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Więckowska M, Cichon N, Szelenberger R, Gorniak L, Bijak M. Ochratoxin A and Its Role in Cancer Development: A Comprehensive Review. Cancers (Basel) 2024; 16:3473. [PMID: 39456567 PMCID: PMC11506779 DOI: 10.3390/cancers16203473] [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: 09/13/2024] [Revised: 10/05/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Ochratoxin A (OTA) is widely recognized for its broad spectrum of toxic effects and is classified as a potential human carcinogen, placed in group 2B by the International Agency for Research on Cancer (IARC). Its presence in food and beverages poses a significant health hazard. Extensive research has documented the efficient absorption and distribution of OTA throughout the body via the bloodstream and tissues, underscoring the associated health risk. Additionally, ongoing studies aim to clarify the link between OTA exposure and carcinogenesis. The obtained results indicate a strong correlation between OTA and renal cell carcinoma (RCC), with potential associations with other malignancies, including hepatocellular carcinoma (HCC), gallbladder cancer (GBC), and squamous cell carcinoma (SCC). OTA is implicated in oxidative stress, lipid peroxidation, apoptosis, DNA damage, adduct formation, miRNA deregulation, and distributions in the cell cycle, all of which may contribute to carcinogenesis. Conclusions: Despite significant research efforts, the topic remains inexhaustible and requires further investigation. The obtained results do not yield definitive conclusions, potentially due to species-specific differences in the animal models used and challenges in extrapolating these results to humans. In our review, we delve deeper into the potential mechanisms underlying OTA-induced carcinogenesis and discuss existing limitations, providing directions for future research.
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Affiliation(s)
| | - Natalia Cichon
- Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; (M.W.); (R.S.); (L.G.); (M.B.)
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Mangione W, Falls Z, Samudrala R. Effective holistic characterization of small molecule effects using heterogeneous biological networks. Front Pharmacol 2023; 14:1113007. [PMID: 37180722 PMCID: PMC10169664 DOI: 10.3389/fphar.2023.1113007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 04/11/2023] [Indexed: 05/16/2023] Open
Abstract
The two most common reasons for attrition in therapeutic clinical trials are efficacy and safety. We integrated heterogeneous data to create a human interactome network to comprehensively describe drug behavior in biological systems, with the goal of accurate therapeutic candidate generation. The Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun multiscale therapeutic discovery, repurposing, and design was enhanced by integrating drug side effects, protein pathways, protein-protein interactions, protein-disease associations, and the Gene Ontology, and complemented with its existing drug/compound, protein, and indication libraries. These integrated networks were reduced to a "multiscale interactomic signature" for each compound that describe its functional behavior as vectors of real values. These signatures are then used for relating compounds to each other with the hypothesis that similar signatures yield similar behavior. Our results indicated that there is significant biological information captured within our networks (particularly via side effects) which enhance the performance of our platform, as evaluated by performing all-against-all leave-one-out drug-indication association benchmarking as well as generating novel drug candidates for colon cancer and migraine disorders corroborated via literature search. Further, drug impacts on pathways derived from computed compound-protein interaction scores served as the features for a random forest machine learning model trained to predict drug-indication associations, with applications to mental disorders and cancer metastasis highlighted. This interactomic pipeline highlights the ability of Computational Analysis of Novel Drug Opportunities to accurately relate drugs in a multitarget and multiscale context, particularly for generating putative drug candidates using the information gleaned from indirect data such as side effect profiles and protein pathway information.
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Affiliation(s)
| | | | - Ram Samudrala
- Jacobs School of Medicine and Biomedical Sciences, Department of Biomedical Informatics, University at Buffalo, Buffalo, NY, United States
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Comparative Analysis of Multiple GWAS Results Identifies Metabolic Pathways Associated with Resistance to A. flavus Infection and Aflatoxin Accumulation in Maize. Toxins (Basel) 2022; 14:toxins14110738. [PMID: 36355988 PMCID: PMC9695789 DOI: 10.3390/toxins14110738] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/14/2022] [Accepted: 10/27/2022] [Indexed: 01/26/2023] Open
Abstract
Aflatoxins are carcinogenic secondary metabolites produced by several species of Aspergillus, including Aspergillus flavus, an important ear rot pathogen in maize. Most commercial corn hybrids are susceptible to infection by A. flavus, and aflatoxin contaminated grain causes economic damage to farmers. The creation of inbred lines resistant to Aspergillus fungal infection or the accumulation of aflatoxins would be aided by knowing the pertinent alleles and metabolites associated with resistance in corn lines. Multiple Quantitative Trait Loci (QTL) and association mapping studies have uncovered several dozen potential genes, but each with a small effect on resistance. Metabolic pathway analysis, using the Pathway Association Study Tool (PAST), was performed on aflatoxin accumulation resistance using data from four Genome-wide Association Studies (GWAS). The present research compares the outputs of these pathway analyses and seeks common metabolic mechanisms underlying each. Genes, pathways, metabolites, and mechanisms highlighted here can contribute to improving phenotypic selection of resistant lines via measurement of more specific and highly heritable resistance-related traits and genetic gain via marker assisted or genomic selection with multiple SNPs linked to resistance-related pathways.
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Kumari S, Sharma S, Advani D, Khosla A, Kumar P, Ambasta RK. Unboxing the molecular modalities of mutagens in cancer. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:62111-62159. [PMID: 34611806 PMCID: PMC8492102 DOI: 10.1007/s11356-021-16726-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 09/22/2021] [Indexed: 04/16/2023]
Abstract
The etiology of the majority of human cancers is associated with a myriad of environmental causes, including physical, chemical, and biological factors. DNA damage induced by such mutagens is the initial step in the process of carcinogenesis resulting in the accumulation of mutations. Mutational events are considered the major triggers for introducing genetic and epigenetic insults such as DNA crosslinks, single- and double-strand DNA breaks, formation of DNA adducts, mismatched bases, modification in histones, DNA methylation, and microRNA alterations. However, DNA repair mechanisms are devoted to protect the DNA to ensure genetic stability, any aberrations in these calibrated mechanisms provoke cancer occurrence. Comprehensive knowledge of the type of mutagens and carcinogens and the influence of these agents in DNA damage and cancer induction is crucial to develop rational anticancer strategies. This review delineated the molecular mechanism of DNA damage and the repair pathways to provide a deep understanding of the molecular basis of mutagenicity and carcinogenicity. A relationship between DNA adduct formation and cancer incidence has also been summarized. The mechanistic basis of inflammatory response and oxidative damage triggered by mutagens in tumorigenesis has also been highlighted. We elucidated the interesting interplay between DNA damage response and immune system mechanisms. We addressed the current understanding of DNA repair targeted therapies and DNA damaging chemotherapeutic agents for cancer treatment and discussed how antiviral agents, anti-inflammatory drugs, and immunotherapeutic agents combined with traditional approaches lay the foundations for future cancer therapies.
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Affiliation(s)
- Smita Kumari
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Sudhanshu Sharma
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Dia Advani
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Akanksha Khosla
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India.
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Whole-Transcriptome Analysis of Non-Coding RNA Alteration in Porcine Alveolar Macrophage Exposed to Aflatoxin B1. Toxins (Basel) 2022; 14:toxins14060373. [PMID: 35737034 PMCID: PMC9230535 DOI: 10.3390/toxins14060373] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/19/2022] [Accepted: 05/25/2022] [Indexed: 11/20/2022] Open
Abstract
Aflatoxin B1 (AFB1) is a type of mycotoxin produced by the fungi Aspergillus flavus and Aspergillus parasiticus and is commonly found in cereals, oils and foodstuffs. In order to understand the toxic effects of AFB1 exposure on Porcine alveolar macrophages (3D4/2 cell), the 3D4/2 cells were exposed to 40 μg/mL AFB1 for 24 h in vitro, and several methods were used for analysis. Edu and TUNEL analysis showed that the proliferation of 3D4/2 cells was significantly inhibited and the apoptosis of 3D4/2 cells was significantly induced after AFB1 exposure compared with that of the control group. Whole-transcriptome analysis was performed to reveal the non-coding RNA alteration in 3D4/2 cells after AFB1 exposure. It was found that the expression of cell-cycle-related and apoptosis-related genes was altered after AFB1 exposure, and lncRNAs and miRNAs were also significantly different among the experimental groups. In particular, AFB1 exposure affected the expression of lncRNAs associated with cellular senescence signaling pathways, such as MSTRG.24315 and MSTRG.80767, as well as related genes, Cxcl8 and Gadd45g. In addition, AFB1 exposure affected the expression of miRNAs associated with immune-related genes, such as miR-181a, miR-331-3p and miR-342, as well as immune-related genes Nfkb1 and Rras2. Moreover, the regulation networks between mRNA-miRNAs and mRNA-lncRNAs were confirmed by the results of RT-qPCR and immunofluorescence. In conclusion, our results here demonstrate that AFB1 exposure impaired proliferation of 3D4/2 cells via the non-coding RNA-mediated pathway.
