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1
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Farzaneh S, Salehipour M, Tafvizi F, Naseh V. The Effect of Curcumin on the Activity of MMP-17 and MMP-24 in Hepatocytes of Mice Exposed to Thioacetamide. Rep Biochem Mol Biol 2024; 13:329-340. [PMID: 40330566 PMCID: PMC12050055 DOI: 10.61186/rbmb.13.3.329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 01/09/2025] [Indexed: 05/08/2025]
Abstract
Background Hepatocellular carcinoma is the most primitive form of liver cancer, which is related to chemo carcinogens such as thioacetamide (TAA) and tissue remodeling molecules such as Matrix metalloproteinases (MMPs). Antioxidants, like curcumin (Cur), can inhibit these factors. In this research, the effect of curcumin on the expression and activity of two MMP enzymes, MMP-14 and MMP-17, which are involved in the carcinogenesis of mice after chronic exposure to thioacetamide, is investigated. Methods In this study, 30 mice were divided into six groups and studied for 4 months. The first group, control; the second group, curcumin; the third group, TAA; the fourth group, TAA and curcumin simultaneously; the fifth group, first treated with TAA for 2 months and then curcumin; and finally, the sixth group, first treated with curcumin for 2 months and then TAA. Afterward, the mice were euthanized, and their liver tissues were transferred to the laboratory for analysis of gene and protein expression. Results The averages of gene expression were calculated using SigmaPlot software and showed that the expression of MMP-17 and MMP-24 genes and the levels of their proteins were significantly increased by thioacetamide (****p < 0001) compared to the control group. Pathological observations indicated necrosis and dysplastic foci in the TAA group. Conclusions Considering the crucial roles of MMPs in various diseases, including hepatocellular carcinoma, the regulation of their gene expression and enzymatic activity is significant in preventing tumor progression. Compounds such as thioacetamide and polyphenols like curcumin can modulate the activity of MMP-17 and MMP-24.
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Affiliation(s)
- Sahar Farzaneh
- Department of Biology, Islamic Azad university of Parand Branch, Parand, Iran.
| | - Masoud Salehipour
- Department of Biology, Islamic Azad university of Parand Branch, Parand, Iran.
| | - Farzaneh Tafvizi
- Department of Biology, Islamic Azad university of Parand Branch, Parand, Iran.
| | - Vahid Naseh
- Department of Biology, Islamic Azad university of Parand Branch, Parand, Iran.
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2
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Dai C, Tian E, Hao Z, Tang S, Wang Z, Sharma G, Jiang H, Shen J. Aflatoxin B1 Toxicity and Protective Effects of Curcumin: Molecular Mechanisms and Clinical Implications. Antioxidants (Basel) 2022; 11:antiox11102031. [PMID: 36290754 PMCID: PMC9598162 DOI: 10.3390/antiox11102031] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/09/2022] [Accepted: 10/10/2022] [Indexed: 11/26/2022] Open
Abstract
One of the most significant classes of mycotoxins, aflatoxins (AFTs), can cause a variety of detrimental outcomes, including cancer, hepatitis, aberrant mutations, and reproductive issues. Among the 21 identified AFTs, aflatoxin B1 (AFB1) is the most harmful to humans and animals. The mechanisms of AFB1-induced toxicity are connected to the generation of excess reactive oxygen species (ROS), upregulation of CYP450 activities, oxidative stress, lipid peroxidation, apoptosis, mitochondrial dysfunction, autophagy, necrosis, and inflammatory response. Several signaling pathways, including p53, PI3K/Akt/mTOR, Nrf2/ARE, NF-κB, NLRP3, MAPKs, and Wnt/β-catenin have been shown to contribute to AFB1-mediated toxic effects in mammalian cells. Curcumin, a natural product with multiple therapeutic activities (e.g., anti-inflammatory, antioxidant, anticancer, and immunoregulation activities), could revise AFB1-induced harmful effects by targeting these pathways. Therefore, the potential therapeutic use of curcumin against AFB1-related side effects and the underlying molecular mechanisms are summarized. This review, in our opinion, advances significant knowledge, sparks larger discussions, and drives additional improvements in the hazardous examination of AFTs and detoxifying the application of curcumin.
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Affiliation(s)
- Chongshan Dai
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
- Correspondence:
| | - Erjie Tian
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China
| | - Zhihui Hao
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Shusheng Tang
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Zhanhui Wang
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Gaurav Sharma
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Haiyang Jiang
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Jianzhong Shen
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
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3
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Application of Non-Aflatoxigenic Aspergillus flavus for the Biological Control of Aflatoxin Contamination in China. Toxins (Basel) 2022; 14:toxins14100681. [PMID: 36287950 PMCID: PMC9611986 DOI: 10.3390/toxins14100681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/18/2022] [Accepted: 09/29/2022] [Indexed: 11/07/2022] Open
Abstract
Biological control through the application of competitive non-aflatoxigenic Aspergillus flavus (A. flavus) to the soil during peanut growth is a practical method for controlling aflatoxin contamination. However, appropriate materials need to be found to reduce the cost of biocontrol products. In this study, a two-year experiment was conducted under field conditions in China, using a native non-aflatoxigenic strain to explore its effect. After three months of storage under high humidity, aflatoxin levels remained low in peanuts from fields treated with the biocontrol agent. Three types of substrates were tested with the biocontrol agent: rice grains, peanut meal (peanut meal fertilizer) and peanut coating. Compared to untreated fields, these formulations resulted in reductions of 78.23%, 67.54% and 38.48%, respectively. Furthermore, the ratios of non-aflatoxigenic A. flavus recovered in the soils at harvest in the treated fields were between 41.11% and 96.67% higher than that in untreated fields (25.00%), indicating that the rice inoculum was the most effective, followed by the peanut meal fertilizer and peanut coating. In 2019, the mean aflatoxin content of freshly harvested peanuts in untreated fields was 19.35 µg/kg higher than that in the fields treated with 7.5 kg/ha rice inoculum, which was 1.37 µg/kg. Moreover, no aflatoxin was detected in the two other plots treated with 10 and 15 kg/ha rice inoculum. This study showed that the native Chinese non-aflatoxigenic strain of A. flavus (18PAsp-zy1) had the potential to reduce aflatoxin contamination in peanuts. In addition, peanut meal can be used as an alternative substrate to replace traditional grains, reducing the cost of biocontrol products.
