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Wangwiwatsin A, Kulwong S, Phuyao C, Titapun A, Loilome W, Klanrit P, Namwat N, Sithithaworn P, Doyle SR, Berriman M, Crellen T, Wellcome Sanger Institute Tree of Life Management, Samples and Laboratory team, Wellcome Sanger Institute Scientific Operations: Sequencing Operations, Wellcome Sanger Institute Tree of Life Core Informatics team, Tree of Life Core Informatics collective. The genome sequence of the liver fluke Opisthorchis viverrini (Poirier, 1886) Stiles & Hassall, 1896. Wellcome Open Res 2025; 10:1. [PMID: 39949572 PMCID: PMC11822251 DOI: 10.12688/wellcomeopenres.23535.1] [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] [Accepted: 12/12/2024] [Indexed: 02/16/2025] Open
Abstract
We present a genome assembly from a specimen of Opisthorchis viverrini (liver fluke; Platyhelminthes; Trematoda; Opisthorchiida; Opisthorchiidae). The genome sequence has a total length of 627.20 megabases. Most of the assembly (97.89%) is scaffolded into 6 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 18.04 kilobases in length.
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Affiliation(s)
- Arporn Wangwiwatsin
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Siriyakorn Kulwong
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Chitsakul Phuyao
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Attapol Titapun
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Watcharin Loilome
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Poramate Klanrit
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Nisana Namwat
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Paiboon Sithithaworn
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Parasitology, Khon Kaen University, Khon Kaen, Thailand
| | | | - Matthew Berriman
- Wellcome Sanger Institute, Hinxton, England, UK
- School of Infection & Immunity, University of Glasgow, Glasgow, Scotland, UK
| | - Thomas Crellen
- Wellcome Sanger Institute, Hinxton, England, UK
- School of Biodiversity One Health and Veterinary Medicine, University of Glasgow, Glasgow, Scotland, UK
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, England, UK
| | - Wellcome Sanger Institute Tree of Life Management, Samples and Laboratory team
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Department of Parasitology, Khon Kaen University, Khon Kaen, Thailand
- Wellcome Sanger Institute, Hinxton, England, UK
- School of Infection & Immunity, University of Glasgow, Glasgow, Scotland, UK
- School of Biodiversity One Health and Veterinary Medicine, University of Glasgow, Glasgow, Scotland, UK
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, England, UK
| | - Wellcome Sanger Institute Scientific Operations: Sequencing Operations
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Department of Parasitology, Khon Kaen University, Khon Kaen, Thailand
- Wellcome Sanger Institute, Hinxton, England, UK
- School of Infection & Immunity, University of Glasgow, Glasgow, Scotland, UK
- School of Biodiversity One Health and Veterinary Medicine, University of Glasgow, Glasgow, Scotland, UK
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, England, UK
| | - Wellcome Sanger Institute Tree of Life Core Informatics team
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Department of Parasitology, Khon Kaen University, Khon Kaen, Thailand
- Wellcome Sanger Institute, Hinxton, England, UK
- School of Infection & Immunity, University of Glasgow, Glasgow, Scotland, UK
- School of Biodiversity One Health and Veterinary Medicine, University of Glasgow, Glasgow, Scotland, UK
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, England, UK
| | - Tree of Life Core Informatics collective
- Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Department of Parasitology, Khon Kaen University, Khon Kaen, Thailand
- Wellcome Sanger Institute, Hinxton, England, UK
- School of Infection & Immunity, University of Glasgow, Glasgow, Scotland, UK
- School of Biodiversity One Health and Veterinary Medicine, University of Glasgow, Glasgow, Scotland, UK
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, England, UK
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Eisenbrand G, Buettner A, Diel P, Epe B, Först P, Grune T, Haller D, Heinz V, Hellwig M, Humpf HU, Jäger H, Kulling S, Lampen A, Leist M, Mally A, Marko D, Nöthlings U, Röhrdanz E, Spranger J, Steinberg P, Vieths S, Wätjen W, Hengstler JG. Commentary of the SKLM to the EFSA opinion on risk assessment of N-nitrosamines in food. Arch Toxicol 2024; 98:1573-1580. [PMID: 38573336 PMCID: PMC11106120 DOI: 10.1007/s00204-024-03726-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 04/05/2024]
Abstract
Dietary exposure to N-nitrosamines has recently been assessed by the European Food Safety Authority (EFSA) to result in margins of exposure that are conceived to indicate concern with respect to human health risk. However, evidence from more than half a century of international research shows that N-nitroso compounds (NOC) can also be formed endogenously. In this commentary of the Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG), the complex metabolic and physiological biokinetics network of nitrate, nitrite and reactive nitrogen species is discussed with emphasis on its influence on endogenous NOC formation. Pioneering approaches to monitor endogenous NOC have been based on steady-state levels of N-nitrosodimethylamine (NDMA) in human blood and on DNA adduct levels in blood cells. Further NOC have not been considered yet to a comparable extent, although their generation from endogenous or exogenous precursors is to be expected. The evidence available to date indicates that endogenous NDMA exposure could exceed dietary exposure by about 2-3 orders of magnitude. These findings require consolidation by refined toxicokinetics and DNA adduct monitoring data to achieve a credible and comprehensive human health risk assessment.
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Affiliation(s)
| | - Andrea Buettner
- Chair of Aroma and Smell Research, Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestrasse 9, 91054, Erlangen, Germany
- Fraunhofer Institute for Process Engineering and Packaging IVV, Giggenhauser Strasse 35, 85354, Freising, Germany
| | - Patrick Diel
- Department of Molecular and Cellular Sports Medicine, Institute of Cardiovascular Research and Sports Medicine, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933, Cologne, Germany
| | - Bernd Epe
- Institute of Pharmaceutical and Biomedical Sciences, University of Mainz, Staudingerweg, 55128, Mainz, Germany
| | - Petra Först
- Food Process Engineering, TUM School of Life Sciences, Technical University of Munich, Weihenstephaner Berg 1, 85354, Freising, Germany
| | - Tillman Grune
- German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technical University of Munich, Gregor-Mendel-Strasse 2, 85354, Freising, Germany
- ZIEL Institute for Food and Health, Technical University of Munich, Weihenstephaner Berg 1, 85354, Freising, Germany
| | - Volker Heinz
- DIL German Institute of Food Technology, Professor-von-Klitzing-Strasse 7, 49610, Quakenbrück, Germany
| | - Michael Hellwig
- Chair of Special Food Chemistry, Technical University Dresden, Bergstrasse 66, 01062, Dresden, Germany
| | - Hans-Ulrich Humpf
- Institute of Food Chemistry, University of Münster, Corrensstrasse 45, 48149, Münster, Germany
| | - Henry Jäger
- University of Natural Resources and Life Sciences, Gregor-Mendel-Strasse 33, 1180, Vienna, Austria
| | - Sabine Kulling
- Department of Safety and Quality of Fruit and Vegetables, Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Haid-und-Neu-Strasse 9, 76131, Karlsruhe, Germany
| | - Alfonso Lampen
- Risk Assessment Strategies, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589, Berlin, Germany
| | - Marcel Leist
- Division for In Vitro Toxicology and Biomedicine, Department of Biology, University of Konstanz, Universitaetsstrasse 10, 78464, Constance, Germany
| | - Angela Mally
- Department of Toxicology, University of Würzburg, Versbacher Strasse 9, 97078, Würzburg, Germany
| | - Doris Marko
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Strasse 38-40, 1090, Vienna, Austria
| | - Ute Nöthlings
- Institute for Nutrition Research and Food Science, Rheinische Friedrich-Wilhelms-University Bonn, Fiedrich-Hirzebruch-Allee 7, 53115, Bonn, Germany
| | - Elke Röhrdanz
- Unit Reproductive and Genetic Toxicology, Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger Allee 3, 53175, Bonn, Germany
| | - Joachim Spranger
- Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Pablo Steinberg
- Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Haid-Und-Neu-Straße 9, 76131, Karlsruhe, Germany
| | - Stefan Vieths
- Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225, Langen, Germany
| | - Wim Wätjen
- Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Weinbergweg 22, 06120, Halle (Saale), Germany
| | - Jan G Hengstler
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystr. 67, 44139, Dortmund, Germany.
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Artchayasawat A, Sriraj P, Boonmars T, Aukkanimart R, Wisetmora A, Borlace GN, Boueroy P, Pumhirunroj B, Laummaunwai P, Rattanasuwan P, Boonjaraspinyo S, Ekobol N, Pitaksakulrat O, Zhiliang W. Reduction of carcinogens in fermented fish (pla-ra and pla-som) by heating. Vet World 2023; 16:1727-1735. [PMID: 37766713 PMCID: PMC10521190 DOI: 10.14202/vetworld.2023.1727-1735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 07/24/2023] [Indexed: 09/29/2023] Open
Abstract
Background and Aim The risk factors for cholangiocarcinoma (CCA) are opisthorchiasis and the intake of a combination of nitroso compounds through the consumption of traditionally fermented fish, which is very popular in areas where liver flukes are endemic. The incidence of CCA remains high because this cultural habit of rural people has been altered. Therefore, decreasing nitrate and nitrite concentrations in fermented fish are an alternative approach to reducing the risk of CCA. Thus, this study aimed to reduce nitrate and nitrite concentrations in fermented foods by heating and investigated its effect on CCA development in a hamster model. Materials and Methods We used Association of Official Analytical Chemists method 973.31 to measure the nitrate and nitrite concentrations in both fermented fish (pla-ra [PR]) and pickled fish (pla-som [PS]) before and after boiling for 5 and 30 min, respectively. The same samples were fed to Opisthorchis viverrini (OV)-infected or -uninfected hamsters for 3 months. Thereafter, the hamsters' liver and blood were collected for analysis. Results The levels of nitrates and nitrites in PS and PR significantly decreased following boiling for 5 and 30 min. The OV-PR and OV-PS groups showed dramatically increased numbers of inflammatory cells, fibrosis surrounding the bile duct, and focal fibrotic areas. However, after boiling the fermented dishes for 5 and 30 min, the extent of inflammatory cell infiltration and intensity of fibrosis in these groups were decreased. Conclusion Our findings suggest that boiling reduces nitrate and nitrite toxicity in fermented dishes, as evidenced by reduced hepatic inflammation. However, regardless of heating, kidney tissues are adversely affected when fermented meals are consumed daily.
