TEMPO. However, its efficacy in prevention of hepatocellular carcinoma has not been investigated so far.
METHODS
Murine model of hepatocarcinogenesis was developed by intraperitoneal administration of N-nitrosodiethylamine to male BALB/c mice. Mito-TEMPO was administered intraperitoneally at weekly intervals, till the completion of the study. The tumours were histopathologically analysed and anti-cancer efficacy of mito-TEMPO was evaluated in terms of survival index, tumour incidence, tumour multiplicity and tumour dielectric parameters. The antioxidant defence status and molecular composition of tumours were assessed. Gap junctions and gap-junctional intercellular communication (GJIC) were studied using ELISA, IHC and Lucifer yellow assay.
RESULTS
Mito-TEMPO treatment increased survival of animals by 30%, decreased tumour incidence (25%) and tumour multiplicity (39%). The dielectric parameters of tumours in Mito-TEMPO group were indicative of retarded carcinogenesis. Mito-TEMPO administration normalized mean saturation levels in phospholipids and improved glycogen content of the hepatic tissue. Gap junctions and GJIC which were severely impaired in hepatocarcinogenesis, improved after mito-TEMPO treatment.
CONCLUSION
Mito-TEMPO was effective in combating hepatocarcinogenesis.
Topics: Alkylating Agents; Animals; Antioxidants; Carcinogenesis; Carcinoma, Hepatocellular; Cyclic N-Oxides; Diethylnitrosamine; Gap Junctions; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mitochondria; Oxidative Stress
PubMed: 30946961
DOI: 10.1016/j.freeradbiomed.2019.03.037 -
Food and Chemical Toxicology : An... Jan 2019Neferine is a bisbenzylisoquinoline alkaloid isolated from the embryos of lotus which has attracted attention for its anti-inflammatory and anti-cancer activities. The...
Neferine is a bisbenzylisoquinoline alkaloid isolated from the embryos of lotus which has attracted attention for its anti-inflammatory and anti-cancer activities. The aim of this study was to evaluate the anti-cancer effect of neferine against diethylnitrosamine (DEN)-induced lung carcinogenesis in Wistar rats and to explore the underlying molecular mechanism. DEN-induced oxidative stress is mediated by alterations in the levels of pulmonary reactive-oxygen species, lipid peroxidation, protein carbonyl content and antioxidant status. Thus, treatment with neferine restored cellular normalcy, highlighting the antioxidant potential of neferine in mitigating the oxidative stress-mediated damage produced during DEN-induced lung carcinogenesis. Histopathological analysis showed disorganized alveolar structure, thickened alveolar wall, infiltration of inflammatory cells in DEN-induced rats, the damage was significantly reduced upon neferine treatment. DEN-induced rats exhibited increased gene expression of NF-κB, COX-2, CYP2E1, VEGF, Bcl-2, PI3K/AKT/mTOR and significantly decreased the gene expression of p53, Bax, caspase-9 and caspase-3. Neferine treatment restored the DEN- induced alteration of these gene expression levels. Further, blotting analysis also revealed increased expression of NF-κB, COX-2, Bcl-2 and decreased expression of Bax, caspase-9 and caspase-3 proteins in DEN-induced rats. Neferine treatment restored the expression of these proteins in DEN- induced lung carcinogenesis.
Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Benzylisoquinolines; Carcinogenesis; Diethylnitrosamine; Humans; Lung Neoplasms; Male; NF-kappa B; Oxidative Stress; Phosphatidylinositol 3-Kinases; Rats; Rats, Wistar; Reactive Oxygen Species
PubMed: 30423403
DOI: 10.1016/j.fct.2018.11.014 -
Oncogene Apr 2017Hepatocellular carcinoma (HCC) is one of the most deadly cancers that still lacks effective treatments. Dysregulation of kinase signaling has frequently been reported to...
Hepatocellular carcinoma (HCC) is one of the most deadly cancers that still lacks effective treatments. Dysregulation of kinase signaling has frequently been reported to contribute to HCC. In this study, we used bioinformatic approaches to identify kinases that regulate gene expression changes in human HCCs and two murine HCC models. We identified a role for calcium/calmodulin-dependent protein kinases II gamma isoform (CAMK2γ) in hepatocarcinogenesis. CAMK2γ mice displayed severely enhanced chemical-induced hepatocarcinogenesis compared with wild-type controls. Mechanistically, CAMK2γ deletion potentiates hepatic activation of mechanistic target of rapamycin complex 1 (mTORC1), which results in hyperproliferation of hepatocytes. Inhibition of mTORC1 by rapamycin effectively attenuates the compensatory proliferation of hepatocytes in CAMK2γ livers. We further demonstrated that CAMK2γ suppressed growth factor- or insulin-induced mTORC1 activation by inhibiting IRS1/AKT signaling. Taken together, our results reveal a novel mechanism by which CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.
Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Carcinogenesis; Cell Death; Cell Line, Tumor; Cell Proliferation; Diethylnitrosamine; Gene Deletion; Hepatocytes; Humans; Liver Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 27819676
DOI: 10.1038/onc.2016.400 -
Scientific Reports May 2017Chronic alcohol consumption increases the risk of hepatocellular carcinoma (HCC). However, little is known about the potential immunological mechanisms by which ethanol...