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Li ZY, Li HL, Ji XW, Shen QM, Wang J, Tan YT, Xiang YB. Dose-Response Association between Adiposity and Liver Cancer Incidence: A Prospective Cohort Study among Non-Smoking and Non-Alcohol-Drinking Chinese Women. Cancer Epidemiol Biomarkers Prev 2021; 30:1200-1207. [PMID: 33849965 DOI: 10.1158/1055-9965.epi-20-1610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/20/2021] [Accepted: 03/31/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Based on a population with very low prevalence of smoking and alcohol drinking, we examined the associations between overall obesity and fat distribution in middle age, obesity in early adulthood, and adult weight gain with the risk of liver cancer incidence. METHODS The associations between body mass index (BMI) at study enrollment and at age 20, waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), adult weight gain, and annual average weight gain with the risk of liver cancer were estimated using Cox regression models. Multivariable-adjusted HRs and 95% confidence intervals (CIs) were calculated. RESULTS After a mean follow-up time of 17.5 years, 241 liver cancer cases were identified from 69,296 participants. The HRs for per 5-kg/m2 increment of BMI, per 10-cm increment of WC and HC, and per 0.1-unit increment of WHtR in middle age were 1.29 (95% CI, 1.07-1.57), 1.23 (95% CI, 1.05-1.43), 1.30 (95% CI, 1.10-1.55), and 1.37 (95% CI, 1.07-1.75), respectively. The HRs for per 5-kg increment of absolute adult weight gain and per 0.5-kg/year increment of annual average weight gain were 1.15 (95% CI, 1.06-1.25) and 1.44 (95% CI, 1.08-1.92). CONCLUSIONS Overall and abdominal obesity in middle age and weight gain through adulthood were positively associated with liver cancer risk among non-smoking and non-alcohol-drinking women. IMPACT Based on a cohort of non-smoking and non-alcohol-drinking women, the current study confirmed the association between obesity in middle age and increased liver cancer risk and suggested weight gain through adulthood as a risk factor for liver cancer.
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Affiliation(s)
- Zhuo-Ying Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong-Lan Li
- State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Wei Ji
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiu-Ming Shen
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Wang
- State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu-Ting Tan
- State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yong-Bing Xiang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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5
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Huang SH, Lin YC, Tung CW. Identification of Time-Invariant Biomarkers for Non-Genotoxic Hepatocarcinogen Assessment. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17124298. [PMID: 32560183 PMCID: PMC7345770 DOI: 10.3390/ijerph17124298] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/12/2020] [Accepted: 06/14/2020] [Indexed: 12/12/2022]
Abstract
Non-genotoxic hepatocarcinogens (NGHCs) can only be confirmed by 2-year rodent studies. Toxicogenomics (TGx) approaches using gene expression profiles from short-term animal studies could enable early assessment of NGHCs. However, high variance in the modulation of the genes had been noted among exposure styles and datasets. Expanding from our previous strategy in identifying consensus biomarkers in multiple experiments, we aimed to identify time-invariant biomarkers for NGHCs in short-term exposure styles and validate their applicability to long-term exposure styles. In this study, nine time-invariant biomarkers, namely A2m, Akr7a3, Aqp7, Ca3, Cdc2a, Cdkn3, Cyp2c11, Ntf3, and Sds, were identified from four large-scale microarray datasets. Machine learning techniques were subsequently employed to assess the prediction performance of the biomarkers. The biomarker set along with the Random Forest models gave the highest median area under the receiver operating characteristic curve (AUC) of 0.824 and a low interquartile range (IQR) variance of 0.036 based on a leave-one-out cross-validation. The application of the models to the external validation datasets achieved high AUC values of greater than or equal to 0.857. Enrichment analysis of the biomarkers inferred the involvement of chronic inflammatory diseases such as liver cirrhosis, fibrosis, and hepatocellular carcinoma in NGHCs. The time-invariant biomarkers provided a robust alternative for NGHC prediction.
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Affiliation(s)
- Shan-Han Huang
- Ph. D. Program in Toxicology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (S.-H.H.); (Y.-C.L.)
| | - Ying-Chi Lin
- Ph. D. Program in Toxicology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (S.-H.H.); (Y.-C.L.)
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chun-Wei Tung
- Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei 11031, Taiwan
- National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli County 35053, Taiwan
- Correspondence:
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6
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Ye Z, Cui P, Wang Y, Yan H, Wang X, Han S, Zhou Y. Simultaneous Determination of Four Aflatoxins in Dark Tea by Multifunctional Purification Column and Immunoaffinity Column Coupled to Liquid Chromatography Tandem Mass Spectrometry. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:11481-11488. [PMID: 31545895 DOI: 10.1021/acs.jafc.9b04933] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Dry tea matrix contains an abundance of caffeine and polyphenols which are different from the food matrix (e.g., protein, lipid, and carbohydrates), and only a few studies have tried aflatoxins determination with tea samples. Here, a specific, accurate, and sensitive method was developed and validated for the simultaneous determination of aflatoxin B1, B2, G1, and G2 in dark teas. Aflatoxins were extracted by acetonitrile/water, press-filtered, and cleaned by multifunctional purification column (MFC) and immunoaffinity column (IAC) in tandem. The cleaned extract was analyzed by liquid chromatography tandem mass spectrometry. The matrix interference was effectively reduced by MFC-IAC cleaning method. Recoveries at the spiking concentrations of 5-60 μg/kg ranged from 77.5 to 93%, with relative standard deviations <11.0%. The correlation coefficients of aflatoxins standard were >0.998. The limits of detection were 0.024-0.21 μg/kg and the limits of quantification were 0.08-0.74 μg/kg. The intra- and interday accuracy ranged from 74 to 87%, and the intra- and interday precisions ranged from 0.4 to 3.1%. After the method validation, the aflatoxins contaminations in 100 collected dark teas were detected, and the results were compared with those of other methods.