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Affiliation(s)
- Atchara Artchayasawat
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Pranee Sriraj
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
- Department of Traditional Medicine, Faculty of Natural Resources, Rajamangala University of Technology ISAN Sakon Nakhon Campus, Sakon Nakhon, 47160, Thailand
| | - Thidarut Boonmars
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Ratchadawan Aukkanimart
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
- Department of Traditional Medicine, Faculty of Natural Resources, Rajamangala University of Technology ISAN Sakon Nakhon Campus, Sakon Nakhon, 47160, Thailand
| | - Ampas Wisetmora
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Glenn N. Borlace
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Parichart Boueroy
- Department of Community Health, Faculty of Public Health, Kasetsart University Chalermphakiat Sakon Nakhon Province Campus, Sakon Nakhon, 47000, Thailand
| | - Benjamabhorn Pumhirunroj
- Program in Animal Science, Faculty of Agricultural Technology, Sakon Nakhon Rajabhat University, Sakon Nakhon, 47000, Thailand
| | - Porntip Laummaunwai
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Panaratana Rattanasuwan
- Department of Anesthesiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Sirintip Boonjaraspinyo
- Department of Community Medicine, Family Medicine and Occupational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Nattapon Ekobol
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Opal Pitaksakulrat
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Wu Zhiliang
- Department of Parasitology and Infectious Disease, Graduate School of Medicine, Gifu University, Japan
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Sripa B, Seubwai W, Vaeteewoottacharn K, Sawanyawisuth K, Silsirivanit A, Kaewkong W, Muisuk K, Dana P, Phoomak C, Lert-Itthiporn W, Luvira V, Pairojkul C, Teh BT, Wongkham S, Okada S, Chamgramol Y. Functional and genetic characterization of three cell lines derived from a single tumor of an Opisthorchis viverrini-associated cholangiocarcinoma patient. Hum Cell 2020; 33:695-708. [PMID: 32207095 DOI: 10.1007/s13577-020-00334-w] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 02/14/2020] [Indexed: 12/21/2022]
Abstract
Three cholangiocarcinoma (CCA) cell line-formerly named, M156, M213 and M214 have been intensively used with discrepancy of their tumor origins. They were assumed to be originated from three different donors without authentication. To verify the origins of these cell lines, the short tandem repeat (STR) analysis of the currently used cell lines, the cell stocks from the establisher and the primary tumor of a CCA patient were performed. Their phenotypic and genotypic originality were compared. The currently used 3 CCA cell lines exhibited similar STR as CCA patient ID-M213 indicating the same origin of these cells. The cell stocks from the establisher, however, revealed the same STR of M213 and M214 cells, but not M156. The misidentification of M214 and M156 is probably due to the mislabeling and cross-contamination of M213 cells during culture. These currently used cell lines were renamed as KKU-213A, -213B and -213C, for the formerly M213, M214 and M156 cells, respectively. These cell lines were established from a male with an intrahepatic mass-forming CCA stage-4B. The tumor was an adenosquamous carcinoma with the liver fluke ova granuloma in evidence. All cell lines had positive CK19 with differential CA19-9 expression. They exhibited aneuploidy karyotypes, distinct cell morphology, cell growth, cytogenetic characteristic and progressive phenotypes. KKU-213C formed a adenosquamous carcinoma, whereas KKU-213A and KKU-213B formed poorly- and well-differentiated squamous cell carcinomas in xenografted mice. mRNA microarray revealed different expression profiles among these three cell lines. The three cell lines have unique characteristics and may resemble the heterogeneity of tumor origin.
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Affiliation(s)
- Banchob Sripa
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Wunchana Seubwai
- Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Kulthida Vaeteewoottacharn
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Kanlayanee Sawanyawisuth
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Atit Silsirivanit
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Worasak Kaewkong
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
- Department of Biochemistry, Faculty of Medical Sciences, Naresuan University, Phitsanulok, 65000, Thailand
| | - Kanha Muisuk
- Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Paweena Dana
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chatchai Phoomak
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Worachart Lert-Itthiporn
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Vor Luvira
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Bin T Teh
- Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Sopit Wongkham
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Seiji Okada
- Division of Hematopoeisis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811, Japan.
| | - Yaovalux Chamgramol
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
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Vale N, Gouveia MJ, Gärtner F, Brindley PJ. Oxysterols of helminth parasites and pathogenesis of foodborne hepatic trematodiasis caused by Opisthorchis and Fasciola species. Parasitol Res 2020; 119:1443-1453. [PMID: 32206886 DOI: 10.1007/s00436-020-06640-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 02/25/2020] [Indexed: 02/06/2023]
Abstract
The foodborne trematodiases refer to a cluster of zoonotic neglected tropical diseases caused by trematodes, with transmission involving ingestion of contaminated plants, fishes, and crustaceans. Over 40 million people are infected with foodborne trematodes and 750 million are at risk of infection. From a public health point of view, important species include Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus, Fasciola hepatica, and Fasciola gigantica. Infection with C. sinensis and O. viverrini is classified as a group 1 biological carcinogen and a major risk factor for cholangiocarcinoma. The carcinogenic potential of the infection with O. felineus is less clear but recent biochemical and histopathological findings revealed that opisthorchiasis felinea also fits this pattern. By contrast, evidence of carcinogenic potential of infection with F. hepatica or F. gigantica, close phylogenetics relatives of Opisthorchis, is less certain. Oxysterols have been essentially described in animal model of opisthorchiasis and associated cholangiocarcinoma. Several oxysterol-like metabolites have been detected not only on developmental stages of O. viverrini and O. felineus but also on biofluids from experimentally infected hamsters as products of the activities of the liver flukes. These sterol derivatives are metabolized to active quinones that can modify host DNA. We have postulated that helminth parasite-associated sterols might induce tumor-like phenotypes in biliary epithelia, the cells of origin of liver fluke infection-associated cholangiocarcinoma, through the formation of DNA adducts, dysregulation of apoptosis, and other homeostatic pathways. Here we review, interpret, and discuss findings of oxysterol-like metabolites detected in liver flukes and their role in carcinogenesis, aiming to enhance understanding the pathogenesis of foodborne trematodiasis caused by Opisthorchis and Fasciola species. In future, further investigations will be necessary in order to comprehend relationship between liver flukes' oxysterols and their role in infection-associated diseases in humans.
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Affiliation(s)
- Nuno Vale
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo 228, 4050-313, Porto, Portugal. .,Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo 228, Porto, Portugal. .,Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal. .,i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal.
| | - Maria João Gouveia
- Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo 228, Porto, Portugal.,Center for the Study of Animal Science, CECA - ICETA, University of Porto, Praça Gomes Teixeira Apt 55142, 4051-401, Porto, Portugal
| | - Fátima Gärtner
- Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo 228, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal.,i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal
| | - Paul J Brindley
- Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine and Health Sciences, George Washington University, Washington, DC, 20052, USA
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Discovering proteins for chemoprevention and chemotherapy by curcumin in liver fluke infection-induced bile duct cancer. PLoS One 2018; 13:e0207405. [PMID: 30440021 PMCID: PMC6237386 DOI: 10.1371/journal.pone.0207405] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 10/30/2018] [Indexed: 12/17/2022] Open
Abstract
Modulation or prevention of protein changes during the cholangiocarcinoma (CCA) process induced by Opisthorchis viverrini (Ov) infection may become a key strategy for prevention and treatment of CCA. Monitoring of such changes could lead to discovery of protein targets for CCA treatment. Curcumin exerts anti-inflammatory and anti-CCA activities partly through its protein-modulatory ability. To support the potential use of curcumin and to discover novel target molecules for CCA treatment, we used a quantitative proteomic approach to investigate the effects of curcumin on protein changes in an Ov-induced CCA-harboring hamster model. Isobaric labelling and tandem mass spectrometry were used to compare the protein expression profiles of liver tissues from CCA hamsters with or without curcumin dietary supplementation. Among the dysregulated proteins, five were upregulated in liver tissues of CCA hamsters but markedly downregulated in the CCA hamsters supplemented with curcumin: S100A6, lumican, plastin-2, 14-3-3 zeta/delta and vimentin. Western blot and immunohistochemical analyses also showed similar expression patterns of these proteins in liver tissues of hamsters in the CCA and CCA + curcumin groups. Proteins such as clusterin and S100A10, involved in the NF-κB signaling pathway, an important signaling cascade involved in CCA genesis, were also upregulated in CCA hamsters and were then suppressed by curcumin treatment. Taken together, our results demonstrate the important changes in the proteome during the genesis of O. viverrini-induced CCA and provide an insight into the possible protein targets for prevention and treatment of this cancer.
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Abstract
During microbial infections, both innate and adaptive immunity are activated. Viruses and bacteria usually induce an acute inflammation in the first setting of infection, which helps the eliciting an effective immune response. In contrast, macroparasites such as helminths are a highly successful group of invaders known to be capable of maintaining a chronic infestation with the minimum instigation. Undoubtedly, generating such an immunoregulatory environment requires the exploitation of various immunosuppressive mechanisms to debilitate host immunity supporting their survival and replication. Several mechanisms have been recognized whereby helminths prolong their infections including an increase of immunoregulatory cells, inhibition of Th1 or Th2 responses, targeting pattern recognition receptors (PRRs) and lowering the immune cells quantity via induction of apoptosis. Apoptosis is a programmed intracellular process involving a series of consecutive downstream signalling event evolved to cell death. It plays a pivotal role in several immunological reactions in particular deletion of autoreactive immune cells. Helminth-triggered apoptosis in immune cells exhausts host immunity, which paves the way for generating a permissive environment and chronic infection. This review provides a compilation of recent investigations discussing the apoptotic mechanisms exploited by different worms and the immunological consequences of immune cell death. Finally, the anti-cancer effects of some worm-derived molecules due to their apoptotic effects are discussed, highlighting as potentially druggable candidates to combat cancer.
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Kim TS, Pak JH, Kim JB, Bahk YY. Clonorchis sinensis, an oriental liver fluke, as a human biological agent of cholangiocarcinoma: a brief review. BMB Rep 2017; 49:590-597. [PMID: 27418285 PMCID: PMC5346318 DOI: 10.5483/bmbrep.2016.49.11.109] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Indexed: 01/11/2023] Open
Abstract
Parasitic diseases remain an unarguable public health problem worldwide. Liver fluke Clonorchis sinensis is a high risk pathogenic parasitic helminth which is endemic predominantly in Asian countries, including Korea, China, Taiwan, Vietnam, and the far eastern parts of Russia, and is still actively transmitted. According to the earlier 8th National Survey on the Prevalence of Intestinal Parasitic Infections in 2012, C. sinensis was revealed as the parasite with highest prevalence of 1.86% in general population among all parasite species surveyed in Korea. This fluke is now classified under one of the definite Group 1 human biological agents (carcinogens) by International Agency of Research on Cancer (IARC) along with two other parasites, Opisthorchis viverrini and Schistosoma haematobium. C. sinensis infestation is mainly linked to liver and biliary disorders, especially cholangiocarcinoma (CCA). For the purposes of this mini-review, we will only focus on C. sinensis and review pathogenesis and carcinogenesis of clonorchiasis, disease condition by C. sinensis infestation, and association between C. sinensis infestation and CCA. In this presentation, we briefly consider the current scientific status for progression of CCA by heavy C. sinensis infestation from the food-borne trematode and development of CCA.