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Stepanov YV, Golovynska I, Dziubenko NV, Kuznietsova HM, Petriv N, Skrypkina I, Golovynskyi S, Stepanova LI, Stohnii Y, Garmanchuk LV, Ostapchenko LI, Yevsa T, Qu J, Ohulchanskyy TY. NMDA receptor expression during cell transformation process at early stages of liver cancer in rodent models. Am J Physiol Gastrointest Liver Physiol 2022; 322:G142-G153. [PMID: 34851733 DOI: 10.1152/ajpgi.00060.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, which is not sensitive to radiotherapy and chemotherapy and very often experiences postoperative relapse. In this regard, effective screening of liver cancer is considered as the most important and urgent task. The aim of our study was to determine whether N-methyl-D-aspartate receptor (NMDAR) and, in particular, its subunits, can serve as biomarkers to distinguish the precancerous liver at early stages of liver fibrosis. We assessed the development of HCC after 10, 15, and 22 wk using a HCC rat model. The expression of NMDAR subunits was monitored at different stages of HCC by means of immunohistochemistry combined with epifluorescence microscopy imaging, Western blotting, and direct bisulfite sequencing. NMDAR subunits were not found in healthy liver tissues. In contrast, NMDAR subunits, in particular NR1 and NR2B, appeared at the stage of severe liver fibrosis (precancerous liver disease) in rats and were expressed during the development of HCC in rats and mice. Using the direct bisulfite sequencing, we detected that increased expression of NMDAR directly correlated with the demethylation of CpG islands in the promoter region of genes encoding receptor subunits. The obtained results confirmed that NMDAR subunits can serve as new biomarkers of precancerous liver disease, severe fibrosis, and its progression towards HCC.NEW & NOTEWORTHY We have shown NMDAR expression in cell transformation process at early stages of cancer, specifically HCC. The aim of our study was to define the disease stages from precancerous liver disease towards liver cancer progression when NMDAR subunits were expressed/detected. A fibrosis/HCC rat model, immunohistochemistry combined with epifluorescence microscopy imaging, Western blotting was used. The dynamics of appearance of NMDAR subunits, their expression and methylation status during the development of HCC were shown and discussed.
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Affiliation(s)
- Yurii V Stepanov
- Center for Biomedical Optics and Photonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Iuliia Golovynska
- Center for Biomedical Optics and Photonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Nataliia V Dziubenko
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Halyna M Kuznietsova
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Nataliia Petriv
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Inessa Skrypkina
- Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - Sergii Golovynskyi
- Center for Biomedical Optics and Photonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Liudmyla I Stepanova
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Yevhenii Stohnii
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Liudmyla V Garmanchuk
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Liudmyla I Ostapchenko
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Tetyana Yevsa
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Junle Qu
- Center for Biomedical Optics and Photonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Tymish Y Ohulchanskyy
- Center for Biomedical Optics and Photonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
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El-Senduny FF, Zidane MM, Youssef MM, Badria FA. An Approach to Treatment of Liver Cancer by Novel Glycyrrhizin Derivative. Anticancer Agents Med Chem 2020; 19:1863-1873. [PMID: 30973113 DOI: 10.2174/1871520619666190411114718] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 03/04/2019] [Accepted: 04/03/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Liver cancer is a life threating disease as it is the fifth most common cancer and the third most common cause of death worldwide with no safe, efficient, and economic drug available for treatment. METHODS This study intended to investigate glycyrrhizin and its derivatives for possible use as a cytotoxic agent and as a drug for liver cancer treatment. Thus, after treatment of liver cancer cell line HepG-2 with 50 μM of each compound, cell viability was determined. RESULTS The cytotoxicity assay showed glycyrrhizin derivatives ME-GA (18β-Glycyrrhetinic-30-methyl ester) and AKBA (3-acetyl-11- keto-β-Boswellic acid) to be the most potent drug against liver cancer cell line HepG-2 with IC50 values 25.50 ± 1.06 and 19.73 ± 0.89 μM, respectively. Both the compounds showed higher selectivity towards hepatocellular carcinoma rather than the normal lung fibroblast cell line WI-38. The presence of methyl ester at C-30 greatly increased the cytotoxicity of ME-GA which might be attributed to its higher activity and selectivity. Both ME-GA and AKBA contributed to inhibit cancer cell migration in the wound healing assay and impeded colony formation. The use of flow cytometry to carry out cell cycle analysis and the determination of possible mechanisms of action for apoptosis revealed that ME-GA arrested the cell cycle at G2/M that led to the inhibition of hepatocellular carcinoma and induced apoptosis via the extrinsic pathway and its ability to increase p53 transactivation. CONCLUSION This work highlights the cytotoxicity of glycyrrhizin and its derivatives for possible use as a chemotherapeutic agent against hepatocellular carcinoma cells HepG-2. The most cytotoxic compound was ME-GA (18β-Glycyrrhetinic-30-methyl ester) with no cytotoxic effect on the normal cell line. In summary, this new derivative may be used as an alternative or complementary medicine for liver cancer.
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Affiliation(s)
- Fardous F El-Senduny
- Department of Biochemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
| | - Mahmoud M Zidane
- Department of Biochemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
| | - Magdy M Youssef
- Department of Biochemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
| | - Farid A Badria
- Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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Wang C, Sun L, Zhao Q. A simple aptamer molecular beacon assay for rapid detection of aflatoxin B1. CHINESE CHEM LETT 2019. [DOI: 10.1016/j.cclet.2019.01.029] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Kaur P, Purewal SS, Sandhu KS, Kaur M. DNA damage protection: an excellent application of bioactive compounds. BIORESOUR BIOPROCESS 2019. [DOI: 10.1186/s40643-019-0237-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
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Metabolites Identified during Varied Doses of Aspergillus Species in Zea mays Grains, and Their Correlation with Aflatoxin Levels. Toxins (Basel) 2018; 10:toxins10050187. [PMID: 29735944 PMCID: PMC5983243 DOI: 10.3390/toxins10050187] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 04/30/2018] [Accepted: 05/04/2018] [Indexed: 11/16/2022] Open
Abstract
Aflatoxin contamination is associated with the development of aflatoxigenic fungi such as Aspergillus flavus and A. parasiticus on food grains. This study was aimed at investigating metabolites produced during fungal development on maize and their correlation with aflatoxin levels. Maize cobs were harvested at R3 (milk), R4 (dough), and R5 (dent) stages of maturity. Individual kernels were inoculated in petri dishes with four doses of fungal spores. Fungal colonisation, metabolite profile, and aflatoxin levels were examined. Grain colonisation decreased with kernel maturity: milk-, dough-, and dent-stage kernels by approximately 100%, 60%, and 30% respectively. Aflatoxin levels increased with dose at dough and dent stages. Polar metabolites including alanine, proline, serine, valine, inositol, iso-leucine, sucrose, fructose, trehalose, turanose, mannitol, glycerol, arabitol, inositol, myo-inositol, and some intermediates of the tricarboxylic acid cycle (TCA—also known as citric acid or Krebs cycle) were important for dose classification. Important non-polar metabolites included arachidic, palmitic, stearic, 3,4-xylylic, and margaric acids. Aflatoxin levels correlated with levels of several polar metabolites. The strongest positive and negative correlations were with arabitol (R = 0.48) and turanose and (R = −0.53), respectively. Several metabolites were interconnected with the TCA; interconnections of the metabolites with the TCA cycle varied depending upon the grain maturity.
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Xiang X, Qin H, You X, Wang Y, Qi L, Ma L, Xiang B, Zhong J, Li L. Expression of P62 in hepatocellular carcinoma involving hepatitis B virus infection and aflatoxin B1 exposure. Cancer Med 2017; 6:2357-2369. [PMID: 28941211 PMCID: PMC5633547 DOI: 10.1002/cam4.1176] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 07/23/2017] [Accepted: 08/04/2017] [Indexed: 01/27/2023] Open
Abstract
This study aims to clarify the relationship and mechanism between expression of autophagy-related protein P62 and prognosis of patients with hepatocellular carcinoma (HCC) involving chronic hepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) exposure. HCC patients who underwent resection were divided into three groups: HBV(+)/AFB1(+) (n = 26), HBV(+)/AFB1(-) (n = 68), and HBV(-)/AFB1(-) (n = 14). The groups were compared in terms of mRNA and protein levels of P62, disease-free survival (DFS), and overall survival (OS) and the expression of NRF2, Nqo1, and AKR7A3 in P62 high-expression and low-expression group. HBV(+)/AFB1(+) group has lower DFS and OS, and higher P62 expression than in the other two groups. P62 expression generally correlated with elevated NRF2 and Nqo1 expression, and reduced AKR7A3 expression. Patients expressing high levels of P62 showed significantly lower DFS and OS rates than patients expressing low levels. HCC involving HBV infection and AFB1 exposure is associated with relatively high risk of tumor recurrence, and this poor prognosis may relate to high P62 expression. High P62 expression activates the NRF2 pathway, promotes tumor recurrence. The downregulation of AKR7A3 also reduced liver detoxification of aflatoxin B1.