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Affiliation(s)
- Ziling Ye
- State Key Laboratory of Tea Biology and Utilization, School of Tea and Food Science Technology , Anhui Agricultural University , Heifei 230036 , China
- Shanghai Key Laboratory of Bio-Energy Crops , Shanghai University , Shanghai 200444 , China
| | - Pu Cui
- School of Life and Environmental Sciences , Huangshan University , Huangshan 245041 , China
- Shanghai Key Laboratory of Bio-Energy Crops , Shanghai University , Shanghai 200444 , China
| | - Yong Wang
- School of Life and Environmental Sciences , Huangshan University , Huangshan 245041 , China
| | - Hangbin Yan
- State Key Laboratory of Tea Biology and Utilization, School of Tea and Food Science Technology , Anhui Agricultural University , Heifei 230036 , China
| | - Xu Wang
- State Key Laboratory of Tea Biology and Utilization, School of Tea and Food Science Technology , Anhui Agricultural University , Heifei 230036 , China
| | - Sanqing Han
- State Key Laboratory of Tea Biology and Utilization, School of Tea and Food Science Technology , Anhui Agricultural University , Heifei 230036 , China
| | - Yu Zhou
- State Key Laboratory of Tea Biology and Utilization, School of Tea and Food Science Technology , Anhui Agricultural University , Heifei 230036 , China
- Shanghai Key Laboratory of Bio-Energy Crops , Shanghai University , Shanghai 200444 , China
- State Key Laboratory of Food Science and Technology , Jiangnan University , Wuxi 214122 , People's Republic of China
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7
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Wang Q, Zhang P, Li Z, Feng X, Lv C, Zhang H, Xiao H, Ding J, Chen X. Evaluation of Polymer Nanoformulations in Hepatoma Therapy by Established Rodent Models. Theranostics 2019; 9:1426-1452. [PMID: 30867842 PMCID: PMC6401493 DOI: 10.7150/thno.31683] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 01/08/2019] [Indexed: 01/10/2023] Open
Abstract
Hepatoma is one of the most severe malignancies usually with poor prognosis, and many patients are insensitive to the existing therapeutic agents, including the drugs for chemotherapy and molecular targeted therapy. Currently, researchers are committed to developing the advanced formulations with controlled drug delivery to improve the efficacy of hepatoma therapy. Numerous inoculated, induced, and genetically engineered hepatoma rodent models are now available for formulation screening. However, animal models of hepatoma cannot accurately represent human hepatoma in terms of histological characteristics, metastatic pathways, and post-treatment responses. Therefore, advanced animal hepatoma models with comparable pathogenesis and pathological features are in urgent need in the further studies. Moreover, the development of nanomedicines has renewed hope for chemotherapy and molecular targeted therapy of advanced hepatoma. As one kind of advanced formulations, the polymer-based nanoformulated drugs have many advantages over the traditional ones, such as improved tumor selectivity and treatment efficacy, and reduced systemic side effects. In this article, the construction of rodent hepatoma model and much information about the current development of polymer nanomedicines were reviewed in order to provide a basis for the development of advanced formulations with clinical therapeutic potential for hepatoma.
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Affiliation(s)
- Qilong Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, P. R. China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Ping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, P. R. China
| | - Zhongmin Li
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Xiangru Feng
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
| | - Chengyue Lv
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
| | - Huaiyu Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Haihua Xiao
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
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Liu KY, Wang LT, Hsu SH. Modification of Epigenetic Histone Acetylation in Hepatocellular Carcinoma. Cancers (Basel) 2018; 10:cancers10010008. [PMID: 29301348 PMCID: PMC5789358 DOI: 10.3390/cancers10010008] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 12/19/2017] [Accepted: 12/30/2017] [Indexed: 12/14/2022] Open
Abstract
Cells respond to various environmental factors such as nutrients, food intake, and drugs or toxins by undergoing dynamic epigenetic changes. An imbalance in dynamic epigenetic changes is one of the major causes of disease, oncogenic activities, and immunosuppressive effects. The aryl hydrocarbon receptor (AHR) is a unique cellular chemical sensor present in most organs, and its dysregulation has been demonstrated in multiple stages of tumor progression in humans and experimental models; however, the effects of the pathogenic mechanisms of AHR on epigenetic regulation remain unclear. Apart from proto-oncogene activation, epigenetic repressions of tumor suppressor genes are involved in tumor initiation, procession, and metastasis. Reverse epigenetic repression of the tumor suppressor genes by epigenetic enzyme activity inhibition and epigenetic enzyme level manipulation is a potential path for tumor therapy. Current evidence and our recent work on deacetylation of histones on tumor-suppressive genes suggest that histone deacetylase (HDAC) is involved in tumor formation and progression, and treating hepatocellular carcinoma with HDAC inhibitors can, at least partially, repress tumor proliferation and transformation by recusing the expression of tumor-suppressive genes such as TP53 and RB1.
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Affiliation(s)
- Kwei-Yan Liu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
| | - Li-Ting Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
| | - Shih-Hsien Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
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9
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Santos NP, Colaço AA, Oliveira PA. Animal models as a tool in hepatocellular carcinoma research: A Review. Tumour Biol 2017; 39:1010428317695923. [PMID: 28347231 DOI: 10.1177/1010428317695923] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Cancer is the first cause of death in developed countries and the second in developing countries. Concerning the most frequent worldwide-diagnosed cancer, primary liver cancer represents approximately 4% of all new cancer cases diagnosed globally. However, among primary liver cancer, hepatocellular carcinoma is by far the most common histological subtype. Notwithstanding the health promotion and disease prevention campaigns, more than half a million new hepatocellular carcinoma cases are reported yearly, being estimated to growth continuously until 2020. Taking this scenario under consideration and the fact that some aspects concerning hepatocellular carcinoma evolution and metastasize process are still unknown, animal models assume a crucial role to understand this disease. The animal models have also provided the opportunity to screen new therapeutic strategies. The present review was supported on research and review papers aiming the complexity and often neglected chemically induced animal models in hepatocarcinogenesis research. Despite the ongoing debate, chemically induced animal models, namely, mice and rat, can provide unique valuable information on the biotransformation mechanisms against xenobiotics and apprehend the deleterious effects on DNA and cell proteins leading to carcinogenic development. In addition, taking under consideration that no model achieves all hepatocellular carcinoma research purposes, criteria to define the " ideal" animal model, depending on the researchers' approach, are also discussed in this review.