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Affiliation(s)
- Tong-Soo Kim
- Department of Parasitology and Tropical Medicine, School of Medicine, Inha University, Incheon 22212, Korea
| | - Jhang Ho Pak
- Department of Convergence Medicine, College of Medicine, University of Ulsan, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea
| | - Jong-Bo Kim
- Department of Biotechnology, Konkuk University, Chungju 27478, Korea
| | - Young Yil Bahk
- Department of Biotechnology, Konkuk University, Chungju 27478, Korea
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9
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Yothaisong S, Namwat N, Yongvanit P, Khuntikeo N, Puapairoj A, Jutabha P, Anzai N, Tassaneeyakul W, Tangsucharit P, Loilome W. Increase in L-type amino acid transporter 1 expression during cholangiocarcinogenesis caused by liver fluke infection and its prognostic significance. Parasitol Int 2015; 66:471-478. [PMID: 26657242 DOI: 10.1016/j.parint.2015.11.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 10/29/2015] [Accepted: 11/30/2015] [Indexed: 11/18/2022]
Abstract
L-type amino acid transporter 1 (LAT1) is highly expressed in various human cancers, including cholangiocarcinoma (CCA), the most common cancer in Northeast Thailand. Chronic inflammation and oxidative stress induced by liver fluke, Opisthorchis viverrini, infection has been recognized as the major cause of CCA in this area. We show here that an increased expression of LAT1 and its co-functional protein CD98 are found during carcinogenesis induced by Ov in hamster CCA tissues. We also demonstrate that oxidative stress induced by H2O2 is time-dependent and dramatically activates LAT1 and CD98 expression in immortal cholangiocytes (MMNK1). In addition, H2O2 treatment increased LAT1 and CD98 expression, as well as an activated form of AKT and mTOR in MMNK1 and CCA cell lines (KKU-M055 and KKU-M213). We also show that suppression of PI3K/AKT pathway activity with a dual PI3K/mTOR inhibitor, BEZ235, causes a reduction in LAT1 and CD98 expression in KKU-M055 and KKU-M213 in parallel with a reduction of activated AKT and mTOR. Interestingly, high expression of LAT1 in human CCA tissues is a significant prognostic factor for shorter survival. Taken together, our data show that LAT1 expression is significantly associated with CCA progression and cholangiocarcinogenesis induced by oxidative stress. Moreover, the expression of LAT1 and CD98 in CCA is possibly regulated by the PI3K/AKT signaling pathway.
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Affiliation(s)
- Supak Yothaisong
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand
| | - Nisana Namwat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand
| | - Puangrat Yongvanit
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand
| | - Narong Khuntikeo
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand
| | - Anucha Puapairoj
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Promsuk Jutabha
- Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Naohiko Anzai
- Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Wichittra Tassaneeyakul
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Panot Tangsucharit
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand.
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Correia da Costa JM, Vale N, Gouveia MJ, Botelho MC, Sripa B, Santos LL, Santos JH, Rinaldi G, Brindley PJ. Schistosome and liver fluke derived catechol-estrogens and helminth associated cancers. Front Genet 2014; 5:444. [PMID: 25566326 PMCID: PMC4274992 DOI: 10.3389/fgene.2014.00444] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 12/04/2014] [Indexed: 12/21/2022] Open
Abstract
Infection with helminth parasites remains a persistent public health problem in developing countries. Three of these pathogens, the liver flukes Clonorchis sinensis, Opisthorchis viverrini and the blood fluke Schistosoma haematobium, are of particular concern due to their classification as Group 1 carcinogens: infection with these worms is carcinogenic. Using liquid chromatography-mass spectrometry (LC-MS/MS) approaches, we identified steroid hormone like (e.g., oxysterol-like, catechol estrogen quinone-like, etc.) metabolites and related DNA-adducts, apparently of parasite origin, in developmental stages including eggs of S. haematobium, in urine of people with urogenital schistosomiasis, and in the adult stage of O. viverrini. Since these kinds of sterol derivatives are metabolized to active quinones that can modify DNA, which in other contexts can lead to breast and other cancers, helminth parasite associated sterols might induce tumor-like phenotypes in the target cells susceptible to helminth parasite associated cancers, i.e., urothelial cells of the bladder in the case of urogenital schistosomiasis and the bile duct epithelia or cholangiocytes, in the case of O. viverrini and C. sinensis. Indeed we postulate that helminth induced cancers originate from parasite estrogen-host epithelial/urothelial cell chromosomal DNA adducts, and here we review recent findings that support this conjecture.
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Affiliation(s)
- José M Correia da Costa
- Center for Parasite Biology and Immunology, National Health Institute Doutor Ricardo Jorge Porto, Portugal ; Center for the Study of Animal Science, Instituto de Ciências e Tecnologias Agrárias e Agroalimentares, University of Porto Porto, Portugal
| | - Nuno Vale
- Department of Chemistry and Biochemistry, Centro de Investigação em Química, University of Porto Porto, Portugal
| | - Maria J Gouveia
- Center for the Study of Animal Science, Instituto de Ciências e Tecnologias Agrárias e Agroalimentares, University of Porto Porto, Portugal ; Department of Chemistry and Biochemistry, Centro de Investigação em Química, University of Porto Porto, Portugal
| | - Mónica C Botelho
- Department of Health Promotion and Chronic Diseases, National Health Institute Doutor Ricardo Jorge Porto, Portugal
| | - Banchob Sripa
- Tropical Disease Research Laboratory, Liver Fluke and Cholangiocarcinoma Research Center, Department of Pathology, Faculty of Medicine, Khon Kaen University Khon Kaen, Thailand
| | - Lúcio L Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute for Oncology of Porto Porto, Portugal
| | - Júlio H Santos
- Center for the Study of Animal Science, Instituto de Ciências e Tecnologias Agrárias e Agroalimentares, University of Porto Porto, Portugal ; Experimental Pathology and Therapeutics Group, Portuguese Institute for Oncology of Porto Porto, Portugal
| | - Gabriel Rinaldi
- Research Center for Neglected Diseases of Poverty, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine & Health Sciences, George Washington University Washington, DC, USA
| | - Paul J Brindley
- Research Center for Neglected Diseases of Poverty, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine & Health Sciences, George Washington University Washington, DC, USA
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Habermeyer M, Roth A, Guth S, Diel P, Engel KH, Epe B, Fürst P, Heinz V, Humpf HU, Joost HG, Knorr D, de Kok T, Kulling S, Lampen A, Marko D, Rechkemmer G, Rietjens I, Stadler RH, Vieths S, Vogel R, Steinberg P, Eisenbrand G. Nitrate and nitrite in the diet: how to assess their benefit and risk for human health. Mol Nutr Food Res 2014; 59:106-28. [PMID: 25164923 DOI: 10.1002/mnfr.201400286] [Citation(s) in RCA: 126] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 07/29/2014] [Accepted: 08/04/2014] [Indexed: 12/15/2022]
Abstract
Nitrate is a natural constituent of the human diet and an approved food additive. It can be partially converted to nitrogen monoxide, which induces vasodilation and thereby decreases blood pressure. This effect is associated with a reduced risk regarding cardiovascular disease, myocardial infarction, and stroke. Moreover, dietary nitrate has been associated with beneficial effects in patients with gastric ulcer, renal failure, or metabolic syndrome. Recent studies indicate that such beneficial health effects due to dietary nitrate may be achievable at intake levels resulting from the daily consumption of nitrate-rich vegetables. N-nitroso compounds are endogenously formed in humans. However, their relevance for human health has not been adequately explored up to now. Nitrate and nitrite are per se not carcinogenic, but under conditions that result in endogenous nitrosation, it cannot be excluded that ingested nitrate and nitrite may lead to an increased cancer risk and may probably be carcinogenic to humans. In this review, the known beneficial and detrimental health effects related to dietary nitrate/nitrite intake are described and the identified gaps in knowledge as well as the research needs required to perform a reliable benefit/risk assessment in terms of long-term human health consequences due to dietary nitrate/nitrite intake are presented.
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Affiliation(s)
- Michael Habermeyer
- Department of Food Chemistry and Toxicology, University of Kaiserslautern, Kaiserslautern, Germany**
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12
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Khunluck T, Kukongviriyapan V, Puapairoj A, Khuntikeo N, Senggunprai L, Zeekpudsa P, Prawan A. Association of NRF2 polymorphism with cholangiocarcinoma prognosis in Thai patients. Asian Pac J Cancer Prev 2014; 15:299-304. [PMID: 24528044 DOI: 10.7314/apjcp.2014.15.1.299] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Cholangiocarcinoma (CCA), a malignancy of biliary duct with a very poor prognosis, is the leading cause of cancer death in countries of the Mekong subregion. Liver fluke infection is the main etiological factor, but genetic variation has been recognized as also important in conferring susceptibility to CCA risk. Nuclear factor (erythroid derived 2)-like 2 (NRF2) is a key transcription factor in detoxification and antioxidant defense. Emerging evidence has demonstrated that genetic polymorphisms in the NRF2 gene may be associated with cancer development. The objectives of this study were to investigate the association of NRF2 genetic polymorphism with CCA risk and to evaluate the influence of the NRF2 genotype on survival time of affected patients. Single nucleotide polymorphisms (SNPs) of the NRF2 gene, including rs6726395: A/G, rs2886161: C/T, rs1806649: C/T, and rs10183914: C/T, were analyzed using TaqMan® SNP genotyping assays. Among 158 healthy northeastern Thai subjects, the allele frequencies were 41, 62, 94, and 92%, respectively. The correlation of NRF2 SNPs and CCA risk was analyzed in the 158 healthy subjects and 198 CCA patients, using unconditional logistic regression. The results showed that whereas the NRF2 SNPs were not associated with CCA risk (p>0.05), Kaplan-Meier analysis of 88 intrahepatic CCA patients showed median survival time with rs6726395 genotypes of GG and AA/AG to be 344±138 (95%CI: 73-615) days and 172±37 (95%CI: 100-244) days, respectively, (p<0.006). On multivariate Cox proportional hazard analysis, the GG genotype of rs6726395 was found to be associated with longer survival with a hazard ratio of 0.54 (95%CI: 0.31-0.94). In addition, non-papillary adenocarcinoma was associated with poor survival with a hazard ratio of 2.09 (95%CI: 1.16-3.75). The results suggest that the NRF2 rs6726395 polymorphism can be a potential prognostic biomarker for CCA patients.