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Affiliation(s)
- Xiao Xiang
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
| | - Hong‐Gui Qin
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
| | - Xue‐Mei You
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
| | - Yan‐Yan Wang
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
| | - Lu‐Nan Qi
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
| | - Liang Ma
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
| | - Bang‐De Xiang
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
| | - Jian‐Hong Zhong
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
| | - Le‐Qun Li
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
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Chemopreventive effect of 18β-glycyrrhetinic acid via modulation of inflammatory markers and induction of apoptosis in human hepatoma cell line (HepG2). Mol Cell Biochem 2016; 416:169-77. [PMID: 27116616 DOI: 10.1007/s11010-016-2705-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 04/13/2016] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is one of the most common lethal diseases worldwide and there is no effective treatment till date. Natural products derived from the plants play an important role in chemoprevention and act as therapeutic antitumor agents. Licorice is a plant that has been used in food and medicine for the treatment of various diseases. 18β-Glycyrrhetinic acid (18β-GA), a pentacyclic triterpenoid obtained from the roots of licorice plant, is reported to possess various pharmacological properties such as antitumor and antiinflammatory activities. The present study was designed to elucidate the chemopreventive effect of 18β-GA through antiinflammation, antiproliferation, and induction of apoptosis in human hepatoma cell line HepG2. 18β-GA significantly inhibits the proliferation of HepG2 cell without affecting the normal liver cell line (Chang's). In the present study, 18β-GA increased the formation of reactive oxygen species, nitric oxide production, and loss of mitochondrial membrane potential, suggesting the involvement of 18β-GA in apoptosis which was also confirmed by assessing the markers involved in apoptosis like caspase-3, caspase-9, Bax:Bcl-2 ratio, and cleaved PARP. 18β-GA also downregulated the expression of inflammatory proteins such as NF-κB, iNOS, and COX-2. Keeping these data into consideration, our results suggest that 18β-GA may be used as a chemopreventive agent in liver cancer.
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Blackadar CB. Historical review of the causes of cancer. World J Clin Oncol 2016; 7:54-86. [PMID: 26862491 PMCID: PMC4734938 DOI: 10.5306/wjco.v7.i1.54] [Citation(s) in RCA: 155] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 10/31/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
In the early 1900s, numerous seminal publications reported that high rates of cancer occurred in certain occupations. During this period, work with infectious agents produced only meager results which seemed irrelevant to humans. Then in the 1980s ground breaking evidence began to emerge that a variety of viruses also cause cancer in humans. There is now sufficient evidence of carcinogenicity in humans for human T-cell lymphotrophic virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, human papillomavirus, Epstein-Barr virus, and human herpes virus 8 according to the International Agency for Research on Cancer (IARC). Many other causes of cancer have also been identified by the IARC, which include: Sunlight, tobacco, pharmaceuticals, hormones, alcohol, parasites, fungi, bacteria, salted fish, wood dust, and herbs. The World Cancer Research Fund and the American Institute for Cancer Research have determined additional causes of cancer, which include beta carotene, red meat, processed meats, low fibre diets, not breast feeding, obesity, increased adult height and sedentary lifestyles. In brief, a historical review of the discoveries of the causes of human cancer is presented with extended discussions of the difficulties encountered in identifying viral causes of cancer.
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14
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Qi LN, Li LQ, Chen YY, Chen ZH, Bai T, Xiang BD, Qin X, Xiao KY, Peng MH, Liu ZM, Liu TW, Qin X, Li S, Han ZG, Mo ZN, Santella RM, Winkler CA, O’Brien SJ, Peng T. Genome-wide and differential proteomic analysis of hepatitis B virus and aflatoxin B1 related hepatocellular carcinoma in Guangxi, China. PLoS One 2013; 8:e83465. [PMID: 24391771 PMCID: PMC3877066 DOI: 10.1371/journal.pone.0083465] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 11/04/2013] [Indexed: 02/06/2023] Open
Abstract
Both hepatitis B virus (HBV) and aflatoxin B1 (AFB1) exposure can cause liver damage as well as increase the probability of hepatocellular carcinoma (HCC). To investigate the underlying genetic changes that may influence development of HCC associated with HBV infection and AFB1 exposure, HCC patients were subdivided into 4 groups depending upon HBV and AFB1 exposure status: (HBV(+)/AFB1(+), HBV(+)/AFB1(-), HBV(-)/AFB1(+), HBV(-)/AFB1(-)). Genetic abnormalities and protein expression profiles were analyzed by array-based comparative genomic hybridization and isobaric tagging for quantitation. A total of 573 chromosomal aberrations (CNAs) including 184 increased and 389 decreased were detected in our study population. Twenty-five recurrently altered regions (RARs; chromosomal alterations observed in ≥10 patients) in chromosomes were identified. Loss of 4q13.3-q35.2, 13q12.1-q21.2 and gain of 7q11.2-q35 were observed with a higher frequency in the HBV(+)/AFB1(+), HBV(+)/AFB1(-) and HBV(-)/AFB1(+) groups compared to the HBV(-)/AFB(-) group. Loss of 8p12-p23.2 was associated with high TNM stage tumors (P = 0.038) and was an unfavorable prognostic factor for tumor-free survival (P =0.045). A total of 133 differentially expressed proteins were identified in iTRAQ proteomics analysis, 69 (51.8%) of which mapped within identified RARs. The most common biological processes affected by HBV and AFB1 status in HCC tumorigenesis were detoxification and drug metabolism pathways, antigen processing and anti-apoptosis pathways. Expression of AKR1B10 was increased significantly in the HBV(+)/AFB1(+) and HBV(-)/AFB1(+) groups. A significant correlation between the expression of AKR1B10 mRNA and protein levels as well as AKR1B10 copy number was observered, which suggest that AKR1B10 may play a role in AFB1-related hepatocarcinogenesis. In summary, a number of genetic and gene expression alterations were found to be associated with HBV and AFB1- related HCC. The possible synergistic effects of HBV and AFB1 in hepatocarcinogenesis warrant further investigations.
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Affiliation(s)
- Lu-Nan Qi
- Department of Hepatobiliary Surgery, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Le-Qun Li
- Department of Hepatobiliary Surgery, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Yuan-Yuan Chen
- Department of Ultrasound, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Zhao-Hong Chen
- Department of Hepatobiliary Surgery, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Tao Bai
- Department of Hepatobiliary Surgery, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Bang-De Xiang
- Department of Hepatobiliary Surgery, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Xiao Qin
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Kai-Yin Xiao
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Min-Hao Peng
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Zhi-Ming Liu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Tang-Wei Liu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Xue Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Shan Li
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Ze-Guang Han
- China National Human Genome Center at Shanghai, Shanghai, China
| | - Zeng-Nan Mo
- Department of Urology and Nephrology Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Regina M. Santella
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, United States of America
| | - Cheryl A. Winkler
- Laboratory of Genomic Diversity, National Cancer Institute, NIH, Frederick, Maryland, United States of America
| | - Stephen J. O’Brien
- Laboratory of Genomic Diversity, National Cancer Institute, NIH, Frederick, Maryland, United States of America
| | - Tao Peng
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
- Laboratory of Genomic Diversity, National Cancer Institute, NIH, Frederick, Maryland, United States of America
- * E-mail:
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Reverberi M, Zjalic S, Ricelli A, Di Meo C, Scarpari M, Fanelli C, Fabbri A. Mushrooms versus fungi: natural compounds from Lentinula edodes inhibit aflatoxin biosynthesis by Aspergillus parasiticus. WORLD MYCOTOXIN J 2011. [DOI: 10.3920/wmj2010.1270] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Although the strategies routinely adopted to limit production of carcinogenic aflatoxins by Aspergillus parasiticus and Aspergillus flavus in foods and feeds can be quite effective, they are often neither environmentally friendly, nor non-toxic for end users. Polysaccharides and glycoproteins, particularly β-glucans from the basidiomycete Lentinula edodes, already known for their health-promoting effects on animals and humans, have previously demonstrated the ability to inhibit aflatoxin biosynthesis by stimulating the antioxidant defences of the toxigenic fungus. Here the results of a study regarding the influence on polysaccharide production by L. edodes of oxidative stress induced using paraquat (PQ) treatment are reported. Paraquat 0.5 and 1 mM resulted in an enhancement of the expression of the β-glucan synthase gene Lefks1 and a consequent stimulating effect (about 30-35%) on β-glucans production. Moreover, oxidative-stress (PQ) induced polysaccharides have a higher aflatoxin inhibiting capacity in two different strains of A. parasiticus in comparison with non-induced polysaccharides. This more efficient inhibition might be explained by a higher content of β-glucans because 1H-NMR analysis revealed no obvious qualitative differences between PQ-induced and non-induced polysaccharides. The results obtained show promise for improving the quantity and efficiency of L. edodes extracts in order to achieve enhanced control over aflatoxin biosynthesis in foods and feeds using health-promoting and environmentally-friendly compounds.