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Affiliation(s)
- Nuno Paula Santos
- 1 Department of Veterinary Sciences, Veterinary and Animal Science Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.,2 Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Aura Antunes Colaço
- 1 Department of Veterinary Sciences, Veterinary and Animal Science Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Paula Alexandra Oliveira
- 1 Department of Veterinary Sciences, Veterinary and Animal Science Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.,2 Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
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10
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Ledda C, Loreto C, Zammit C, Marconi A, Fago L, Matera S, Costanzo V, Sanzà GF, Palmucci S, Ferrante M, Costa C, Fenga C, Biondi A, Pomara C, Rapisarda V. Non‑infective occupational risk factors for hepatocellular carcinoma: A review (Review). Mol Med Rep 2017; 15:511-533. [PMID: 28000892 PMCID: PMC5364850 DOI: 10.3892/mmr.2016.6046] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 07/01/2016] [Indexed: 02/07/2023] Open
Abstract
Liver cancer is the second leading worldwide cause of cancer‑associated mortalities. Hepatocellular carcinoma, which accounts for the majority of liver tumors, ranks fifth among types of human cancer. Well‑established risk factors for liver cancer include the hepatitis B and C viruses, aflatoxins, alcohol consumption, and oral contraceptives. Tobacco smoking, androgenic steroids, and diabetes mellitus are suspected risk factors. Current knowledge regarding non‑infective occupational risk factors for liver cancer is inconclusive. The relevance of liver disorders to occupational medicine lies in the fact that the majority of chemicals are metabolized in the liver, and toxic metabolites generated via metabolism are the predominant cause of liver damage. However, their non‑specific clinical manifestations that are similar in a number of liver diseases make diagnosis difficult. Furthermore, concomitant conditions, such as viral hepatitis and alcohol or drug abuse, may mask liver disorders that result from occupational hepatotoxic agents and block the demonstration of an occupational cause. The identification of environmental agents that result in human cancer is a long and often difficult process. The purpose of the present review is to summarize current knowledge regarding the association of non‑infective occupational risk exposure and HCC, to encourage further research and draw attention to this global occupational public health problem.
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Affiliation(s)
- Caterina Ledda
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
- Hygiene and Public Health, Department of Medical Sciences, Surgical and Advanced Technologies ‘GF Ingrassia’, University of Catania, I-95123 Catania, Italy
| | - Carla Loreto
- Human Anatomy and Histology, Department of Biomedical and Biotechnology Sciences, University of Catania, I-95123 Catania, Italy
| | - Christian Zammit
- Anatomy Department, Faculty of Medicine and Surgery, University of Malta, MSD-2080 Msida, Malta
| | - Andrea Marconi
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Lucrezia Fago
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Serena Matera
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Valentina Costanzo
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Giovanni Fuccio Sanzà
- Division of Radiology, ‘Policlinico-Vittorio Emanuele’ University Hospital, University of Catania, I-95123 Catania, Italy
| | - Stefano Palmucci
- Division of Radiology, ‘Policlinico-Vittorio Emanuele’ University Hospital, University of Catania, I-95123 Catania, Italy
| | - Margherita Ferrante
- Hygiene and Public Health, Department of Medical Sciences, Surgical and Advanced Technologies ‘GF Ingrassia’, University of Catania, I-95123 Catania, Italy
| | - Chiara Costa
- Occupational Medicine, Department of the Environment, Safety, Territory, Food and Health Sciences, University of Messina, I-98125 Messina, Italy
| | - Concettina Fenga
- Occupational Medicine, Department of the Environment, Safety, Territory, Food and Health Sciences, University of Messina, I-98125 Messina, Italy
| | - Antonio Biondi
- General Surgery, Department of General Surgery and Medical-Surgical Specialties, University of Catania, I-95123 Catania, Italy
| | - Cristoforo Pomara
- Anatomy Department, Faculty of Medicine and Surgery, University of Malta, MSD-2080 Msida, Malta
- Forensic Pathology, Department of Clinical and Experimental Medicine, University of Foggia, I-71122 Foggia, Italy
| | - Venerando Rapisarda
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
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11
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Kim KI, Chung HK, Park JH, Lee YJ, Kang JH. Alpha-fetoprotein-targeted reporter gene expression imaging in hepatocellular carcinoma. World J Gastroenterol 2016; 22:6127-6134. [PMID: 27468205 PMCID: PMC4945974 DOI: 10.3748/wjg.v22.i27.6127] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 05/02/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in Eastern Asia, and its incidence is increasing globally. Numerous experimental models have been developed to better our understanding of the pathogenic mechanism of HCC and to evaluate novel therapeutic approaches. Molecular imaging is a convenient and up-to-date biomedical tool that enables the visualization, characterization and quantification of biologic processes in a living subject. Molecular imaging based on reporter gene expression, in particular, can elucidate tumor-specific events or processes by acquiring images of a reporter gene’s expression driven by tumor-specific enhancers/promoters. In this review, we discuss the advantages and disadvantages of various experimental HCC mouse models and we present in vivo images of tumor-specific reporter gene expression driven by an alpha-fetoprotein (AFP) enhancer/promoter system in a mouse model of HCC. The current mouse models of HCC development are established by xenograft, carcinogen induction and genetic engineering, representing the spectrum of tumor-inducing factors and tumor locations. The imaging analysis approach of reporter genes driven by AFP enhancer/promoter is presented for these different HCC mouse models. Such molecular imaging can provide longitudinal information about carcinogenesis and tumor progression. We expect that clinical application of AFP-targeted reporter gene expression imaging systems will be useful for the detection of AFP-expressing HCC tumors and screening of increased/decreased AFP levels due to disease or drug treatment.