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Affiliation(s)
- Tueanjai Khunluck
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand E-mail :
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13
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Hrudey SE, Bull RJ, Cotruvo JA, Paoli G, Wilson M. Drinking water as a proportion of total human exposure to volatile N-nitrosamines. RISK ANALYSIS : AN OFFICIAL PUBLICATION OF THE SOCIETY FOR RISK ANALYSIS 2013; 33:2179-2208. [PMID: 23786353 DOI: 10.1111/risa.12070] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Some volatile N-nitrosamines, primarily N-nitrosodimethylamine (NDMA), are recognized as products of drinking water treatment at ng/L levels and as known carcinogens. The U.S. EPA has identified the N-nitrosamines as contaminants being considered for regulation as a group under the Safe Drinking Water Act. Nitrosamines are common dietary components, and a major database (over 18,000 drinking water samples) has recently been created under the Unregulated Contaminant Monitoring Rule. A Monte Carlo modeling analysis in 2007 found that drinking water contributed less than 2.8% of ingested NDMA and less than 0.02% of total NDMA exposure when estimated endogenous formation was considered. Our analysis, based upon human blood concentrations, indicates that endogenous NDMA production is larger than expected. The blood-based estimates are within the range that would be calculated from estimates based on daily urinary NDMA excretion and an estimate based on methylated guanine in DNA of lymphocytes from human volunteers. Our analysis of ingested NDMA from food and water based on Monte Carlo modeling with more complete data input shows that drinking water contributes a mean proportion of the lifetime average daily NDMA dose ranging from between 0.0002% and 0.001% for surface water systems using free chlorine or between 0.001% and 0.01% for surface water systems using chloramines. The proportions of average daily dose are higher for infants (zero to six months) than other age cohorts, with the highest mean up to 0.09% (upper 95th percentile of 0.3%).
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Affiliation(s)
- Steve E Hrudey
- Analytical & Environmental Toxicology, Department of Laboratory Medicine & Pathology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
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Vale N, Gouveia MJ, Botelho M, Sripa B, Suttiprapa S, Rinaldi G, Gomes P, Brindley PJ, Correia da Costa JM. Carcinogenic liver fluke Opisthorchis viverrini oxysterols detected by LC-MS/MS survey of soluble fraction parasite extract. Parasitol Int 2013; 62:535-42. [PMID: 23973383 PMCID: PMC3797210 DOI: 10.1016/j.parint.2013.08.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 08/02/2013] [Accepted: 08/07/2013] [Indexed: 12/11/2022]
Abstract
Liquid chromatography in tandem mass spectrometry (LC-MS/MS) has emerged as an informative tool to investigate oxysterols (oxidized derivatives of cholesterol) in helminth parasite associated cancers. Here, we used LC-MS/MS to investigate in soluble extracts of the adult developmental stage of Opisthorchis viverrini from experimentally infected hamsters. Using comparisons with known bile acids and the metabolites of estrogens, the LC-MS data indicated the existence of novel oxysterol derivatives in O. viverrini. Most of these derivatives were ramified at C-17, in similar fashion to bile acids and their conjugated salts. Several were compatible with the presence of an estrogen core, and/or hydroxylation of the steroid aromatic ring A, hydroxylation of both C-2 and C-3 of the steroid ring and further oxidation into an estradiol-2,3-quinone.
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Affiliation(s)
- Nuno Vale
- CIQUP, Chemistry and Biochemistry Department, Faculty of Sciences, University of Porto, Rua Campo Alegre, 687, 4169-007 Porto, Portugal.
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15
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Jusakul A, Loilome W, Namwat N, Techasen A, Kuver R, Ioannou G, Savard C, Haigh WG, Yongvanit P. Anti-apoptotic phenotypes of cholestan-3β,5α,6β-triol-resistant human cholangiocytes: characteristics contributing to the genesis of cholangiocarcinoma. J Steroid Biochem Mol Biol 2013; 138:368-75. [PMID: 23959098 PMCID: PMC3825754 DOI: 10.1016/j.jsbmb.2013.08.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Revised: 07/29/2013] [Accepted: 08/06/2013] [Indexed: 12/30/2022]
Abstract
The oxysterols cholestan-3β,5α,6β-triol (Triol) and 3-keto-cholest-4-ene (3K4) are increased in Opisthorchis viverrini-associated hamster cholangiocarcinoma and induce DNA damage and apoptosis via a mitochondria-dependent mechanism in MMNK-1 human cholangiocytes. Based on these observations, we hypothesized that chronic exposure of cholangiocytes to these pathogenic oxysterols may allow a growth advantage to a subset of these cells through selection for resistance to apoptosis, thereby contributing to cholangiocarcinogenesis. To test this hypothesis, we cultured MMNK-1 cells long-term in the presence of Triol. Alteration in survival and apoptotic factors of Triol-exposed cells were examined. Cells cultured long-term in the presence of Triol were resistant to H2O2-induced apoptosis, and demonstrated an increase in the phosphorylation of p38-α, CREB, ERK1/2 and c-Jun. Elevations in the ratio of Bcl-2/Bax and in the protein levels of anti-apoptotic factors including cIAP2, clusterin, and survivin were detected. These results show that long-term exposure of MNNK-1 cells to low doses of Triol selects for kinase-signaling molecules which regulate resistance to apoptosis and thereby enhance cell survival. Clonal expansion of such apoptosis-resistant cells may contribute to the genesis of cholangiocarcinoma.
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Affiliation(s)
- Apinya Jusakul
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Medicine, University of Washington School of Medicine and the Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Nisana Namwat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Anchalee Techasen
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Rahul Kuver
- Department of Medicine, University of Washington School of Medicine and the Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - George Ioannou
- Department of Medicine, University of Washington School of Medicine and the Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - Christopher Savard
- Department of Medicine, University of Washington School of Medicine and the Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - W. Geoffrey Haigh
- Department of Medicine, University of Washington School of Medicine and the Department of Veterans Affairs Medical Center, Seattle, WA, USA
| | - Puangrat Yongvanit
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Corresponding author: Puangrat Yongvanit, Ph.D., Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand, Phone: +66(43)-348386, Fax: +66(43)-348386,
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Khoontawad J, Laothong U, Roytrakul S, Pinlaor P, Mulvenna J, Wongkham C, Yongvanit P, Pairojkul C, Mairiang E, Sithithaworn P, Pinlaor S. Proteomic identification of plasma protein tyrosine phosphatase alpha and fibronectin associated with liver fluke, Opisthorchis viverrini, infection. PLoS One 2012; 7:e45460. [PMID: 23029023 PMCID: PMC3445495 DOI: 10.1371/journal.pone.0045460] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Accepted: 08/22/2012] [Indexed: 12/02/2022] Open
Abstract
Opisthorchiasis caused by Opisthorchis viverrini induces periductal fibrosis via host immune/inflammatory responses. Plasma protein alteration during host-parasite interaction-mediated inflammation may provide potential diagnostic and/or prognostic biomarkers. To search for target protein changes in O. viverrini-infected hamsters, a 1-D PAGE gel band was trypsin-digested and analyzed by a LC-MS/MS-based proteomics approach in the plasma profile of infected hamsters, and applied to humans. Sixty seven proteins were selected for further analysis based on at least two unique tryptic peptides with protein ID score >10 and increased expression at least two times across time points. These proteins have not been previously identified in O. viverrini-associated infection. Among those, proteins involved in structural (19%), immune response (13%), cell cycle (10%) and transcription (10%) were highly expressed. Western blots revealed an expression level of protein tyrosine phosphatase alpha (PTPα) which reached a peak at 1 month and subsequently tended to decrease. Fibronectin significantly increased at 1 month and tended to increase with time, supporting proteomic analysis. PTPα was expressed in the cytoplasm of inflammatory cells, while fibronectin was observed mainly in the cytoplasm of fibroblasts and the extracellular matrix at periductal fibrosis areas. In addition, these protein levels significantly increased in the plasma of O. viverrini-infected patients compared to healthy individuals, and significantly decreased at 2-months post-treatment, indicating their potential as disease markers. In conclusion, our results suggest that plasma PTPα and fibronectin may be associated with opisthorchiasis and the hamster model provides the basis for development of novel diagnostic markers in the future.
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Affiliation(s)
- Jarinya Khoontawad
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Umawadee Laothong
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sittiruk Roytrakul
- Proteomics Research Laboratory, Genome Institute Biotechnology, Pathumthani, Thailand
| | - Porntip Pinlaor
- Centre for Research and Development in Medical Diagnostic Laboratory, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Jason Mulvenna
- Department of Infectious Disease and Cancer, Faculty of Computational Biology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
| | - Chaisiri Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Puangrat Yongvanit
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Eimorn Mairiang
- Department of Radiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Paiboon Sithithaworn
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- * E-mail:
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Juasook A, Boonmars T, Wu Z, Loilome W, Veteewuthacharn K, Namwat N, Sudsarn P, Wonkchalee O, Sriraj P, Aukkanimart R. Immunosuppressive Prednisolone Enhances Early Cholangiocarcinoma in Syrian Hamsters with Liver Fluke Infection and Administration of N-nitrosodimethylamine. Pathol Oncol Res 2012; 19:55-62. [DOI: 10.1007/s12253-012-9557-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 07/23/2012] [Indexed: 12/16/2022]
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18
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Anti-inflammatory effect of prednisolone on the growth of human liver fluke in experimental opisthorchiasis. Parasitol Res 2011; 110:2271-9. [DOI: 10.1007/s00436-011-2759-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2011] [Accepted: 12/05/2011] [Indexed: 01/06/2023]
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19
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Smout MJ, Sripa B, Laha T, Mulvenna J, Gasser RB, Young ND, Bethony JM, Brindley PJ, Loukas A. Infection with the carcinogenic human liver fluke, Opisthorchis viverrini. MOLECULAR BIOSYSTEMS 2011; 7:1367-75. [PMID: 21311794 PMCID: PMC3739706 DOI: 10.1039/c0mb00295j] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Throughout Southeast Asia there is a strikingly high incidence of cholangiocarcinoma (CCA--hepatic cancer of the bile duct epithelium), particularly in people from rural settings in Laos and Northeast Thailand who are infected with the liver fluke, Opisthorchis viverrini, one of only three carcinogenic eukaryotic pathogens. More ubiquitous carcinogenic microbes, such as Helicobacter pylori, induce cancer in less than 1% of infected people, while as many as one-sixth of people with opisthorchiasis will develop CCA. The mechanisms by which O. viverrini causes cancer are multi-factorial, involving mechanical irritation from the activities and movements of the flukes, immunopathology, dietary nitrosamines and the secretion of parasite proteins that promote a tumourigenic environment. Genomic and proteomic studies of the liver fluke secretome have accelerated the discovery of parasite proteins with known/potential roles in pathogenesis and tumourigenesis, establishing a framework towards understanding, and ultimately preventing, the morbidity and mortality attributed to this highly carcinogenic parasite.