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Affiliation(s)
- M. Reverberi
- Department of Environmental Biology, Sapienza University of Rome, L. go Cristina di Svezia 24, 00165 Rome, Italy
| | - S. Zjalic
- Department of Mediterranean Agriculture and Aquaculture, University of Zadar, M. Pavlinovica bb, 23 000 Zadar, Croatia
| | - A. Ricelli
- Istituto di Chimica Biomolecolare, CNR, P. le Aldo Moro 5, 00189 Rome, Italy
| | - C. Di Meo
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy
| | - M. Scarpari
- Department of Environmental Biology, Sapienza University of Rome, L. go Cristina di Svezia 24, 00165 Rome, Italy
| | - C. Fanelli
- Department of Environmental Biology, Sapienza University of Rome, L. go Cristina di Svezia 24, 00165 Rome, Italy
| | - A. Fabbri
- Department of Environmental Biology, Sapienza University of Rome, L. go Cristina di Svezia 24, 00165 Rome, Italy
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16
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Ahn J, Kim D, Kim H, Jahng KY. Quantitative determination of mycotoxins in urine by LC-MS/MS. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2011; 27:1674-82. [PMID: 20818517 DOI: 10.1080/19440049.2010.505201] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Naturally occurring mycotoxins are responsible for a wide array of adverse health effects. The measurement of urinary mycotoxin levels is a useful means of assessing an individual's exposure, but the development of sensitive and accurate analytical methods for detecting mycotoxins and their metabolites in urine samples is challenging. Urinary mycotoxins are present in low pg ml⁻¹ concentrations, and the chromatographic identification of their metabolites can be obscured by other endogenous metabolites. We developed an analytical method focused on the selection of two appropriate multiple-reaction monitoring transition for unambiguous identification and quantification of carcinogenic aflatoxin M₁ (AFM₁), ochratoxin A (OTA) and fumonisin B₁, B₂ (FB₁, FB₂) in urine samples from a small volunteer group in a pilot study. AFM₁, OTA, FB₁ and FB₂ were concentrated selectively, interfering substances were removed using an immunoaffinity column (IAC), and mycotoxins were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in combination with a stable-isotope standard-dilution assay (SIDA). The method was sensitive enough to measure mycotoxins and their metabolites at pg ml⁻¹ levels in urine. The combination of LC-MS/MS and SIDA was critical to distinguishing pseudo-OTα interference from genuine OTα. Twelve urine samples contained OTA ranging from 0.013 to 0.093 ng ml⁻¹ (mean = 0.031 ng ml⁻¹). AFM₁ were detected in one sample at a 0.002 ng ml⁻¹ level, while FB₁ and FB₂ were undetectable in all 12 samples. None of the samples in this pilot study contained a detectable level of OTα, despite the presence of OTA, and this may suggest the need for further epidemiological investigation of OTA exposure in the Korean population.
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Affiliation(s)
- J Ahn
- National Agricultural Products Quality Management Service, Seoul, Korea.
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17
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Yusof YAM, Saad SM, Makpol S, Shamaan NA, Ngah WZW. Hot water extract of Chlorella vulgaris induced DNA damage and apoptosis. Clinics (Sao Paulo) 2010; 65:1371-7. [PMID: 21340229 PMCID: PMC3020351 DOI: 10.1590/s1807-59322010001200023] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Revised: 10/26/2010] [Accepted: 10/26/2010] [Indexed: 02/02/2023] Open
Abstract
OBJECTIVES The aim of this study was to determine the antiproliferative and apoptotic effects of hot water extracts of Chlorella vulgaris on hepatoma cell line HepG2. INTRODUCTION The search for food and spices that can induce apoptosis in cancer cells has been a major study interest in the last decade. Chlorella vulgaris, a unicellular green algae, has been reported to have antioxidant and anti-cancer properties. However, its chemopreventive effects in inhibiting the growth of cancer cells have not been studied in great detail. METHODS HepG2 liver cancer cells and WRL68 normal liver cells were treated with various concentrations (0-4 mg/ml) of hot water extract of C. vulgaris after 24 hours incubation. Apoptosis rate was evaluated by TUNEL assay while DNA damage was assessed by Comet assay. Apoptosis proteins were evaluated by Western blot analysis. RESULTS Chlorella vulgaris decreased the number of viable HepG2 cells in a dose dependent manner (p < 0.05), with an IC50 of 1.6 mg/ml. DNA damage as measured by Comet assay was increased in HepG2 cells at all concentrations of Chlorella vulgaris tested. Evaluation of apoptosis by TUNEL assay showed that Chlorella vulgaris induced a higher apoptotic rate (70%) in HepG2 cells compared to normal liver cells, WRL68 (15%). Western blot analysis showed increased expression of pro-apoptotic proteins P53, Bax and caspase-3 in the HepG2 cells compared to normal liver cells WRL68, and decreased expression of the anti-apoptotic protein Bcl-2. CONCLUSIONS Chlorella vulgaris may have anti-cancer effects by inducing apoptosis signaling cascades via an increased expression of P53, Bax and caspase-3 proteins and through a reduction of Bcl-2 protein, which subsequently lead to increased DNA damage and apoptosis.
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Affiliation(s)
- Yasmin Anum Mohd Yusof
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
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18
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Ranchal I, González R, Bello RI, Ferrín G, Hidalgo AB, Linares CI, Aguilar-Melero P, González-Rubio S, Barrera P, Marchal T, Nakayama KI, de la Mata M, Muntané J. The reduction of cell death and proliferation by p27(Kip1) minimizes DNA damage in an experimental model of genotoxicity. Int J Cancer 2009; 125:2270-80. [PMID: 19672859 DOI: 10.1002/ijc.24621] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer worldwide. The expression of p27 has been related to reduced severity of tumor grade and recurrence of HCC. The study assessed the role of p27 on the cell proliferation and death, and DNA mutagenesis in experimental genotoxicity induced by aflatoxin B1 (AFB(1)) in cultured hepatocytes obtained from control and p27(Kip1) deficient mice. The overexpression of p27 was assessed with wild type p27(Kip1) expression vector in HepG2 cells. The expression of p27, p21 and p53 was assessed in well and poorly-differentiated liver tumors. DNA damage and cell death induced by AFB(1) were related to a reduction of p27 and p21 expression in cultured hepatocytes. AFB(1)-induced nuclear phosphorylated (Ser 10) p27 degradation was related to a rise of nuclear KIST, Rsk-1 and Rsk-2 expression and cytoplasm phosphorylated (Thr 198) p27 expression. The overexpression of p27 reduced cell proliferation, cell death and DNA damage in AFB(1)-treated hepatocytes. The enhanced survival of patients with well differentiated compared to poorly-differentiated tumors was related to high expression of p27, p21 and p53 in liver sections. The study showed that the p27 reduced cell proliferation and death, as well as the accumulation of DNA damage in hepatocarcinogenesis.
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Affiliation(s)
- Isidora Ranchal
- Liver Research Unit, Reina Sofia University Hospital, Córdoba, Spain
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19
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Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009; 41:89-295. [PMID: 19514967 DOI: 10.1080/03602530902843483] [Citation(s) in RCA: 541] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.
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Affiliation(s)
- Shu-Feng Zhou
- School of Health Sciences, RMIT University, Bundoora, Victoria, Australia.
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20
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Wrieden WL, Anderson AS. Measurement of food and alcohol intake in relation to chronic liver disease. Stat Methods Med Res 2009; 18:285-301. [PMID: 19036908 DOI: 10.1177/0962280208094694] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
It is well established that the consumption of alcohol is implicated in both the cause and progression of chronic liver disease. The quantity of drink that is consumed, the pattern of drinking and type of alcoholic beverages consumed are all possible factors in disease aetiology. The impact of specific dietary components on the cause and progression of chronic liver disease is unclear although it is known that obesity, and hence the over-consumption of energy, is a predictor of fatty liver. Work to elucidate the role of both diet and alcohol in the aetiology of liver disease is hindered by the methods currently available to measure dietary (including alcohol) intake. The validity and reliability of retrospective methods of assessing diet are limited by their reliance on memory and, for the 24 h recall, the short-time period of intake assessed and its inability to assess variability across the week. Prospective methods which measure food and drink intake at the time of consumption, and include weighed or estimated food diaries, are useful for prospective cohort studies but are expensive and have a high respondent burden. For estimation of alcohol intake retrospectively, the Cognitive Lifetime Drinking questionnaire, which prompts responses using a lifetime calendar, is a useful tool but still depends on memory. More work is required to develop valid, reliable and easily administered tools for measurement of both diet and alcohol.
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Affiliation(s)
- Wendy L Wrieden
- Centre for Public Health Nutrition Research, Division of Medicine and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
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Jiang J, Gusev Y, Aderca I, Mettler TA, Nagorney DM, Brackett DJ, Roberts LR, Schmittgen TD. Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res 2008. [PMID: 18223217 DOI: 10.1158/1087-0432.ccr-07-0523] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE MicroRNA (miRNA) is a new class of small, noncoding RNA. The purpose of this study was to determine if miRNAs are differentially expressed in hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN More than 200 precursor and mature miRNAs were profiled by real-time PCR in 43 and 28 pairs of HCC and adjacent benign liver, respectively, and in normal liver specimens. RESULTS Several miRNAs including miR-199a, miR-21, and miR-301 were differentially expressed in the tumor compared with adjacent benign liver. A large number of mature and precursor miRNAs were up-regulated in the adjacent benign liver specimens that were both cirrhotic and hepatitis-positive compared with the uninfected, noncirrhotic specimens (P < 0.01). Interestingly, all of the miRNAs in this comparison had increased expression and none were decreased. The expression of 95 randomly selected mRNAs was not significantly altered in the cirrhotic and hepatitis-positive specimens, suggesting a preferential increase in the transcription of miRNA. Comparing the miRNA expression in the HCC tumors with patient's survival time revealed two groups of patients; those with predominantly lower miRNA expression and poor survival and those with predominantly higher miRNA expression and good survival (P < 0.05). A set of 19 miRNAs significantly correlated with disease outcome. A number of biological processes including cell division, mitosis, and G(1)-S transition were predicted to be targets of the 19 miRNAs in this group. CONCLUSION We show that a global increase in the transcription of miRNA genes occurs in cirrhotic and hepatitis-positive livers and that miRNA expression may prognosticate disease outcome in HCC.