Chronic alcohol consumption increases the risk of hepatocellular carcinoma (HCC). However, little is known about the potential immunological mechanisms by which ethanol affects tumor progression. Here, adult male mice were administered multiple doses of diethylnitrosamine (DEN). Four and a half months later, the DEN-treated mice were placed on a liquid Lieber-DeCarli control diet or diet containing 5% ethanol for 2.5 months. At the end of the study, liver tissue samples were obtained to analyze pathology, gene expression, and hepatic mononuclear cells (MNCs). Results showed that ethanol feeding exacerbates the progression of hepatic tumors (characterized by the ratio of liver weight to body weight, and the tumor volume and diameter) in DEN-treated mice. Mechanistically, chronic alcohol consumption decreased the number of antitumor CD8 T cells but increased the number of tumor-associated macrophages (TAMs) in the liver in DEN-initiated tumorigenesis. Besides, TAMs were prone to be M2 phenotype after alcohol consumption. Moreover, chronic alcohol consumption aggravated inflammation, fibrosis, and epithelial-mesenchymal transition (EMT) in the pathological process of HCC. These data demonstrate that chronic alcohol consumption exacerbates DEN-induced hepatocarcinogenesis by enhancing protumor immunity, impairing antitumor immunity and aggravating hepatic pathological injury. Targeting the immune system is a potential therapeutic regimen for alcohol-promoted HCC.
Topics: Alcohol Drinking; Animals; Carcinogenesis; Carcinoma, Hepatocellular; Diethylnitrosamine; Disease Progression; Ethanol; Hepatocytes; Humans; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Mice
PubMed: 28566719
DOI: 10.1038/s41598-017-02887-7 -
Life Sciences Nov 2021Hepatocellular carcinoma (HCC) is a potentially life-threatening cancer. In the current study, anti-HCC efficacy of amygdalin, or metformin alone or in combination in...
AIM
Hepatocellular carcinoma (HCC) is a potentially life-threatening cancer. In the current study, anti-HCC efficacy of amygdalin, or metformin alone or in combination in comparison to doxorubicin was studied.
MAIN METHODS
Both in-vitro and in-vivo based models. HepG-2 and Huh-7 cell lines as established in-vitro model for HCC were treated with different concentrations of indicated drugs to evaluate the cytotoxicity and determine IC for 24, 48 and 72 h. Moreover, the effect of different treatments on apoptosis and cell cycle using flow cytometric analysis were studied. Hepatocellular carcinoma induced in rats by diethyl-nitrosamine and carbon tetrachloride was established, to further investigate the efficacy of indicated drugs. Aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase were measured by spectrophotometer, alpha-fetoprotein, cytochrome-c, caspase-3 and malondialdehyde were measured by ELISA, and liver biopsies were also evaluated histopathologically.
KEY FINDINGS
In-vitro results showed that the combination has a promising effect when compared to amygdalin or metformin alone as it is more cytotoxic and have higher ability for induction of apoptosis and arresting cell cycle. In-vivo doxorubicin has a good effect for treating HCC. Also, the combination showed a promising prognostic effect depending on the cytotoxic activity and tumor marker when compared to amygdalin or metformin alone.
SIGNIFICANCE
Based on the current data, it was hypothesized that amygdalin and metformin especially when used in combination will be a promising approach with low side effects for enhancement of HCC.
Topics: Amygdalin; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Protocols; Biomarkers, Tumor; Carcinoma, Hepatocellular; Diethylnitrosamine; Doxorubicin; Hep G2 Cells; Humans; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Metformin; Prognosis; Rats; Rats, Wistar; alpha-Fetoproteins
PubMed: 34536497
DOI: 10.1016/j.lfs.2021.119961 -
Cellular and Molecular Gastroenterology... 2021Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in...
BACKGROUND & AIMS
Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in specific cancers. Herein, we investigated how TTP contributes to the development of liver inflammation and fibrosis, which are key drivers of hepatocarcinogenesis, as well as to the onset and progression of hepatocellular carcinoma (HCC).
METHODS
TTP expression was investigated in mouse/human models of hepatic metabolic diseases and cancer. The role of TTP in nonalcoholic steatohepatitis and HCC development was further examined through in vivo/vitro approaches using liver-specific TTP knockout mice and a panel of hepatic cancer cells.
RESULTS
Our data demonstrate that TTP loss in vivo strongly restrains development of hepatic steatosis and inflammation/fibrosis in mice fed a methionine/choline-deficient diet, as well as HCC development induced by the carcinogen diethylnitrosamine. In contrast, low TTP expression fostered migration and invasion capacities of in vitro transformed hepatic cancer cells likely by unleashing expression of key oncogenes previously associated with these cancerous features. Consistent with these data, TTP was significantly down-regulated in high-grade human HCC, a feature further correlating with poor clinical prognosis. Finally, we uncover hepatocyte nuclear factor 4 alpha and early growth response 1, two key transcription factors lost with hepatocyte dedifferentiation, as key regulators of TTP expression.
CONCLUSIONS
Although TTP importantly contributes to hepatic inflammation and cancer initiation, its loss with hepatocyte dedifferentiation fosters cancer cells migration and invasion. Loss of TTP may represent a clinically relevant biomarker of high-grade HCC associated with poor prognosis.
Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Datasets as Topic; Diethylnitrosamine; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Hepatocytes; Humans; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice; Non-alcoholic Fatty Liver Disease; Primary Cell Culture; Prognosis; RNA-Seq; Survival Analysis; Tristetraprolin
PubMed: 32987153
DOI: 10.1016/j.jcmgh.2020.09.012