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Affiliation(s)
- Michael J Smout
- Queensland Tropical Health Alliance, James Cook University, Cairns, QLD, Australia
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20
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Prakobwong S, Khoontawad J, Yongvanit P, Pairojkul C, Hiraku Y, Sithithaworn P, Pinlaor P, Aggarwal BB, Pinlaor S. Curcumin decreases cholangiocarcinogenesis in hamsters by suppressing inflammation-mediated molecular events related to multistep carcinogenesis. Int J Cancer 2010; 129:88-100. [PMID: 20824699 DOI: 10.1002/ijc.25656] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2010] [Accepted: 08/23/2010] [Indexed: 01/13/2023]
Abstract
Cholangiocarcinoma (CCA) is a highly metastatic tumor linked to liver fluke infection and consumption of nitrosamine-contaminated foods and is a major health problem especially in South-Eastern Asia. In search for a suitable chemopreventive agents, we investigated the effect of curcumin, a traditional anti-inflammatory agent derived from turmeric (Curcuma longa), on CCA development in an animal model by infection with the liver fluke Opisthorchis viverrini and administration of N-nitrosodimethylamine and fed with curcumin-supplemented diet. The effect of curcumin-supplemented diet on histopathological changes and survival were assessed in relation to NF-κB activation, and the expression of NF-κB-related gene products involved in inflammation, DNA damage, apoptosis, cell proliferation, angiogenesis and metastasis. Our results showed that dietary administration of this nutraceutical significantly reduced the incidence of CCA and increased the survival of animals. This correlated with the suppression of the activation of transcription factors including NF-κB, AP-1 and STAT-3, and reduction in the expression of proinflammatory proteins such as COX-2 and iNOS. The formation of iNOS-dependent DNA lesions (8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine) was inhibited. Curcumin suppressed the expression of proteins related to cell survival (bcl-2 and bcl-xL), proliferation (cyclin D1 and c-myc), tumor invasion (MMP-9 and ICAM-1) and angiogenesis (VEGF), and microvessel density. Induction of apoptotic events as indicated by caspase activation and PARP cleavage was also noted. Our results suggest that curcumin exhibits an anticarcinogenic potential via suppression of various events involved in multiple steps of carcinogenesis, which is accounted for by its ability to suppress proinflammatory pathways.
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Affiliation(s)
- Suksanti Prakobwong
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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21
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Laothong U, Pinlaor P, Hiraku Y, Boonsiri P, Prakobwong S, Khoontawad J, Pinlaor S. Protective effect of melatonin against Opisthorchis viverrini-induced oxidative and nitrosative DNA damage and liver injury in hamsters. J Pineal Res 2010; 49:271-82. [PMID: 20626588 DOI: 10.1111/j.1600-079x.2010.00792.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The liver fluke, Opisthorchis viverrini, is the risk factor of cholangiocarcinoma, which is a major health problem in northeastern Thailand. Production of reactive oxygen and nitrogen species during the host's response leads to oxidative and nitrosative stress contributing to carcinogenesis. We investigated the protective effect of melatonin against O. viverrini-induced oxidative and nitrosative stress and liver injury. Hamsters were infected with O. viverrini followed by oral administration of various doses of melatonin (5, 10, and 20 mg/kg body weight) for 30 days. Uninfected hamsters served as controls. Compared to the levels in O. viverrini-infected hamsters without melatonin treatment, the indoleamine decreased the formation of oxidative and nitrosative DNA lesions, 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-nitroguanine, in the nucleus of bile duct epithelium and inflammatory cells, in parallel with a reduction in 3-nitrotyrosine. Melatonin also reduced the expression of heme oxygenase-1 and cytokeratin 19, nitrate/nitrite levels, and bile duct proliferation in the liver. Alanine transaminase activity and the levels of 8-isoprostane and vitamin E were also dose dependently decreased in the plasma of melatonin-treated hamsters. Melatonin reduced the mRNA expression of oxidant-generating genes [inducible nitric oxide synthase, nuclear factor-kappa B (NF-κB), and cyclooxygenase-2] and proinflammatory cytokines (TNF-α and IL-1β), accompanied by an increase in the expression of antioxidant genes [nuclear erythroid 2-related factor 2 (Nrf2) and manganese superoxide dismutase]. Thus, melatonin may be an effective chemopreventive agent against O. viverrini-induced cholangiocarcinoma by reducing oxidative and nitrosative DNA damage via induction of Nrf2 and inhibition of NF-κB-mediated pathways.
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Affiliation(s)
- Umawadee Laothong
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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22
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Frasca G, Panico AM, Bonina F, Messina R, Rizza L, Musumeci G, Rapisarda P, Cardile V. Involvement of inducible nitric oxide synthase and cyclooxygenase-2 in the anti-inflammatory effects of a red orange extract in human chondrocytes. Nat Prod Res 2010; 24:1469-1480. [PMID: 20812134 DOI: 10.1080/14786410903169987] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
In the present study, a complex of compounds (red orange complex, ROC), obtained from three red orange varieties (Citrus sinensis varieties: Moro, Tarocco and Sanguinello), containing cyanidin glycosides, hydroxycinnamic acids, flavanone glycosides and ascorbic acid, was screened to discover new lead compounds in the suppression of the production of key molecules released during inflammatory events in interleukin-1beta (IL-beta) stimulated human primary chondrocytes. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX)-2 and intercellular adhesion molecule-1 (ICAM-1), and the release of nitric oxide, prostaglandin (PG)E(2) and interleukin-8 (IL-8) were determined. Indomethacin was used as an anti-inflammatory drug reference. ROC acts as a potent inhibitor of iNOS and COX-2 gene expression while also suppressing the production of PGE(2) and nitrite in human chondrocytes. In addition, ROC induces a significant decrease in ICAM expression and IL-8 release. These findings suggest that ROC exerts anti-inflammatory effects probably through the suppression of COX-2 and iNOS expression.
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Affiliation(s)
- G Frasca
- Department of Physiological Sciences, University of Catania, I-95125 Catania, Italy
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KHOONTAWAD J, WONGKHAM C, HIRAKU Y, YONGVANIT P, PRAKOBWONG S, BOONMARS T, PINLAOR P, PINLAOR S. Proteomic identification of peroxiredoxin 6 for host defence againstOpisthorchis viverriniinfection. Parasite Immunol 2010; 32:314-23. [DOI: 10.1111/j.1365-3024.2009.01189.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Huang YJ, Zhang BB, Ma N, Murata M, Tang AZ, Huang GW. Nitrative and oxidative DNA damage as potential survival biomarkers for nasopharyngeal carcinoma. Med Oncol 2010; 28:377-84. [PMID: 20339958 DOI: 10.1007/s12032-010-9434-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2009] [Accepted: 01/25/2010] [Indexed: 12/14/2022]
Abstract
Currently, there are no satisfactory biomarkers available to screen for nasopharyngeal carcinoma (NPC). Nitric oxide (NO), produced by inducible nitric oxide synthase (iNOS), has been suggested to cause nitrative and oxidative stress, leading to the accumulation of 8-nitroguanine (8-NitroG) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) and the subsequent transversion mutation of DNA. The aim of this study was to evaluate iNOS expression and the status of nitrative and oxidative stress in NPC. Fifty-nine cases of NPC and 39 cases of chronic nasopharyngitis were investigated to examine the expression of iNOS and the formation of 8-NitroG and 8-OHdG, using double-immunofluorescent staining. The statistical differences in immunoreactivities were analyzed using the Mann-Whitney test. Thirty-six patients from the 57 cases of NPC and 36 healthy controls were investigated to examine the level of serum 8-OHdG, using enzyme-linked immunosorbent assay (ELISA). The statistical differences were analyzed using a t test. Strong DNA lesions were observed in the cancer cells of NPC patients. All cases of NPC were positive for 8-NitroG and 8-OHdG, and 54 (94.7%) were positive for iNOS. NPC samples exhibited significantly more intense staining for 8-NitroG, 8-OHdG and iNOS than those of chronic nasopharyngitis (P < 0.05, respectively). The mean value of serum 8-OHdG in the 36 NPC patients was 0.538 ± 0.336 ng/ml compared to 0.069 ± 0.059 ng/ml for the healthy controls. The difference in the serum levels of 8-OHdG between the NPC patients and controls was statistically significant (P < 0.05). Our present findings suggest that pathological stimulation of nasopharyngeal tissue, caused by bacterial, viral or parasitic inflammation, may lead to nitrative and oxidative DNA lesions, caused by NO. This may contribute to the cause and development of NPC. Thus, 8-NitroG and 8-OHdG could be potential biomarkers for evaluating the risk of NPC. Better understanding of the molecular mechanisms underlying nitrative and oxidative DNA damage may provide clues to molecular targets for new approaches of NPC prevention.
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Affiliation(s)
- Yuan-Jiao Huang
- Medical Scientific Research Center, Guangxi Medical University, 530021 Nanning, People's Republic of China.