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Affiliation(s)
- Jinmai Jiang
- College of Pharmacy, Ohio State University, Columbus, OH 43210, USA
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22
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Jiang J, Gusev Y, Aderca I, Mettler TA, Nagorney DM, Brackett DJ, Roberts LR, Schmittgen TD. Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res 2008; 14:419-27. [PMID: 18223217 PMCID: PMC2755230 DOI: 10.1158/1078-0432.ccr-07-0523] [Citation(s) in RCA: 421] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE MicroRNA (miRNA) is a new class of small, noncoding RNA. The purpose of this study was to determine if miRNAs are differentially expressed in hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN More than 200 precursor and mature miRNAs were profiled by real-time PCR in 43 and 28 pairs of HCC and adjacent benign liver, respectively, and in normal liver specimens. RESULTS Several miRNAs including miR-199a, miR-21, and miR-301 were differentially expressed in the tumor compared with adjacent benign liver. A large number of mature and precursor miRNAs were up-regulated in the adjacent benign liver specimens that were both cirrhotic and hepatitis-positive compared with the uninfected, noncirrhotic specimens (P < 0.01). Interestingly, all of the miRNAs in this comparison had increased expression and none were decreased. The expression of 95 randomly selected mRNAs was not significantly altered in the cirrhotic and hepatitis-positive specimens, suggesting a preferential increase in the transcription of miRNA. Comparing the miRNA expression in the HCC tumors with patient's survival time revealed two groups of patients; those with predominantly lower miRNA expression and poor survival and those with predominantly higher miRNA expression and good survival (P < 0.05). A set of 19 miRNAs significantly correlated with disease outcome. A number of biological processes including cell division, mitosis, and G(1)-S transition were predicted to be targets of the 19 miRNAs in this group. CONCLUSION We show that a global increase in the transcription of miRNA genes occurs in cirrhotic and hepatitis-positive livers and that miRNA expression may prognosticate disease outcome in HCC.
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MESH Headings
- Carcinoma, Hepatocellular/complications
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/mortality
- Disease Progression
- Gene Expression Profiling
- Hepatitis, Viral, Human/complications
- Hepatitis, Viral, Human/genetics
- Hepatitis, Viral, Human/metabolism
- Humans
- Liver Cirrhosis/complications
- Liver Cirrhosis/genetics
- Liver Cirrhosis/metabolism
- Liver Neoplasms/complications
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/mortality
- MicroRNAs/metabolism
- Prognosis
- RNA, Messenger/metabolism
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Affiliation(s)
- Jinmai Jiang
- College of Pharmacy, Ohio State University, Columbus, Ohio
| | - Yuriy Gusev
- Department of Surgery, University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma
| | - Ileana Aderca
- Divisions of Gastroenterology and Hepatology and Gastroenterological Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Teresa A. Mettler
- Divisions of Gastroenterology and Hepatology and Gastroenterological Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - David M. Nagorney
- Divisions of Gastroenterology and Hepatology and Gastroenterological Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Daniel J. Brackett
- Department of Surgery, University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma
| | - Lewis R. Roberts
- Divisions of Gastroenterology and Hepatology and Gastroenterological Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota
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Huang X, Ji G, Wu Y, Wan B, Yu L. LAMA4, highly expressed in human hepatocellular carcinoma from Chinese patients, is a novel marker of tumor invasion and metastasis. J Cancer Res Clin Oncol 2007; 134:705-14. [DOI: 10.1007/s00432-007-0342-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2007] [Accepted: 11/19/2007] [Indexed: 12/11/2022]
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Abstract
Molecular Pathogenesis of Hepatocellular CarcinomaThe most important risk factors for the development of human hepatocellular carcinoma (HCC) are chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), high dietary exposure to hepatic carcinogen aflatoxin B1 and alcohol abuse. Hepatitis B virus exerts its effects through integration of the viral DNA into the hepatocyte genome, or through acting as transcriptional regulator for several cellular proto-oncogenes and tumor-suppressor genes. Hepatitis C virus may affect hepatocytes via the transcriptional regulation activity of the HCV core protein or via the HCV non structural proteins NS5A, NS5B and NS2, interfering with the regulation of cell cycle and apoptosis. Environmental exposure to aflatoxin B1 can cause a specific missense mutation in codon 249 of the p53 tumor-suppressor gene. Habitual alcohol consumption leads to production of reactive oxygen species and peroxidation damage to DNA. The objective of this review is to make you acquainted with the most common risk factors and the most frequent genetic aberrations associated with the development of HCC.
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25
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Unusan N. Occurrence of aflatoxin M1 in UHT milk in Turkey. Food Chem Toxicol 2006; 44:1897-900. [PMID: 16893597 DOI: 10.1016/j.fct.2006.06.010] [Citation(s) in RCA: 103] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2005] [Revised: 03/28/2006] [Accepted: 06/08/2006] [Indexed: 10/24/2022]
Abstract
Aflatoxin M1 (AFM1) appears in milk as a direct result of the ingestion of food contaminated with aflatoxin B1 by cattle. The role of milk in human nutrition is well-known. The purpose of the study was to determine the levels of AFM1 in UHT milk samples in Central Anatolia, Turkey. The occurrence of AFM1 contamination in UHT milk samples was investigated by ELISA (Enzyme Linked Immunosorbent Assay) technique. A total of 129 samples of commercial UHT whole milk were analysed. The mean value was 108.17 ng/L. There was a high incidence rate of AFM1, with 75 (58.1%) milk samples being contaminated. Although 68 (53%) were below the limit, the remaining 61 (47%) were well above the limit permitted by the EU. Four of the samples exceeded the prescribed limit of US regulations. It can be concluded that AFM1 levels in the samples purchased in Central Anatolia Region, appear to be a serious public health problem at the moment. Dairy farmers must be educated by the government authorities on potential health consequences of aflatoxins.
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Affiliation(s)
- Nurhan Unusan
- Selcuk University, Education Faculty, 42090 Konya, Turkey.
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26
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Glintborg B, Weimann A, Kensler TW, Poulsen HE. Oltipraz chemoprevention trial in Qidong, People's Republic of China: unaltered oxidative biomarkers. Free Radic Biol Med 2006; 41:1010-4. [PMID: 16934685 DOI: 10.1016/j.freeradbiomed.2006.06.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2005] [Revised: 06/09/2006] [Accepted: 06/25/2006] [Indexed: 10/24/2022]
Abstract
Aflatoxin, which leads to formation of carcinogen-DNA adducts as well as oxidized DNA, is a well-known risk factor for development of hepatocellular carcinoma. The aim of the present study was to investigate if the chemopreventive agent oltipraz had an effect on DNA oxidation measured as oxidized guanine derivatives in urine among healthy individuals living in a region of China at high risk of exposure to aflatoxin and development of hepatocellular carcinoma. Two hundred thirty-three healthy residents of Qidong, PRC, were randomized to 8 weeks treatment with placebo, oltipraz 125 mg daily, or oltipraz 500 mg weekly, with a subsequent 8-week follow-up period. Urine samples were collected as overnight voids. Samples collected 4 weeks into the treatment period and 6 weeks into the follow-up period were analyzed for oxidized guanine derivatives with a HPLC-MS/MS method. A repeated-measures analysis of variance showed no significant differences between the randomization groups regarding changes in oxidized guanine derivatives. In the present double-blind, randomized, placebo-controlled trial performed among healthy individuals, oltipraz had no major effect on oxidative DNA damage. Mechanisms other than prevention of oxidative DNA damage may be of higher importance when oltipraz is used as a chemopreventive agent in humans.
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Affiliation(s)
- Bente Glintborg
- Department of Clinical Pharmacology Q7642, H:S Rigshospitalet, Tagensvej 20, Copenhagen, Denmark
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Etzel RA. What the primary care pediatrician should know about syndromes associated with exposures to mycotoxins. Curr Probl Pediatr Adolesc Health Care 2006; 36:282-305. [PMID: 16935759 DOI: 10.1016/j.cppeds.2006.05.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Disease associated with exposure to mycotoxins is known as the "Great Masquerader" of the 21st century because of its complex natural history involving different tissues and resembling different diseases at each stage in its evolution. It can present with a variety of nonspecific clinical signs and symptoms such as rash, conjunctivitis, epistaxis, apnea, cough, wheezing, nausea, and vomiting. Some cases of vomiting illness, bone marrow failure, acute pulmonary hemorrhage, and recurrent apnea and/or "pneumonia" are associated with exposure to mycotoxins. Familiarity with the symptoms of exposure to the major classes of mycotoxins enables the clinician to ask pertinent questions about possible fungal exposures and to remove the infant or child from the source of exposure, which could be contaminated food(s), clothing and furniture, or the indoor air of the home. Failure to prevent recurrent exposure often results in recurrent illness. A variety of other conditions, including hepatocellular and esophageal cancer and neural tube defects, are associated with consumption of foods contaminated with mycotoxins. Awareness of the short- and long-term consequences of exposures to these natural toxins helps pediatricians to serve as better advocates for children and families.