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12
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13
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Genome-Wide Transcriptome Analysis of Cotton (Gossypium hirsutum L.) Identifies Candidate Gene Signatures in Response to Aflatoxin Producing Fungus Aspergillus flavus. PLoS One 2015; 10:e0138025. [PMID: 26366857 PMCID: PMC4569580 DOI: 10.1371/journal.pone.0138025] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 08/24/2015] [Indexed: 11/19/2022] Open
Abstract
Aflatoxins are toxic and potent carcinogenic metabolites produced from the fungi Aspergillus flavus and A. parasiticus. Aflatoxins can contaminate cottonseed under conducive preharvest and postharvest conditions. United States federal regulations restrict the use of aflatoxin contaminated cottonseed at >20 ppb for animal feed. Several strategies have been proposed for controlling aflatoxin contamination, and much success has been achieved by the application of an atoxigenic strain of A. flavus in cotton, peanut and maize fields. Development of cultivars resistant to aflatoxin through overexpression of resistance associated genes and/or knocking down aflatoxin biosynthesis of A. flavus will be an effective strategy for controlling aflatoxin contamination in cotton. In this study, genome-wide transcriptome profiling was performed to identify differentially expressed genes in response to infection with both toxigenic and atoxigenic strains of A. flavus on cotton (Gossypium hirsutum L.) pericarp and seed. The genes involved in antifungal response, oxidative burst, transcription factors, defense signaling pathways and stress response were highly differentially expressed in pericarp and seed tissues in response to A. flavus infection. The cell-wall modifying genes and genes involved in the production of antimicrobial substances were more active in pericarp as compared to seed. The genes involved in auxin and cytokinin signaling were also induced. Most of the genes involved in defense response in cotton were highly induced in pericarp than in seed. The global gene expression analysis in response to fungal invasion in cotton will serve as a source for identifying biomarkers for breeding, potential candidate genes for transgenic manipulation, and will help in understanding complex plant-fungal interaction for future downstream research.
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KIM JEEYOUNG, AHN HUIJEONG, WOO HEUNGMYONG, LEE EUNSONG, LEE GEUNSHIK. Generation of liver-specific TGF-α and c-Myc-overexpressing fibroblasts for future creation of a liver cancer porcine model. Mol Med Rep 2014; 10:329-35. [DOI: 10.3892/mmr.2014.2217] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 03/28/2014] [Indexed: 11/05/2022] Open
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15
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Santella RM, Wu HC. Environmental Exposures and Hepatocellular Carcinoma. J Clin Transl Hepatol 2013; 1:138-43. [PMID: 26357611 PMCID: PMC4521280 DOI: 10.14218/jcth.2013.008xx] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Revised: 04/29/2013] [Accepted: 05/21/2013] [Indexed: 01/27/2023] Open
Abstract
Infection with hepatitis B and/or hepatitis C virus is a well-established risk factor for the development of hepatocellular carcinoma (HCC). However, it is now clear that certain occupational, environmental, and lifestyle factors also play a role in cancer development. Among these factors are smoking, alcohol consumption, workplace exposure to vinyl chloride, and exposure to polycylic aromatic hydrocarbons and aflatoxins. There is also evidence that several other chemical and infectious agents have a role in inducing HCC in humans. Epidemiologic studies and the use of biomarkers have provided essential data to demonstrate the importance of some of these factors in human risk, while animal studies have suggested that other chemicals may also play a role. Although immunization against hepatitis B virus infection remains the primary method of preventing HCC in regions of the world where this virus is a primary etiologic agent, there is currently no vaccine for hepatitis C virus. Thus, limiting exposure to other known risk factors remains an important mechanism in preventing HCC.
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Affiliation(s)
- Regina M. Santella
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA
| | - Hui-Chen Wu
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA
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16
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Inhibition of non-toxigenic Aspergillus niger FS10 isolated from Chinese fermented soybean on growth and aflatoxin B1 production by Aspergillus flavus. Food Control 2013. [DOI: 10.1016/j.foodcont.2012.12.013] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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17
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Yu J. Current understanding on aflatoxin biosynthesis and future perspective in reducing aflatoxin contamination. Toxins (Basel) 2012; 4:1024-57. [PMID: 23202305 PMCID: PMC3509697 DOI: 10.3390/toxins4111024] [Citation(s) in RCA: 190] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Revised: 10/08/2012] [Accepted: 10/09/2012] [Indexed: 01/20/2023] Open
Abstract
Traditional molecular techniques have been used in research in discovering the genes and enzymes that are involved in aflatoxin formation and genetic regulation. We cloned most, if not all, of the aflatoxin pathway genes. A consensus gene cluster for aflatoxin biosynthesis was discovered in 2005. The factors that affect aflatoxin formation have been studied. In this report, the author summarized the current status of research progress and future possibilities that may be used for solving aflatoxin contamination.
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Affiliation(s)
- Jiujiang Yu
- Southern Regional Research Center, Agricultural Research Service, United States Department of Agriculture (USDA/ARS), New Orleans, LA 70112, USA.
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18
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Abstract
Primary liver cancer remains one of the most lethal malignancies worldwide. As this disease is lethal in most cases, research has to be done to improve our understanding of the disease and to offer insights for possible treatment options. Animal models have been widely used in the research of primary liver cancer. Here, we review the progress and prospects for the development of animal models of primary liver cancer, highlighting the best candidates for future preclinical investigations.