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25
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Fox JG, Shen Z, Muthupalani S, Rogers AR, Kirchain SM, Dewhirst FE. Chronic hepatitis, hepatic dysplasia, fibrosis, and biliary hyperplasia in hamsters naturally infected with a novel Helicobacter classified in the H. bilis cluster. J Clin Microbiol 2009; 47:3673-81. [PMID: 19759229 PMCID: PMC2772605 DOI: 10.1128/jcm.00879-09] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Revised: 06/29/2009] [Accepted: 08/30/2009] [Indexed: 01/15/2023] Open
Abstract
We recently described helicobacter-associated progressive, proliferative, and dysplastic typhlocolitis in aging (18- to 24-month-old) Syrian hamsters. Other pathogens associated with typhlocolitis in hamsters, Clostridium difficile, Lawsonia intracellularis, and Giardia spp., were not indentified. The presence of Helicobacter genus-specific DNA was noted by PCR in cecal and paraffin-embedded liver samples from aged hamsters by the use of Helicobacter-specific PCR primers. By 16S rRNA analysis, the Helicobacter sp. isolated from the liver tissue was identical to the cecal isolates from hamsters. The six hamster 16S rRNA sequences form a genotypic cluster most closely related to Helicobacter sp. Flexispira taxon 8, part of the Helicobacter bilis/H. cinaedi group. Livers from aged helicobacter-infected hamsters showed various stages of predominantly portocentric and, to a lesser extent, perivenular fibrosis. Within nodules, there was cellular atypia consistent with nodular dysplasia. The livers also exhibited a range of chronic active portal/interface and lobular inflammation, with significant portal hepatitis being present. The inflammation was composed of a mixture of lymphocytes, neutrophils, and macrophages, indicative of its chronic-active nature in these aged hamsters infected with Helicobacter spp. The isolation of novel Helicobacter spp., their identification by PCR from the diseased livers of aged hamsters, and their taxonomic classification as belonging to the Helicobacter bilis cluster strengthen the argument that H. bilis and closely related Helicobacter spp. play an etiological role in hepatobiliary disease in both animals and humans.
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MESH Headings
- Animals
- Biliary Tract Diseases/microbiology
- Biliary Tract Diseases/veterinary
- Cecum/microbiology
- Cluster Analysis
- Cricetinae
- DNA, Bacterial/chemistry
- DNA, Bacterial/genetics
- DNA, Bacterial/isolation & purification
- DNA, Ribosomal/chemistry
- DNA, Ribosomal/genetics
- Fibrosis/microbiology
- Fibrosis/veterinary
- Helicobacter/classification
- Helicobacter/genetics
- Helicobacter/isolation & purification
- Helicobacter/pathogenicity
- Helicobacter Infections/microbiology
- Helicobacter Infections/pathology
- Helicobacter Infections/veterinary
- Hepatitis, Chronic/microbiology
- Hepatitis, Chronic/pathology
- Hepatitis, Chronic/veterinary
- Hyperplasia/microbiology
- Hyperplasia/veterinary
- Inflammation/pathology
- Liver/microbiology
- Liver/pathology
- Liver Cirrhosis/microbiology
- Liver Cirrhosis/pathology
- Liver Cirrhosis/veterinary
- Lymphocytes/immunology
- Macrophages/immunology
- Mesocricetus/microbiology
- Molecular Sequence Data
- Neutrophils/immunology
- Polymerase Chain Reaction
- Polymorphism, Restriction Fragment Length
- RNA, Bacterial/genetics
- RNA, Bacterial/isolation & purification
- RNA, Ribosomal, 16S/genetics
- Sequence Analysis, DNA
- Sequence Homology, Nucleic Acid
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Affiliation(s)
- J G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Ave., Bldg. 16-825, Cambridge, MA 02139, USA.
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26
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Time profiles of the expression of metalloproteinases, tissue inhibitors of metalloproteases, cytokines and collagens in hamsters infected with Opisthorchis viverrini with special reference to peribiliary fibrosis and liver injury. Int J Parasitol 2009; 39:825-35. [PMID: 19168069 DOI: 10.1016/j.ijpara.2008.12.002] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2008] [Revised: 11/04/2008] [Accepted: 12/05/2008] [Indexed: 02/06/2023]
Abstract
The liver fluke Opisthorchis viverrini is endemic in southeastern Asia, and causes cholangiocarcinoma and liver fibrosis. We investigated the time profile of the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in relation to peribiliary fibrosis in O. viverrini-infected hamsters. Hepatic mRNA expression of MMPs, TIMPs, cytokines and collagens I and III was assessed by quantitative reverse transcription-PCR. Zymography and immunohistochemistry were also used to examine MMPs-2 and -9 expression. After infection, an increase of peribiliary fibrosis was time-dependent. Opisthorhis viverrini-induced gene expression in hamster liver, with increased mRNA expression levels of IL-1beta, TNF-alpha, TGF-beta, and collagens I and III, was observed at 21 days p.i. Expression of MMPs-2, -13 and -14 and TIMPs-1 and -3 genes, was significantly higher at 1 month, and maximal levels of most MMPs (MMPs-2, -9, -13 and -14) were observed at 2 months p.i. The cytoplasmic levels of MMP-2 and MMP-9 were similar to mRNA expression. Immunohistochemistry revealed that MMP-9 was expressed mainly in the cytoplasm of inflammatory cells at the invasive front of the fibrous area. In contrast, the highest levels of mRNA expression of TIMPs-2 and -3, and TGF-beta were observed 10 months p.i. Concentration of TIMP-2 protein in the plasma correlated with its transcriptional level (r=0.320, P=0.040). Peribiliary fibrosis correlated positively with liver hydroxyproline content (r=0.846, P<0.001), plasma hydroxyproline concentration (r=0.770, P<0.001), plasma TIMP-2 level (r=0.335, P=0.046), and mRNA expression levels of MMP-7 (r=0.511, P=0.006), TIMP-1 (r=0.320, P=0.040), TIMP-2 (r=0.428, P=0.026), and TIMP-3 (r=0.553, P=0.003). This study suggests that expression of MMPs is associated with an inflammatory reaction in the early phase and TIMPs expression at the late phase may contribute to both fibrosis and liver injury. MMPs and TIMPs may serve as diagnostic markers for the severity of O. viverrini-induced liver injury.
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Mayer DA, Fried B. The role of helminth infections in carcinogenesis. ADVANCES IN PARASITOLOGY 2008; 65:239-96. [PMID: 18063098 DOI: 10.1016/s0065-308x(07)65004-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This review examines the significant literature on the role of helminth infections in carcinogenesis. Both parasitic infections and cancer have complex natural histories and long latent periods during which numerous exogenous and endogenous factors interact to obfuscate causality. Although only two helminths, Schistosoma haematobium and Opisthorchis viverrini, have been proven to be definitely carcinogenic to humans, others have been implicated in facilitating malignant transformation. The known mechanisms of helminth-induced cancer include chronic inflammation, modulation of the host immune system, inhibition of intracellular communication, disruption of proliferation-antiproliferation pathways, induction of genomic instability and stimulation of malignant stem cell progeny. Approximately 16% of all cancer cases worldwide are attributable to pathogenic agents, including schistosomes and liver flukes. This equates to 1,375,000 preventable cancer deaths per year. Means to reduce the incidence of helminth-associated malignancies are discussed.
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Affiliation(s)
- David A Mayer
- Department of Surgery, New York Medical College, Valhalla, New York 10595, USA
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28
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Segawa Y, Oda Y, Yamamoto H, Uryu H, Shiratsuchi H, Hirakawa N, Tomita K, Yamamoto T, Oda S, Yamada T, Komune S, Tsuneyoshi M. Overexpression of inducible nitric oxide synthase and accumulation of 8-OHdG in nasopharyngeal carcinoma. Histopathology 2007; 52:213-23. [DOI: 10.1111/j.1365-2559.2007.02920.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Pinlaor S, Hiraku Y, Yongvanit P, Tada-Oikawa S, Ma N, Pinlaor P, Sithithaworn P, Sripa B, Murata M, Oikawa S, Kawanishi S. iNOS-dependent DNA damage via NF-kappaB expression in hamsters infected with Opisthorchis viverrini and its suppression by the antihelminthic drug praziquantel. Int J Cancer 2006; 119:1067-72. [PMID: 16570287 DOI: 10.1002/ijc.21893] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Inflammation-mediated DNA damage triggered by Opisthorchis viverrini (OV) infection is a major risk factor of cholangiocarcinoma (CCA). We have recently reported that nitrative and oxidative DNA damage participates in CCA development caused by repeated infection with OV [Pinlaor et al., Carcinogenesis 2004; 25:1535-42]. Therefore, to clarify the preventive effect of the antihelminthic drug praziquantel against cholangiocarcinogenesis, we assessed the effect of this drug on nitrative and oxidative DNA damage, including the formation of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and the expression of inducible nitric oxide synthase (iNOS) by immunohistochemistry in OV-infected hamsters. We also examined the expression of nuclear factor-kappaB (NF-kappaB), which functions as a tumor promoter in inflammation-associated cancer. Our results showed that although 1-week treatment with praziquantel did not kill parasites completely in hamsters on days 14 and 30, this drug dramatically reduced inflammatory cell infiltration. Double immunofluorescence staining showed that drug treatment almost completely diminished OV-induced 8-nitroguanine and 8-oxodG formation in bile duct epithelial cells. Quantitative analysis using an electrochemical detector coupled to HPLC revealed that 8-oxodG level in the liver of OV-infected hamsters was significantly decreased by drug treatment (p<0.05). Western blotting and immunohistochemistry revealed that the expression of NF-kappaB and iNOS in bile duct epithelium was reduced by drug treatment. The amount of nitrate plus nitrite in the liver and plasma was significantly decreased after drug treatment. It is concluded that praziquantel can exhibit a preventive effect against OV-induced cholangiocarcinoma by inhibiting iNOS-dependent DNA damage through not only elimination of parasites but also a potential antiinflammatory effect.
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Limpaiboon T, Tapdara S, Jearanaikoon P, Sripa B, Bhudhisawasdi V. Prognostic significance of microsatellite alterations at 1p36 in cholangiocarcinoma. World J Gastroenterol 2006; 12:4377-82. [PMID: 16865781 PMCID: PMC4087750 DOI: 10.3748/wjg.v12.i27.4377] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate loss of heterozygosity (LOH) and microsatellite instability (MSI) on the chromosomal region 1p36-pter in cholangiocarcinoma (CCA) patients and determine the association between microsatellite alterations and clinicopathological parameters.
METHODS: Ten polymorphic microsatellite markers were determined for LOH and MSI using GS-3000 gel scan fragment autoanalyzer.
RESULTS: Sixty-eight out of 90 cases (75.6%) showed LOH in one or more loci. LOH was found most frequently at D1S199 (40.0%), D1S507 (34.6%), D1S2845 (30.5%), and D1S2734 (30.1%). MSI was found in 34 of 90 cases (37.8%) at one or more loci. Fine mapping at 1p36 showed two distinctive regions of common loss, which were D1S2845 and the 25.5-cM region between D1S507 and D1S2734, indicating the existence of putative tumor suppressor genes that is likely to play important roles in the development of CCA. Patients with LOH at D1S234 showed less lymphatic invasion (P = 0.017), whereas patients with LOH at D1S2676 exhibited more lymphatic invasion than those without (P = 0.031). LOH at D1S2845 showed a significant correlation with nerve invasion (P = 0.029). Moreover, patients who demonstrated MSI at D1S228 showed a poor prognosis (P = 0.0026).