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Affiliation(s)
- Ruth A Etzel
- Division of Environmental and Occupational Health, George Washington University, School of Public Health and Health Services, Washington, DC, USA
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Ko MS, Lee SJ, Kim JW, Lim JW, Kim SG. Differential effects of the oxidized metabolites of oltipraz on the activation of CCAAT/enhancer binding protein-beta and NF-E2-related factor-2 for GSTA2 gene induction. Drug Metab Dispos 2006; 34:1353-60. [PMID: 16714377 DOI: 10.1124/dmd.106.009514] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Comprehensive mechanistic studies suggest that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferase (GST). Previously, we have shown that the activation of CCAAT/enhancer binding protein-beta (C/EBPbeta), promoted by oltipraz, contributes to the transcriptional induction of the GSTA2 gene. Studies also indicated that exposure of animals to oltipraz triggers nuclear accumulation of NF-E2-related factor-2 (Nrf2) with an increase in Nrf2's antioxidant response element (ARE) binding activity. Given the previous reports that C/EBPbeta activation contributes to oltipraz's induction of the GSTA2 gene and that Nrf2 activation by oltipraz was variable depending on the concentrations, this study investigated whether the major oxidized metabolites of oltipraz induce GSTA2 through the activation of C/EBPbeta and/or Nrf2. Immunoblot analysis revealed that M1 [4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one] and M2 (7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine), but not M3 (7-methyl-8-(methylsulfinyl)-6-(methylthio)H-pyrrolo[1,2-a]pyrazine) and M4 (7-methyl-6,8-bis(methylsulfinyl)H-pyrrolo[1,2-a]pyrazine), induced GSTA2 in H4IIE cells. M1 and M2 also increased the luciferase activity from pGL-1651, which contained the luciferase structural gene downstream of the -1.65-kilobase GSTA2 promoter region. Nuclear C/EBPbeta levels were enhanced by the metabolites but not by M3 or M4. Among the oxidized metabolites examined, only M2, which elicited cell death at a relatively high concentration, activated Nrf2, as indicated by nuclear accumulation of Nrf2 and its ARE binding activity. The present study provides evidence that M1 and M2, but not M3 and M4, induce GSTA2 and that M1 induces GSTA2 only via C/EBPbeta activation, whereas M2 does so by activating Nrf2 as well as C/EBPbeta. These results substantiate the differential effects of oltipraz's metabolites on C/EBPbeta- and/or Nrf2-mediated GSTA2 induction.
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Affiliation(s)
- Myong Suk Ko
- College of Pharmacy, National Research Laboratory, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, Korea
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Toteja GS, Mukherjee A, Diwakar S, Singh P, Saxena BN, Sinha KK, Sinha AK, Kumar N, Nagaraja KV, Bai G, Prasad CAK, Vanchinathan S, Roy R, Parkar S. Aflatoxin B1 contamination in wheat grain samples collected from different geographical regions of India: A multicenter study. J Food Prot 2006; 69:1463-7. [PMID: 16786876 DOI: 10.4315/0362-028x-69.6.1463] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
In a multicenter study conducted by the Indian Council of Medical Research, 1,646 samples of wheat grain collected from rural and urban areas of 10 states representing different geographical regions of India were analyzed for aflatoxin B1 (AFB1). AFB1 concentrations of > or = 5 microg kg(-1) were recorded in 40.3% of the samples, and concentrations above the Indian permissible regulatory limit of 30 microg kg(-1) were found in 16% of the samples. The proportion of samples with AFB1 concentrations above the Indian regulatory limit ranged from 1.7 to 55.8% in different states, with the minimum in Haryana and the maximum in Orissa. The variation in wheat contamination among states seems to be mainly the result of unsatisfactory storage conditions. Median AFB1 concentrations of 11, 18, and 32 microg kg(-1) were observed in samples from Uttar Pradesh, Assam, and Orissa, respectively; concentrations in other states were <5 microg kg(-1). The maximum AFB1 concentration of 606 microg kg(-1) was observed in a sample from the state of Uttar Pradesh. The calculated probable daily intakes of AFB1 through consumption of contaminated wheat for the population in some states were much higher than the suggested provisional maximum tolerable daily intake. Human health hazards associated with such AFB1 exposure over time cannot be ruled out.
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Affiliation(s)
- G S Toteja
- Central Coordinating Unit, Indian Council of Medical Research, New Delhi 110029, India.
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30
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Reddy L, Odhav B, Bhoola K. Aflatoxin B1-induced toxicity in HepG2 cells inhibited by carotenoids: morphology, apoptosis and DNA damage. Biol Chem 2006; 387:87-93. [PMID: 16497168 DOI: 10.1515/bc.2006.012] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Aflatoxin B1 (AFB1) is a fungal toxin that has been associated with primary hepatocellular carcinoma (HCC) in humans. This study was undertaken to determine the cellular and molecular mechanisms by which the antioxidants beta-carotene and lycopene inhibit AFB1-induced toxic changes in human hepatocytes (HepG2 cells). An in vitro system was optimized to test the chemoprotective effects of lycopene and beta-carotene on HepG2 cells exposed to different concentrations of AFB1. Ultrastructurally, HepG2 cells cultured in the presence of AFB1 showed mitochondrial damage, nuclear condensation and a loss of cell-to-cell contact; the latter was reflected in the observation of dysfunctional gap junctions, resulting in a loss of cell-to-cell communication. At the genomic level, AFB1 formed AFB1-N7-guanine adducts, caused apoptotic cell death and suppressed p53 protein expression. In the presence of the carotenoids, survival of cells exposed to AFB1 was increased, and there was also a significant increase in cellular mitochondrial activity. Our results demonstrate that HepG2 cells pretreated with lycopene and beta-carotene are protected from the toxic effects of AFB1 at both the cellular and molecular levels.
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Affiliation(s)
- Lalini Reddy
- Department of Biotechnology, Durban Institute of Technology, Durban 4000, South Africa
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31
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Reverberi M, Fabbri AA, Zjalic S, Ricelli A, Punelli F, Fanelli C. Antioxidant enzymes stimulation in Aspergillus parasiticus by Lentinula edodes inhibits aflatoxin production. Appl Microbiol Biotechnol 2005; 69:207-15. [PMID: 15838675 DOI: 10.1007/s00253-005-1979-1] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2005] [Revised: 03/21/2005] [Accepted: 03/23/2005] [Indexed: 10/25/2022]
Abstract
Biosynthesis of aflatoxins, toxic metabolites produced by Aspergillus parasiticus, is correlated to the fungal oxidative stress and cell ageing. In this paper, the mechanism underlying the aflatoxin-inhibiting effect of the Lentinula edodes culture filtrates was studied by analysing their anti-oxidant activity and beta-glucan content. Mushroom beta-glucans are pharmacologically active compounds stimulating anti-oxidant responses in animal cells. L. edodes lyophilised filtrates stimulate A. parasiticus anti-oxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and aflatoxin inhibition was better correlated with beta-glucan content than with anti-oxidant activity of the filtrates. RT-PCR analyses on treated mycelia showed a delay in the activation of aflR, and norA, genes of aflatoxin cluster and a synchronous activation of hsf2-like, a homologue of a yeast transcription factor involved in oxidative stress responses. The first evidence of hsf2-like in A. parasiticus and its activation during aflatoxin biosynthesis is reported. L. edodes filtrates could play a role as external stimulus affecting the anti-oxidant status in the fungal cell that, in turn, leads to aflatoxin inhibition. In the fungal cell, beta-glucans present in the filtrates could stimulate the activation of transcription factors related to anti-oxidant response and anti-oxidant enzyme activity with a contemporaneous delay of aflatoxin genes transcription, which led to a marked reduction of aflatoxin production. This research suggests new perspectives to set suitable strategies against aflatoxins and L. edodes could be considered a promising tool.
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Affiliation(s)
- M Reverberi
- Dipartimento di Biologia Vegetale, Università degli Studi La Sapienza, Largo Cristina di Svezia 24, Rome, Italy.
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32
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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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33
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Bonilla Guerrero R, Roberts LR. The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma. J Hepatol 2005; 42:760-77. [PMID: 15826727 DOI: 10.1016/j.jhep.2005.02.005] [Citation(s) in RCA: 146] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Ruben Bonilla Guerrero
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology and Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
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34
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Staab CA, Vondracek M, Custodio H, Johansson K, Nilsson JA, Morgan P, Höög JO, Cotgreave I, Grafström RC. Modelling of normal and premalignant oral tissue by using the immortalised cell line, SVpgC2a: a review of the value of the model. Altern Lab Anim 2005; 32:401-5. [PMID: 15651925 DOI: 10.1177/026119290403200412] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Normal oral keratinocytes (NOKs), and a Simian virus 40 T-antigen-immortalised oral keratinocyte line termed SVpgC2a, were cultured in an effort to model the human oral epithelium in vitro, including normal and dysplastic tissue. Monolayer and organotypic cultures of NOKs and SVpgC2a were successfully established in a standardised serum-free medium with high levels of amino acids, by using regular tissue culture plastic for monolayers and collagen gels containing oral fibroblasts as the base for generating tissue equivalents. NOKs express many characteristics of normal tissue, including those associated with terminal squamous differentiation. After > 150 passages, SVpgC2a cells retained an immortal, nontumourigenic phenotype that, relative to NOKs, was associated with aberrant morphology, enhanced proliferation, deficiency in terminal differentiation, proneness to apoptosis, and variably altered expression of structural epithelial markers. Transcript and protein profiling, as well as activity assays, demonstrated the expression of multiple xenobiotic-metabolising enzymes in SVpgC2a cells, some of which were higher in comparison to NOKs. A generally preserved, or even activated, ability for xenobiotic metabolism in long-term cultures of SVpgC2a cells indicated that this cell line could be useful in safety testing protocols--for example, in the development of consumer products in the oral health care field. However, SVpgC2a cells displayed some features reminiscent of a severe oral dysplasia, implying that this cell line could also to some extent serve as a model of a premalignant oral epithelium.