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Choi KC, Chung WT, Kwon JK, Jang YS, Yu JY, Park SM, Lee JC. Chemoprevention of a flavonoid fraction from Rhus verniciflua Stokes on aflatoxin B1-induced hepatic damage in mice. J Appl Toxicol 2010; 31:150-6. [PMID: 20737424 DOI: 10.1002/jat.1575] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2010] [Revised: 06/20/2010] [Accepted: 06/21/2010] [Indexed: 01/05/2023]
Abstract
Since aflatoxin B(1) (AFB(1))-mediated hepatic damage is related to the production of AFB(1)-8,9-epoxide and reactive oxygen species, bioactive compounds having antioxidant potentials are suggested to be capable of reducing AFB(1)-induced toxicity. We previously purified a mixture of flavonoids that we named RCMF (Rhus verniciflua Stokes chloroform-methanol fraction), from a traditional Korean food additive and herbal medicine. RCMF exhibited various biological effects, including antioxidant and antitumor activities. In this study, we examined whether RCMF protects against AFB(1)-induced liver injury using in vitro and in vivo systems. Pretreatment of HepG2 cells with RCMF significantly reduced AFB(1)-stimulated production of ROS and malondialdehyde (MDA) to the control levels. RCMF also prevented the reduction in HepG2 cell viability caused by AFB(1). Oral administration of RCMF to mice significantly suppressed an AFB(1)-induced increase in serum levels of alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase. It also prevented MDA formation and blocked decreases in glutathione levels and superoxide dismutase activities in the livers of AFB(1)-treated mice. In addition, RCMF supplementation prevented an AFB(1) -induced decrease in serum titers of IgA and IgG1. Collectively, these results suggest that RCMF attenuates AFB(1)-mediated damage to the liver, and that this effect is at least partially related to the restoration of antioxidant defense systems and an increase in AFB(1)-GSH conjugate formation.
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Affiliation(s)
- Ki-Choon Choi
- National Livestock Research Institute, RDA, Suweon, Korea
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20
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Wu MH, Ma WL, Hsu CL, Chen YL, Ou JHJ, Ryan CK, Hung YC, Yeh S, Chang C. Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription. Sci Transl Med 2010; 2:32ra35. [PMID: 20484730 PMCID: PMC3032595 DOI: 10.1126/scitranslmed.3001143] [Citation(s) in RCA: 159] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatitis B virus (HBV)-induced hepatitis and carcinogen-induced hepatocellular carcinoma (HCC) are associated with serum androgen concentration. However, how androgen or the androgen receptor (AR) contributes to HBV-induced hepatocarcinogenesis remains unclear. We found that hepatic AR promotes HBV-induced hepatocarcinogenesis in HBV transgenic mice that lack AR only in the liver hepatocytes (HBV-L-AR(-/y)). HBV-L-AR(-/y) mice that received a low dose of the carcinogen N'-N'-diethylnitrosamine (DEN) have a lower incidence of HCC and present with smaller tumor sizes, fewer foci formations, and less alpha-fetoprotein HCC marker than do their wild-type HBV-AR(+/y) littermates. We found that hepatic AR increases the HBV viral titer by enhancing HBV RNA transcription through direct binding to the androgen response element near the viral core promoter. This activity forms a positive feedback mechanism with cooperation with its downstream target gene HBx protein to promote hepatocarcinogenesis. Administration of a chemical compound that selectively degrades AR, ASC-J9, was able to suppress HCC tumor size in DEN-HBV-AR(+/y) mice. These results demonstrate that targeting the AR, rather than the androgen, could be developed as a new therapy to battle HBV-induced HCC.
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MESH Headings
- Androgen Receptor Antagonists
- Animals
- Antineoplastic Agents/pharmacology
- Base Sequence
- Carcinoma, Hepatocellular/chemically induced
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/prevention & control
- Carcinoma, Hepatocellular/virology
- Cell Transformation, Viral/genetics
- Curcumin/analogs & derivatives
- Curcumin/pharmacology
- Diethylnitrosamine
- Disease Models, Animal
- Gene Expression Regulation, Neoplastic
- Hep G2 Cells
- Hepatitis B/complications
- Hepatitis B/genetics
- Hepatitis B virus/genetics
- Humans
- Liver/metabolism
- Liver/pathology
- Liver/virology
- Liver Neoplasms/chemically induced
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/prevention & control
- Liver Neoplasms/virology
- Male
- Mice
- Mice, Knockout
- Mice, Transgenic
- Molecular Sequence Data
- Promoter Regions, Genetic
- RNA, Viral/metabolism
- Receptors, Androgen/deficiency
- Receptors, Androgen/genetics
- Receptors, Androgen/metabolism
- Time Factors
- Transcription, Genetic
- Transfection
- Tumor Burden
- Viral Load
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Affiliation(s)
- Ming-Heng Wu
- Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Wen-Lung Ma
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA
- Sex Hormone Research Center, Graduate Institute of Clinical Medical Science, Department of Obstetrics and Gynecology, China Medical University/Hospital, Taichung 404, Taiwan
| | - Cheng-Lung Hsu
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung University/Memorial Hospital, Taoyuan 33305, Taiwan
| | - Yuh-Ling Chen
- Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90089, USA
| | - Charlotte Kathryn Ryan
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Yao-Ching Hung
- Sex Hormone Research Center, Graduate Institute of Clinical Medical Science, Department of Obstetrics and Gynecology, China Medical University/Hospital, Taichung 404, Taiwan
| | - Shuyuan Yeh
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Chawnshang Chang
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA
- Sex Hormone Research Center, Graduate Institute of Clinical Medical Science, Department of Obstetrics and Gynecology, China Medical University/Hospital, Taichung 404, Taiwan
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21
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Leenders MWH, Nijkamp MW, Rinkes IHMB. Mouse models in liver cancer research: A review of current literature. World J Gastroenterol 2008; 14:6915-23. [PMID: 19058325 PMCID: PMC2773853 DOI: 10.3748/wjg.14.6915] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary liver cancer remains one of the most lethal malignancies worldwide. Due to differences in prevalence of etiological factors the incidence of primary liver cancer varies among the world, with a peak in East-Asia. As this disease is still lethal in most of the cases, research has to be done to improve our understanding of the disease, offering insights for possible treatment options. For this purpose, animal models are widely used, especially mouse models. In this review, we describe the different types of mouse models used in liver cancer research, with emphasis on genetically engineered mice used in this field. We focus on hepatocellular carcinoma (HCC), as this is by far the most common type of primary liver cancer, accounting for 70%-85% of cases.