CONCLUSION: Allelic loss plays a major role in microsatellite alterations at chromosome 1p36, which may contribute to carcinogenesis and pathogenesis of liver fluke related CCA and these alterations can be used as molecular prognostic indicators for CCA patients.
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Affiliation(s)
- Temduang Limpaiboon
- Department of Clinical Chemistry, Center for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
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Thanasai J, Limpaiboon T, Jearanaikoon P, Bhudhisawasdi V, Khuntikeo N, Sripa B, Miwa M. Amplification of D22S283 as a favorable prognostic indicator in liver fluke related cholangiocarcinoma. World J Gastroenterol 2006; 12:4338-44. [PMID: 16865775 PMCID: PMC4087744 DOI: 10.3748/wjg.v12.i27.4338] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the DNA copy number of target genes NF2, TIMP3, ST13, TOB2, BIK, and TP and the reference microsatellite markers D22S283, D22S423, and D22S274 mapped on 22q12-qter in liver fluke related cholangiocarcinoma (CCA) and define its correlation with clinical parameters.
METHODS: Quantitative real time PCR (qPCR) was used for determining allelic imbalances in 65 liver fluke related CCA tissues. Statistical correlations between allelic imbalances and clinicopathological parameters, i.e. age, sex, tumor stage, histological type, blood vessel invasion, nerve invasion and lymphatic invasion were evaluated by means of the χ2 test. Cox regression analysis was used for determining patient’s survival.
RESULTS: Amplifications of the TP (22q13.33), TOB2 (22q13.2-13.31), D22S283 (22q12.3), TIMP3 (22q12.3) and NF2 (22q12.2) were found in 35 (53.8%), 28 (43.1%), 27 (41.5%), 24 (36.9%), and 24 (36.9%), respectively. Losses at the D22S423 (22q13.1-13.2) and BIK (22q13.31) were detected in 26 (40%) and 23 (35.4%), respectively. Significant correlations were observed between lymphatic invasion and allelic losses of BIK (P = 0.025) and D22S283 (P = 0.041). Univariate and multivariate Cox regression analysis revealed D22S283 amplification as an independent predictor of good prognosis (P = 0.006, death hazard ratio = 0.411, 95% CI = 0.217-0.779) and blood vessel invasion as an independent poor prognostic factor (P = 0.042, death hazard ratio = 1.911, 95% CI = 1.022-3.571) in CCA patients.
CONCLUSION: This study provides evidence for the involvement of gene amplification and deletion on chromosome 22q in liver fluke related CCA. This is the first report of D22S283 amplification as an independent indicator of favorable prognosis in liver fluke related CCA.
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Affiliation(s)
- Jongkonnee Thanasai
- Graduate School, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
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Ohshima H, Sawa T, Akaike T. 8-nitroguanine, a product of nitrative DNA damage caused by reactive nitrogen species: formation, occurrence, and implications in inflammation and carcinogenesis. Antioxid Redox Signal 2006; 8:1033-45. [PMID: 16771693 DOI: 10.1089/ars.2006.8.1033] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The authors review studies on 8-nitroguanine (8-NO(2)-G) formed by reactions of guanine, guanosine, and 2 - deoxyguanosine, either free or in DNA or RNAwith reactive nitrogen species (RNS) generated from peroxynitrite, the myeloperoxidase-H(2)O(2)-nitrite system, and others. Use of antibodies against 8-NO(2)-G has revealed increased formation of 8-NO(2)-G in various pathological conditions, including RNA virus-induced pneumonia in mice, intrahepatic bile ducts of hamsters infected with the liver fluke Opisthorchis viverrini, and gastric mucosa of patients with Helicobacter pylori-induced gastritis. Immunoreactivity has been found in the cytosol as well as in the nucleus of inflammatory cells and epithelial cells in inflamed tissues, but not in normal tissues. 8- NO(2)-G in DNA is potentially mutagenic, yielding G:C to T:A transversion, possibly through its rapid depurination to form an apurinic site and/or miscoding with adenine. 8-NO(2)-G in RNA may interfere with RNA functions and metabolism. Nitrated guanine nucleosides and nucleotides in the nucleotide pool may contribute to oxidative stress via production of superoxide mediated by various reductases and may disturb or modulate directly various important enzymes such as GTP-binding proteins and cGMP-dependent enzymes. Further studies are warranted to establish the roles of 8-NO(2)-G in various pathophysiological conditions and inflammation-associated cancer.
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Boonla C, Sripa B, Thuwajit P, Cha-On U, Puapairoj A, Miwa M, Wongkham S. MUC1 and MUC5AC mucin expression in liver fluke-associated intrahepatic cholangiocarcinoma. World J Gastroenterol 2005; 11:4939-46. [PMID: 16124042 PMCID: PMC4321906 DOI: 10.3748/wjg.v11.i32.4939] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expressions of MUC1 and MUC5AC in intrahepatic cholangiocarcinoma (ICC). Association of expressions of mucins MUC1 and MUC5AC with clinical findings, metastasis, and survival of the liver fluke-associated ICC patients was determined.
METHODS: The expressions of MUC1 and MUC5AC mucins were examined by immunohistochemical staining in 87 cases of histologically-proven ICC. The expressions of mucins in relationship between clinicopathological significance and prognosis of the patients were evaluated.
RESULTS: Fifty-two patients (60%) exhibited both MUC1 and MUC5AC expressions, whereas 31% expressed either MUC1 or MUC5AC, and 9% expressed neither. High MUC1 immunoreactivity displayed a significant correlation with tumor progression as reflected by vascular invasion (P<0.001), whereas high expression of MUC5AC significantly correlated with neural invasion (P = 0.022) and advanced ICC stage (P = 0.008). Patients with high expression of MUC1 had a significantly shorter survival (P = 0.0002). According to multivariate analyses, MUC1 reactivity (P = 0.026), histological grading and stage of tumor represented the least probability of survival.
CONCLUSION: MUC1 is overexpressed in liver fluke-associated cholangiocarcinoma and relates to vascular invasion and poor prognosis, whereas MUC5AC mucin is neoexpressed and relates to neural invasion and advanced ICC stage. High MUC1 expression in tumor may be useful for predicting the poor outcome of ICC patients.
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Affiliation(s)
- Chanchai Boonla
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
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Sawa T, Ohshima H. Nitrative DNA damage in inflammation and its possible role in carcinogenesis. Nitric Oxide 2005; 14:91-100. [PMID: 16099698 DOI: 10.1016/j.niox.2005.06.005] [Citation(s) in RCA: 139] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2005] [Revised: 06/21/2005] [Accepted: 06/21/2005] [Indexed: 12/17/2022]
Abstract
Chronic inflammation has long been recognized as a risk factor for human cancer at various sites. Examples include Helicobacter pylori-induced gastritis for gastric cancer, inflammatory bowel disease (ulcerative colitis and Crohn's disease) for colorectal cancer and chronic viral hepatitis for liver cancer. Here we review the role in carcinogenesis of nitrative damage to nucleic acids, DNA and RNA, which occurs during inflammation through the generation of reactive nitrogen species, such as peroxynitrite, nitroxyl, and nitrogen dioxide. Enhanced formation of 8-nitroguanine, representative of nitrative damage to nucleobases, has been detected in various inflammatory conditions. The biochemical nature of DNA damage mediated by reactive nitrogen species is discussed in relation to its possible involvement in mutations, genetic instability, and cell death. Better understanding of the mechanisms and role of such nitrative damage in chronic inflammation-associated human cancer is a necessary basis to develop new strategies for cancer prevention by modulating the process of inflammation.
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Affiliation(s)
- Tomohiro Sawa
- International Agency for Research on Cancer, 150 Cours Albert Thomas, 69008 Lyon, France.
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36
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37
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Nam KT, Kim DY, Park MS, Jang DD, Yang KH, Han JH, Yoon BI. Suppression of Cholangiocarcinoma Development by Aminoguanidine in the Liver Fluke-infested Hamster. J Toxicol Pathol 2005. [DOI: 10.1293/tox.18.65] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Ki-Taek Nam
- National Institute of Toxicological Research, KFDA
| | - Dae-Yong Kim
- Department of Veterinary Pathology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University
| | - Mi-Sun Park
- Department of Veterinary Pathology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University
| | | | - Ki-Hwa Yang
- National Institute of Toxicological Research, KFDA
| | - Jeong-Hee Han
- Department of Veterinary Medicine, Kangwon National University
| | - Byung-Il Yoon
- Department of Veterinary Medicine, Kangwon National University
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38
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Dusinská M, Collins A, Kazimírová A, Barancoková M, Harrington V, Volkovová K, Staruchová M, Horská A, Wsólová L, Kocan A, Petrík J, Machata M, Ratcliffe B, Kyrtopoulos S. Genotoxic effects of asbestos in humans. Mutat Res 2004; 553:91-102. [PMID: 15288536 DOI: 10.1016/j.mrfmmm.2004.06.027] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2004] [Revised: 05/06/2004] [Accepted: 05/07/2004] [Indexed: 04/30/2023]
Abstract
Risks of carcinogenic and non-carcinogenic effects from asbestos continue owing to the persistence of the fibres in building materials and other products. For this reason, epidemiological and mechanistic research on the toxic effects of asbestos and mineral fibres is still needed. The present molecular epidemiological study was conducted in a former asbestos cement plant in Slovakia. Altogether 82 subjects were investigated, 61 exposed subjects (24 smokers and 37 non-smokers), and 21 factory controls (8 smokers and 13 non-smokers). Workers were exposed to asbestos for between 5 and 40 years. Though the exposure to asbestos during past 40 years was relatively high, at the time of sampling the concentrations of asbestos in the production hall exceeded the Slovak occupational limit (0.001 fibre/cm3) by a factor of only 3-5. The office area levels were below this limit. Biomarkers of exposure, effect and individual susceptibility were measured, including DNA damage (strand breaks [SBs], base oxidation and alkylation, using the comet assay); cytogenetic parameters; and individual DNA repair capacity (incision at 8-oxoguanine measured using a modified comet assay). Oxidised pyrimidines were significantly higher in exposed men compared with non-exposed (P = 0.04). There was also a positive association between SBs (P = 0.04) and age, and alkylation damage to DNA (P = 0.04) and age. Moreover, oxidised pyrimidines (P = 0.01) and alkylated bases (P = 0.001) strongly correlated with years of occupational exposure. Micronucleus frequency did not differ between exposed and control subjects. Repair capacity overall did not show any effect of exposure, though female controls had higher incision rates than did female exposed subjects. However, exposed asbestos workers had significantly higher numbers of chromosomal aberrations (P = 0.01) compared with control group. This finding is consistent with the known association of chromosome aberrations with cancer-risk.