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Affiliation(s)
- Claudia A Staab
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
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35
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Huang X, Lu D, Ji G, Sun Y, Ma L, Chen Z, Zhang L, Huang J, Yu L. Hepatitis B virus (HBV) vaccine-induced escape mutants of HBV S gene among children from Qidong area, China. Virus Res 2004; 99:63-8. [PMID: 14687948 DOI: 10.1016/j.virusres.2003.10.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Hepatitis B virus (HBV) infection is the main factor, which induces hepatocellular carcinoma (HCC) in Qidong high-risk area, China. To prevent HBV infection is the most important strategy to inhibit the HCC carcinogenesis. A large project was performed in Qidong area to protect newborn babies from the HBV infection that 80,000 children born between 1984 and 1990 were vaccinated. After three times of follow-up studies, 15 screened children were found to have symptoms of illness showing persistent elevation of serum glutamic-pyruvic transaminase (ALT). From these previously collected data, we found that the ALT levels of five vaccinees with negative hepatitis B surface antigen (HBsAg) were significantly higher than those of 10 vaccinees with positive HBsAg. Furthermore, with the passage of time, the difference of ALT levels between the two groups (HBsAg negative and positive groups) diminishes. After cloning and sequencing of the HBsAg "a" epitope coding sequences, we found that mutations in "a" epitope were correlated with the absence of detectable anti-HBsAg, while no mutations were seen in the anti-HBsAg positive infections. We also found that majority of point mutations were occurred in the coding sequences of the first loop structure in "a" epitope. The structure of double loop conformation in "a" epitope was conservative, and important for HBV antigenicity. These changes in a double loop conformation would escape neutralization by vaccine-induced antibody.
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Affiliation(s)
- Xinghua Huang
- Institute of Genetics, School of Life Sciences, Fudan University, 200433 Shanghai, PR China.
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36
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Affiliation(s)
- Jordi Bruix
- BCLC Group, Liver Unit, Digestive Disease Institute, Hospital Clínic, IDIBAPS, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.
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37
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Abstract
Chronic infection with hepatitis B virus (HBV) is an important clinical problem due to its worldwide distribution and potential of adverse sequelae including hepatocellular carcinoma (HCC). Hepatitis B e antigen (HBeAg) is a biomarker of active viral proliferation in hepatocytes and infectivity. The prevalence of HBeAg among subjects chronically infected with HBV decreases with the increase in age. Case series studies have found a lowest seroprevalence of HBeAg in HCC patients compared with patients affected with chronic hepatitis B and liver cirrhosis. Case-control studies have shown a significantly higher seroprevalence of HBeAg in HCC cases than matched controls. A recent long-term follow-up study has shown a significantly elevated HCC risk for seropositives of both hepatitis B surface antigen (HBsAg) and HBeAg compared with seropositives of HBsAg only and seronegatives. The biological gradient remained in further stratification analyses by serum level of alanine transaminase and status of liver cirrhosis detected by ultrasonography. The cumulative HCC risk from age 30 to 70 years has been estimated to be 87% for those who were persistently seropositive on HBsAg and HBeAg, 12% for those with persistent seropositivity of HBsAg only, and 1% for those who were seronegative on HBsAg and HBeAg.
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Affiliation(s)
- San-Lin You
- Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei 10018, Taiwan
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38
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Williams SN, Pickwell GV, Quattrochi LC. A combination of tea (Camellia senensis) catechins is required for optimal inhibition of induced CYP1A expression by green tea extract. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2003; 51:6627-6634. [PMID: 14558788 DOI: 10.1021/jf030181z] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
It was previously demonstrated that the commercial green tea extract Polyphenon 100 (P100), and to a lesser extent (-)-epigallocatechin-3-gallate (EGCG), partially antagonizes 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced transcription of human CYP1A1 (Williams, S. N.; Shih, H.; Guenette, D. K.; Brackney, W.; Denison, M. S.; Pickwell, G. V.; Quattrochi, L. C. Chem.-Biol. Interact. 2000, 128, 211-229). Here, P100 is compared to a reconstituted mixture of the four major tea catechins (referred to as P100R) to determine whether inhibition was due to additional polyphenols in the extract or from synergistic interactions among the tea catechins. It was found that cotreatment of cells with TCDD and either P100 or P100R inhibited TCDD-induced CYP1A promoter-driven luciferase reporter activity (HepG2 cells) and CYP1A expression (HepG2 and primary human hepatocytes), similarly. These results indicate that modulation of human CYP1A expression by P100 can be attributed entirely to the combination of the four tea catechins. These findings may be important in the evaluation of future chemoprevention strategies using green tea and single catechin agents.
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Affiliation(s)
- Susanne N Williams
- Department of Medicine, Section of Medical Toxicology, University of Colorado Health Sciences Center, Denver, CO 80262, USA
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39
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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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40
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Bintvihok A, Ponpornpisit A, Tangtrongpiros J, Panichkriangkrai W, Rattanapanee R, Doi K, Kumagai S. Aflatoxin contamination in shrimp feed and effects of aflatoxin addition to feed on shrimp production. J Food Prot 2003; 66:882-5. [PMID: 12747701 DOI: 10.4315/0362-028x-66.5.882] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
One hundred fifty samples of shrimp feed were collected from the eastern and southern regions of Thailand, and aflatoxins B1, B2, G1, and G2 (AFB1, AFB2, AFG1, and AFG2) in them were analyzed. AFB1 contamination ranged from a nondetectable level (< 0.003 ppb) to 0.651 ppb. Metabolites of AFB1 were less abundant than AFB1. To study the effects of aflatoxin in feed on shrimp production, black tiger shrimp were divided into four groups of 30 shrimp per group, tested in triplicate, and fed diets containing 0 (control), 5, 10, or 20 ppb of AFB1 for 10 consecutive days. After 7 or 10 days of consumption on each diet, the shrimp were weighed and sacrificed for laboratory examination. AFB1 and its metabolites were not detected in shrimp muscle. The mortality rate was slightly higher in the AFB1-treated groups than in the control group. The body weight of the surviving shrimp was decreased to 46 to 59% of the initial body weight in the AFB1-treated groups but not in the control group. Histopathological findings indicated hepatopancreatic damage by AFB1 with biochemical changes of the hemolymph. These results show that aflatoxin contamination in shrimp feed may cause economic losses by lowering the production of shrimp. Feed contaminated at the level of 20 ppb or lower (i.e., at the observed natural contamination level) may pose a very low risk, if any, to human health.
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Affiliation(s)
- A Bintvihok
- Department of Pharmacology, Faculty of Veterinary Science, Chulalongkorn University, Henri Dunang Street, Bangkok 10330, Thailand
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41
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Huang XH, Sun LH, Lu DD, Sun Y, Ma LJ, Zhang XR, Huang J, Yu L. Codon 249 mutation in exon 7 of p53 gene in plasma DNA: maybe a new early diagnostic marker of hepatocellular carcinoma in Qidong risk area, China. World J Gastroenterol 2003; 9:692-5. [PMID: 12679912 PMCID: PMC4611430 DOI: 10.3748/wjg.v9.i4.692] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: One of the characteristics of hepatocellular carcinoma (HCC) in Qidong area is the selective mutation resulting in a serine substitution at codon 249 of the p53 gene (1, 20), and it has been identified as a “hotspot” mutation in heptocellular carcinomas occurring in populations exposed to aflatoxin and with high prevalence of hepatitis B virus carriers (2, 3, 9, 10, 16, 24). We evaluated in this paper whether this “hotspot” mutation could be detected in cell-free DNA circulating in plasma of patients with hepatocellular carcinoma and cirrhosis in Qidong, China, and tried to illustrate the significance of the detection of this molecular biomarker.
METHODS: We collected blood samples from 25 hepatocellular carcinoma patients, 20 cirrhotic patients and 30 healthy controls in Qidong area. DNA was extracted and purified from 200 µl of plasma from each sample. The 249Ser p53 mutation was detected by restriction digestion analysis and direct sequencing of exon-7 PCR products.
RESULTS: We found in exon 7 of p53 gene G→T transversion at the third base of codon 249 resulting 249Arg→249Ser mutation in 10/25 (40%) hepatocellular carcinoma cases, 4/20 (20%) cirrhotics, and 2/30 (7%) healthy controls. The adjusted odds ratio for having the mutation was 22.1 (95%CI, 3.2~91.7) for HCC cases compared to controls.