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22
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Investigation of acute effects of aflatoxin on rat proximal and distal colon spontaneous contractions. Food Chem Toxicol 2008; 46:2876-80. [PMID: 18620790 DOI: 10.1016/j.fct.2008.05.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2008] [Revised: 05/22/2008] [Accepted: 05/26/2008] [Indexed: 11/24/2022]
Abstract
Aflatoxins are one of the most potent toxic, mutagenic, teratogenic, cancerogenic, and immunosuppresive substances that naturally occurring contaminants of food. There are some studies in various animal species that have reported aflatoxin effects on gastrointestinal systems, but acute effects of aflatoxins have not been clearly investigated. In this study, we aimed to investigate the acute gastrointestinal effects of total aflatoxin on rat isolated proximal and distal colon. Aflatoxin was given cumulatively at 10(-8)-10(-5)M concentrations and the amplitude and frequency of proximal and distal colon contractions were increased significantly. In the presence of atropine sulfate (23.6 nM) and morphine (0.3 microM) the amplitude and frequency of aflatoxin induced spontan contractions in the proximal and distal colon decreased significantly, on the other hand, L-NNA (0.3 microM) increased contractions' amplitude and frequency significantly in the proximal colon but not in the distal colon. In conclusion, aflatoxin may increase the amplitude and frequency of contractions by increasing muscarinic activity or by decreasing NO synthase and/or release in proximal colon and by increasing muscarinic activity in the distal colon. These findings of aflatoxin on isolated rat proximal and distal colon may explain their acute gastrointestinal effects in humans and animals.
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23
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Lian M, Liu Y, Yu SZ, Qian GS, Wan SG, Dixon KR. Hepatitis B virus x gene and cyanobacterial toxins promote aflatoxin B 1-induced hepatotumorigenesis in mice. World J Gastroenterol 2006; 12:3065-72. [PMID: 16718789 PMCID: PMC4124383 DOI: 10.3748/wjg.v12.i19.3065] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the combinative role of aflatoxin B1 (AFB1), cyanobacterial toxins (cyanotoxins), and hepatitis B virus (HBV) x gene in hepatotumorigenicity.
METHODS: One-week-old animals carrying HBV x gene and their wild-type littermates were intraperitoneally (ip) injected with either single-dose AFB1 [6 mg/kg body weight (bw)], repeated-dose cyanotoxins (microcystin-LR or nodularin, 10 μg/kg bw once a week for 15 wk), DMSO (vehicle control) alone, or AFB1 followed by cyanotoxins a week later, and were sacrificed at 24 and 52 wk post-treatment.
RESULTS: AFB1 induced liver tumors in 13 of 29 (44.8%) transgenic mice at 52 wk post-treatment, significantly more frequent than in wild-type mice (13.3%). This significant difference was not shown in the 24-wk study. Compared with AFB1 exposure alone, MC-LR and nodularin yielded approximately 3-fold and 6-fold increases in the incidence of AFB1-induced liver tumors in wild-type animals at 24 wk, respectively. HBV x gene did not further elevate the risk associated with co-exposure to AFB1 and cyanotoxins. With the exception of an MC-LR-dosed wild-type mouse, no liver tumor was observed in mice treated with cyanotoxins alone at 24 wk. Neither DMSO-treated transgenic mice nor their wild-type littermates had pathologic alterations relevant to hepatotumorigenesis in even up to 52 wk.
CONCLUSION: HBV x gene and nodularin promote the development of AFB1-induced liver tumors. Co-exposure to AFB1 and MC-LR tends to elevate the risk of liver tumors at 24 wk relative to exposure to one of them. The combinative effect of AFB1, cyanotoxins and HBVx on hepatotumorigenesis is weak at 24 wk.
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Affiliation(s)
- Min Lian
- School of Public Health, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
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24
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Chang CK, Astrakianakis G, Thomas DB, Seixas NS, Ray RM, Gao DL, Wernli KJ, Fitzgibbons ED, Vaughan TL, Checkoway H. Occupational exposures and risks of liver cancer among Shanghai female textile workers--a case-cohort study. Int J Epidemiol 2005; 35:361-9. [PMID: 16373377 DOI: 10.1093/ije/dyi282] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Liver cancer is the fifth most frequent malignancy worldwide. Viral hepatitis B and C, alcohol, and aflatoxin are the major established risk factors. Little is known about the aetiological contributions of occupational exposures, as previous occupational epidemiological studies of liver cancer suggest few agent-specific associations. We investigated associations of occupational exposures to dusts and chemicals in a cohort of female textile workers. METHODS Cancer incidence was determined among 267,400 female textile workers in Shanghai, China, who had been enrolled in an intervention trial of breast self-exam efficacy during 1989-98. Subjects were interviewed at baseline regarding basic demographics, smoking habits, alcohol consumption, and contraceptive practices. A case-cohort study of 360 liver cancer cases and 3,186 age-stratified randomly chosen subcohort subjects was conducted within this cohort. Exposures to workplace dusts and chemicals were reconstructed from complete work history data, historical exposure monitoring data for selected agents, and a specially designed job-exposure matrix for the textile industry. Relative risks and dose-response trends were estimated by Cox proportional hazards modelling, adapted for the case-cohort design. Latency analyses with different lag years were also applied. RESULTS 2,095,904 person-years were contributed by this female cohort. The results of the case-cohort analysis revealed a protective effect of cotton fibre exposure years [adjusted hazards ratio (HR) = 0.64; 95% confidence interval (95% CI) 0.44-0.92] or endotoxin exposure (adjusted HR = 0.60; 95% CI 0.41-0.88) for the fourth quartile with significant trends for 20 year exposure lags. CONCLUSIONS This study suggests that chronic exposure to endotoxin or some other component of cotton dust exposure may have reduced liver cancer risk in this population.
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Affiliation(s)
- Chin-Kuo Chang
- Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA.