CONCLUSION: These data show that the 249Ser p53 mutation in plasma is strongly associated with hepatocellular carcinoma in Qidong patients. We found this mutation was also detected, although it was at a much lower frequency, in plasma DNA of Qidong cirrhotics and healthy controls; We consider that these findings, together with the usual method of HCC diagnosis, will give more information in early diagnosis of HCC, and 249Ser p53 mutation should be developed to a new early diagnostic marker for HCC.
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Affiliation(s)
- Xing-Hua Huang
- The State Key Laboratory of Genetic Engineering, Fudan University, 200433, Shanghai, China
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42
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Garrido NS, Iha MH, Santos Ortolani MR, Duarte Fávaro RM. Occurrence of aflatoxins M(1) and M(2) in milk commercialized in Ribeirão Preto-SP, Brazil. FOOD ADDITIVES AND CONTAMINANTS 2003; 20:70-3. [PMID: 12519721 DOI: 10.1080/0265203021000035371] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Aflatoxins are toxic metabolites found in foods and feeds. When ruminants eat foodstuffs containing aflatoxins B(1) and B(2), these toxins are metabolized and excreted as aflatoxin M(1) and M(2) in milk. The aim was to determine the incidence of these aflatoxins in commercial milk collected from supermarkets in Ribeirão Preto-SP, Brazil, and consisting of 60 ultrahigh temperature (UHT) milk samples and 79 pasteurized milk samples. The milk samples were analysed according to method 986.16 of AOAC International. None of the milk samples analysed were contaminated with aflatoxin M(2), and aflatoxin M(1) was detected in 29 (20.9%) of samples in the range 50-240 ng l(-1). The results show that despite a high occurrence of aflatoxin M(1) in commercial pasteurized and UHT milk sold in Ribeirão Preto in 1999 and 2000, the contamination level of these toxins could not be considered a serious public health problem according to MERCOSUR Technical Regulations. However, levels in 20.9% of the milk samples exceeded the concentration of 50 ng l(-1) permitted by the European Union. Although it is not necessary to continue monitoring the incidence and levels of aflatoxins M(1) and M(2) in milk samples, surveillance could be appropriate.
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Affiliation(s)
- N S Garrido
- Instituto Adolfo Lutz, Laboratório I de Ribeirão Preto, Rua Minas, 877, Ribeirão Preto, São Paulo, Brazil
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43
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Kuhn DM, Ghannoum MA. Indoor mold, toxigenic fungi, and Stachybotrys chartarum: infectious disease perspective. Clin Microbiol Rev 2003; 16:144-72. [PMID: 12525430 PMCID: PMC145304 DOI: 10.1128/cmr.16.1.144-172.2003] [Citation(s) in RCA: 180] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Damp buildings often have a moldy smell or obvious mold growth; some molds are human pathogens. This has caused concern regarding health effects of moldy indoor environments and has resulted in many studies of moisture- and mold-damaged buildings. Recently, there have been reports of severe illness as a result of indoor mold exposure, particularly due to Stachybotrys chartarum. While many authors describe a direct relationship between fungal contamination and illness, close examination of the literature reveals a confusing picture. Here, we review the evidence regarding indoor mold exposure and mycotoxicosis, with an emphasis on S. chartarum. We also examine possible end-organ effects, including pulmonary, immunologic, neurologic, and oncologic disorders. We discuss the Cleveland infant idiopathic pulmonary hemorrhage reports in detail, since they provided important impetus for concerns about Stachybotrys. Some valid concerns exist regarding the relationship between indoor mold exposure and human disease. Review of the literature reveals certain fungus-disease associations in humans, including ergotism (Claviceps species), alimentary toxic aleukia (Fusarium), and liver disease (Aspergillys). While many papers suggest a similar relationship between Stachybotrys and human disease, the studies nearly uniformly suffer from significant methodological flaws, making their findings inconclusive. As a result, we have not found well-substantiated supportive evidence of serious illness due to Stachybotrys exposure in the contemporary environment. To address issues of indoor mold-related illness, there is an urgent need for studies using objective markers of illness, relevant animal models, proper epidemiologic techniques, and examination of confounding factors.
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Affiliation(s)
- D M Kuhn
- Division of Infectious Diseases, Department of Medicine, University Hospitals of Cleveland, and Case Western Reserve University, Cleveland, Ohio 44106, USA
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Abdulrazzaq YM, Osman N, Ibrahim A. Fetal exposure to aflatoxins in the United Arab Emirates. ANNALS OF TROPICAL PAEDIATRICS 2002; 22:3-9. [PMID: 11926047 DOI: 10.1179/027249302125000094] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
This is a prospective study in which aflatoxin levels were measured in umbilical cord blood from 201 women delivered consecutively in Tawam and Al Ain hospitals in order to determine whether the fetuses had been significantly exposed to the toxin. Aflatoxin B1, M1 and M2 were measured using high performance liquid chromatography. Aflatoxins were detected in 110 (54.7%) samples, 27 of which were positive for B1, 106 for M1 and 31 for M2. There was a significant negative correlation (p < 0.001) between birthweight and levels of aflatoxin. The high rate of detection of aflatoxins confirms that a significant number of infants in the UAE are exposed to these toxins which reflects maternal ingestion of aflatoxin-containing food. The presence of aflatoxin resulted in lower birthweights.
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Affiliation(s)
- Yousef M Abdulrazzaq
- Department of Paediatrics, Faculty of Medicine & Health Sciences, UAE University, Al Ain, United Arab Emirates.
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Pang E, Wong N, Lai PBS, To KF, Lau WY, Johnson PJ. Consistent chromosome 10 rearrangements in four newly established human hepatocellular carcinoma cell lines. Genes Chromosomes Cancer 2002; 33:150-9. [PMID: 11793441 DOI: 10.1002/gcc.1220] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Cancer cell lines represent an invaluable resource for isolation of novel genes relevant to tumor pathogenesis and as in vitro models. In this study, we report on the successful establishment of four cell lines from hepatocellular carcinoma tissue. These cell lines, designated HKCI-1, HKCI-2, HKCI-3, and HKCI-4, have been growing continuously for more than 24 months and have been passaged more than 50 times. A comprehensive cytogenetic characterization on the primary tumors and the derived cell lines was achieved by the combined approach of spectral karyotyping and comparative genomic hybridization. Chromosomal imbalances from the primary tumors were also maintained in the cell lines and included gains of 1q, 6p, 7, 10p, 17q, and 20 and loss of 4q. Recurring translocations included t(X;11), t(1;10), t(4;16), i(5)(p10), t(7;21), t(8;17), t(9;22), i(10)(p10), t(14;20), t(16;22), and t(17;19). It was noteworthy that consistent chromosome 10 aberrations, in particular t(1;10)(q10;p10), were detected in all four cell lines. Furthermore, microsatellite analysis on primary tumor and derived cell lines indicated a common deleted region of 10q23-q26. The functional importance of chromosome 10 aberrations in relation to the pathogenesis of HCC is unknown; however, the high frequency with which such aberrations were maintained in the cell lines suggests proliferative advantages of 10q loss or 10p gain in the multistep development of hepatic neoplasia.
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Affiliation(s)
- Elizabeth Pang
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N. T., SAR Hong Kong, China
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Vogel A, Kneip S, Barut A, Ehmer U, Tukey RH, Manns MP, Strassburg CP. Genetic link of hepatocellular carcinoma with polymorphisms of the UDP-glucuronosyltransferase UGT1A7 gene. Gastroenterology 2001; 121:1136-44. [PMID: 11677206 DOI: 10.1053/gast.2001.28655] [Citation(s) in RCA: 107] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma is associated with risk factors including hepatitis C, hepatitis B, cirrhosis, genetic liver diseases, and environmental carcinogens. Uridine 5'-diphosphate-glucuronosyltransferases are a superfamily of detoxifying enzymes capable of tobacco-borne carcinogen detoxification and cellular protection. This study examines the association of UGT1A7 and UGT1A9 gene polymorphisms with hepatocellular carcinoma. METHODS Genomic DNA from the blood of 59 patients with hepatocellular carcinoma and 70 control subjects without evidence of cancer was analyzed by UGT1A7- and UGT1A9-specific PCR, sequencing analysis, and temperature gradient gel electrophoresis. RESULTS Three UGT1A7 missense mutations were detected defining the UGT1A7*2, UGT1A7*3, and UGT1A7*4 alleles. Wild-type UGT1A7 alleles were present in 41.4% of controls but only in 6.8% of cancer patients (P < 0.001; odds ratio [OR], 9.73; 95% confidence interval [CI], 3.17-29.83). UGT1A7 polymorphisms were present in 93.2% of hepatocellular cancer patients, 74.5% carried the UGT1A7*3 allele (P < 0.001; OR, 10.76; 95% CI, 4.75-24.38), which combines the W208R, N129K, and R131K mutations and encodes a protein with low carcinogen detoxification activity. No UGT1A9 polymorphisms were detected. CONCLUSIONS The significant association of hepatocellular carcinoma with the UGT1A7*3 allele encoding a low detoxification activity protein is identified and implicates UGT1A7 as a risk gene of hepatocarcinogenesis in addition to a role as potential marker for cancer risk assessment in chronic liver disease.
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Affiliation(s)
- A Vogel
- Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
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Affiliation(s)
- J W Kosmeder
- Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy & Department of Surgical Oncology, College of Medicine, University of Illlinois @ Chicago, Chicago, IL 60612, USA
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