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25
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Kirk GD, Lesi OA, Mendy M, Szymañska K, Whittle H, Goedert JJ, Hainaut P, Montesano R. 249(ser) TP53 mutation in plasma DNA, hepatitis B viral infection, and risk of hepatocellular carcinoma. Oncogene 2005; 24:5858-67. [PMID: 16007211 DOI: 10.1038/sj.onc.1208732] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hepatocellular carcinoma (HCC) from regions with high dietary exposure to aflatoxins and endemic for hepatitis B virus (HBV) often contain a specific mutation at codon 249 in TP53 (249(ser); AGG to AGT, Arg to Ser). This mutation is also detectable in circulating cell-free DNA from the plasma of HCC patients and healthy subjects in these regions. We have examined the joint effect of plasma 249(ser) and HBV infection in a case-control study design involving 348 control, 98 cirrhotic, and 186 HCC participants from The Gambia, West Africa, an area of high HCC incidence. The 249(ser) mutation was detected in 3.5% of controls, 15.3% of cirrhotics, and 39.8% of HCC cases (adjusted odds ratios (OR): 4.83, (95% confidence interval (CI): 1.71-13.7) for cirrhosis and 20.3 (8.19-50.0) for HCC). HBsAg positivity along with plasma 249(ser) was observed in 45/183 (24.6%) HCC cases compared to only one (0.3%) control. Risk for HCC was associated with markers of HBV alone (OR: 10.0, 95% CI: 5.16-19.6), 249(ser) alone (OR: 13.2, 95% CI: 4.99-35.0), and both markers present (OR: 399, 95% CI: 48.6-3270). These results suggest a multiplicative effect on HCC risk resulting from the mutational effect of aflatoxin on TP53, as monitored by detection of plasma 249(ser), with concomitant chronic infection with HBV.
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26
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Abstract
A causal association between genetic alterations and cancer is supported by extensive experimental and epidemiological data. Mutational inactivation of tumor suppressor genes and activation of oncogenes are associated with the development of a wide range of cancers. The link between mutagenesis and carcinogenesis is particularly evident for cancers induced by chemical exposures, which, in some cases, lead to characteristic patterns of mutations. These "genotoxic," direct-acting carcinogens form covalent adducts with DNA, which cause mutations during DNA replication. The link between mutagenesis and carcinogenesis is also supported by the observation that DNA repair defects are associated with an increased cancer risk. Normally, DNA repair mechanisms serve to suppress mutagenesis by correcting DNA damage before it can lead to heritable mutations. It has been postulated that mutagenesis plays a role in both the initiation phase and the progression phase of carcinogenesis, and that an essential step in the carcinogenic process is the development of a mutator state in which the normal cellular processes that suppress mutagenesis become compromised. Given the link between mutations and cancer, attempts have been made to use the mutational profile of cancer cells as an indicator of the causative agent. While this may be a valid approach in some cases, it is complicated by the role of endogenous processes in promoting mutagenesis. In addition, many important carcinogenic agents may enhance mutagenesis indirectly through suppression of DNA repair functions or stimulation of inappropriate cell proliferation. Epigenetic phenomena may also suppress gene expression without causing overt changes in DNA sequence.
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Affiliation(s)
- Kathleen Dixon
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
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27
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Townson SM. Environmental Pollutants and Breast Cancer. Cancer Invest 2004; 22:474-6. [PMID: 15493368 DOI: 10.1081/cnv-200029078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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28
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Scheidegger KA, Payne GA. Unlocking the Secrets Behind Secondary Metabolism: A Review ofAspergillus flavusfrom Pathogenicity to Functional Genomics. ACTA ACUST UNITED AC 2003. [DOI: 10.1081/txr-120024100] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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Abstract
The signal transducer and activator of transcription (STAT)-3 regulates basic biological processes and it has been reported to be constitutively active in different types of malignant tumours. STAT-3 is active during the regenerative growth of the liver, but there are hardly any data about its presence in liver tumours. We investigated and found a high activity of STAT-3 using an electrophoretic mobility shift assay (EMSA) in chemically-induced rat hepatocellular carcinomas (HCCs). Dexamethasone treatment downregulated both STAT-3 activity and cell proliferation in the tumours. Therefore, the activity of the STAT-3 signal transduction pathway seems to be required for the growth of HCCs and could be a potential new target for therapeutic trials of this tumour type.
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Affiliation(s)
- A Sánchez
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, MD, Bethesda, USA
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30
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Salama SA, Au WW. Susceptibility and biomarker knowledge for improvement of environmental health. Int J Hyg Environ Health 2003; 206:401-12. [PMID: 12971696 DOI: 10.1078/1438-4639-00237] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
At the international level, environmental health problems are usually most serious in countries that have the least resources to deal with the problems. Therefore, international efforts have been initiated to achieve equitable environmental health globally. One approach is to conduct international collaborative studies. This approach has been successful in the building of scientific infrastructure in these countries so that they can address their own environmental health concerns and to sustain the environmental health programs. Using liver and oral cancers as models for discussion, examples of success in the identification of etiology and the mechanisms for the diseases are provided. For example, biomarkers are used to provide early warning signals for the disease. In addition, the application of the collected information for developing disease prevention and intervention programs is presented. Expertise in genetic susceptibility is used to provide a more precise understanding of the cancer process. With the precise knowledge, the information can potentially be used to screen for high-risk individuals and to develop "designer" intervention procedures against specific biochemical defects. Success in disease prevention is dependent upon multidisciplinary collaborations at the local and international levels.
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Affiliation(s)
- Salama A Salama
- Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, Texas 77555-1110, USA
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Abstract
DNA from Aspergillus sp. has been reported not to contain 5-methylcytosine. However, it has been found that Aspergillus nidulans responds to 5-azacytidine, a drug that is a strong inhibitor of DNA methyltransferases. Therefore, we have re-examined the occurrence of 5-methylcytosine in DNA from Aspergillus flavus by using a highly sensitive and specific method for detection of modified bases in genomic DNA comprising high-performance liquid chromatography separation of nucleosides, labeling of the nucleoside with deoxynucleoside kinase and two-dimensional thin-layer chromatography. Our results show that 5-methylcytosine is present in DNA from A. flavus. We estimate the relative amounts of 5-methylcytosine to cytosine to be approximately 1/400.
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Affiliation(s)
- H Gowher
- Institut für Biochemie, FB 8, Heinrich-Buff-Ring 58, 3392 Giessen, Germany
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Draper WM. Biological monitoring: exquisite research probes, risk assessment, and routine exposure measurement. Anal Chem 2001; 73:2745-60. [PMID: 11432702 DOI: 10.1021/ac010394s] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- W M Draper
- Sanitation and Radiation Laboratory, California Department of Health Services, Berkeley 94704, USA
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