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Affiliation(s)
- Mária Dusinská
- Institute of Preventive and Clinical Medicine, Slovak Medical University, Limbová 12, Bratislava 83303, Slovak Republic.
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Pinlaor S, Hiraku Y, Ma N, Yongvanit P, Semba R, Oikawa S, Murata M, Sripa B, Sithithaworn P, Kawanishi S. Mechanism of NO-mediated oxidative and nitrative DNA damage in hamsters infected with Opisthorchis viverrini: a model of inflammation-mediated carcinogenesis. Nitric Oxide 2004; 11:175-83. [PMID: 15491850 DOI: 10.1016/j.niox.2004.08.004] [Citation(s) in RCA: 143] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2004] [Revised: 07/22/2004] [Indexed: 02/07/2023]
Abstract
Inflammation mediated by infection is an important factor causing carcinogenesis. Opisthorchis viverrini (OV) infection is a risk factor of cholangiocarcinoma (CHCA), probably through chronic inflammation. Formation of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and expression of inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) were assessed in the liver of hamsters infected with OV. We newly produced specific anti-8-nitroguanine antibody without cross-reaction. Double immunofluorescence staining revealed that 8-oxodG and 8-nitroguanine were formed mainly in the same inflammatory cells and epithelium of bile ducts from day 7 and showed the strongest immunoreactivity on days 21 and 30, respectively. It is noteworthy that 8-oxodG and 8-nitroguanine still remained in epithelium of bile ducts on day 180, although amount of alanine aminotransferase activity returned to normal level. A time course of 8-nitroguanine was associated with iNOS expression. Furthermore, this study demonstrated that HO-1 expression and subsequent iron accumulation may be involved in enhancement of oxidative DNA damage in epithelium of small bile ducts. In conclusion, nitrative and oxidative DNA damage via iNOS expression in hamsters infected with OV may participate in CHCA carcinogenesis.
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Affiliation(s)
- Somchai Pinlaor
- Department of Environmental and Molecular Medicine, Mie University School of Medicine, Mie 514-8507, Japan
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Pinlaor S, Yongvanit P, Hiraku Y, Ma N, Semba R, Oikawa S, Murata M, Sripa B, Sithithaworn P, Kawanishi S. 8-nitroguanine formation in the liver of hamsters infected with Opisthorchis viverrini. Biochem Biophys Res Commun 2003; 309:567-71. [PMID: 12963027 DOI: 10.1016/j.bbrc.2003.08.039] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Nucleic acid damage by reactive nitrogen and oxygen species may contribute to the carcinogenesis associated with chronic infection and inflammation. We examined 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation and nitric oxide (NO) production in hamsters infected with Opisthorchis viverrini (OV). Formation of 8-nitroguanine was assessed immunohistochemically with an antibody specific for 8-nitroguanine. 8-nitroguanine formation was found mainly in the cytoplasm and slightly in the nucleus of inflammatory cells and epithelial lining of bile duct at inflammatory areas in the liver. 8-nitroguanine immunoreactivity reached the highest intensity on day 30. A time profile of 8-nitroguanine formation was closely associated with that of plasma nitrate/nitrite. HPLC with an electrochemical detector revealed that the amount of 8-oxodG in the liver reached the maximal level on day 21. The mechanisms of 8-oxodG and 8-nitroguanine formation via O2*- and NO production triggered by OV infection were discussed in relation to cholangiocarcinoma development.
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Affiliation(s)
- Somchai Pinlaor
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
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41
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Wongkham S, Sheehan JK, Boonla C, Patrakitkomjorn S, Howard M, Kirkham S, Sripa B, Wongkham C, Bhudhisawasdi V. Serum MUC5AC mucin as a potential marker for cholangiocarcinoma. Cancer Lett 2003; 195:93-9. [PMID: 12767517 DOI: 10.1016/s0304-3835(02)00691-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Aberrant expression of MUC5AC mucin is obvious in cholangiocarcinoma tissues, however, this mucin has never been detected in the serum. Using immunoblotting marked with antibody vs. MUC5AC core protein, we could detect MUC5AC mucin in the serum of 112 from 179 cholangiocarcinoma patients (62.6% sensitivity), two of the 62 with benign hepatobiliary diseases, six of the 60 with hepato-gastrointestinal cancer, and none in either the 60 active opisthorchiasis or 74 healthy persons. Detection of serum mucin in the serum of cholangiocarcinoma patients corresponded well to the MUC5AC expressed in individual tissues. Serum MUC5AC may be used to enhance the diagnostic accuracy of cholangiocarcinoma.
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Affiliation(s)
- Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
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Abstract
BACKGROUND Infection with liver flukes has been reported to be associated with bile duct malignancy. METHODS The review is based on a literature search (Medline) and, in some cases, direct contact with authors or principal investigators. RESULTS A large body of evidence indicates that Opisthorchis viverrini is a definite cause of human cholangiocarcinoma, whereas Clonorchis sinensis is a probable cause. The evidence regarding Opisthorchis felineus is insufficient to assess its role in carcinogenesis. Possible mechanisms of carcinogenesis include chronic irritation, nitric oxide formation, intrinsic nitrosation and activation of drug-metabolizing enzymes. Early detection of bile duct malignancy is difficult and not clinically available at present, although cholangiocarcinoma-associated soluble antigen has been reported in an experimental study to be a useful early marker of cancer development. Long-term survival after surgical treatment of liver fluke-associated cancer is similar to that reported in patients without liver fluke infestation. CONCLUSION Liver fluke-associated cholangiocarcinoma is still a health problem in developing countries. Mechanisms of carcinogenesis should be explored further in order to reduce the impact of this disease.
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Affiliation(s)
- P Watanapa
- Departments of Surgery and Physiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10 700, Thailand
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Limpaiboon T, Krissadarak K, Sripa B, Jearanaikoon P, Bhuhisawasdi V, Chau-in S, Romphruk A, Pairojkul C. Microsatellite alterations in liver fluke related cholangiocarcinoma are associated with poor prognosis. Cancer Lett 2002; 181:215-22. [PMID: 12175538 DOI: 10.1016/s0304-3835(02)00052-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
We have characterized the role of genetic alterations in the development of liver fluke related cholangiocarcinoma. We analyzed the loss of heterozygosity (LOH) and microsatellite instability (MSI) of hMSH2, hMLH1, and p53 genes in 55 patients with intrahepatic cholangiocarcinoma by using polymerase chain reaction based microsatellite markers D2S119, D3S1611, and TP53, respectively and determined the association between microsatellite alterations and patient survival. A total of 27 (49.1%) out of 55 cases exhibited microsatellite alterations in one locus or more. Of 55 samples, 11 (20%) demonstrated MSI at D2S119 and four (7%) showed MSI at D3S1611. LOH was shown in seven out of 36 (19%) informative cases for D3S1611 and 16 out of 50 (32%) for TP53. Microsatellite alterations at loci studied were significantly associated with poor survival (P=0.0098). This study suggests that genetic alterations of DNA mismatch repair genes and tumor suppressor gene p53 may be involved in cholangiocarcinogenesis and these alterations may be of value as prognostic indicators for liver fluke related cholangiocarcinoma.
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Affiliation(s)
- Temduang Limpaiboon
- Department of Clinical Chemistry, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
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Sripa B, Kaewkes S. Gall bladder and extrahepatic bile duct changes in Opisthorchis viverrini-infected hamsters. Acta Trop 2002; 83:29-36. [PMID: 12062790 DOI: 10.1016/s0001-706x(02)00052-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Opisthorchis viverrini infection is associated with several hepatobiliary diseases, but few reports have described extrahepatic lesions in opisthorchiasis. We therefore sequentially investigated histological changes of the gall bladder and extrahepatic bile duct in hamsters infected with 25 (group 1), 50 (group 2) and 100 (group 3) metacercariae for up to 180 days. Acute inflammatory reactions, including congestion, neutrophil and eosinophil infiltration, occurred in the gall bladder as early as day 7 of groups 2 and 3 and on day 14 in group 1; the extrahepatic bile ducts exhibited the changes on day 3 post-infection (p.i.). Mononuclear cell infiltration, mucus hypersecretion and fibrosis were gradually observed thereafter. Active inflammation reached a plateau at approximately 60 days in all infected groups. The well-established chronic histological changes of the gall bladder and extrahepatic bile duct were fibrosis and mononuclear cell infiltration with lymphoid aggregation and, additionally, ductal dilatation for the latter. Overall, the pathological changes in the extrahepatic bile duct were more severe than those in the gall bladder for the same dose and period of infection. The results demonstrate that pathological changes in the gall bladder and extrahepatic bile duct do occur in O. viverrini infection and may be extrapolated to human infection.
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Affiliation(s)
- Banchob Sripa
- Department of Pathology, Division of Experimental Pathology, Faculty of Medicine, Khon Kaen University, 40002, Khon Kaen, Thailand.
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Abstract
Research on the free radical gas, nitric oxide (NO), during the past twenty years is one of the most rapid growing areas in biology. NO seems to play a part in almost every organ and tissue. However, there is considerable controversy and confusion in understanding its role. The liver is one organ that is clearly influenced by NO. Acute versus chronic exposure to NO has been associated with distinct patterns of liver disease. In this paper we review and discuss the involvement of NO in various liver diseases collated from observations by various researchers. Overall, the important factors in determining the beneficial versus harmful effects of NO are the amount, duration, and site of NO production. A low dose of NO serves to maximize blood perfusion, prevent platelet aggregation and thrombosis, and neutralize toxic oxygen radicals in the liver during acute sepsis and reperfusion events. NO also demonstrates antimicrobial and antiapoptosis properties during acute hepatitis infection and other inflammatory processes. However, in the setting of chronic liver inflammation, when a large sustained amount of NO is present, NO might become genotoxic and lead to the development of liver cancer. Additionally, during prolonged ischemia, high levels of NO may have cytotoxic effects leading to severe liver injury. In view of the various possible roles that NO plays, the pharmacologic modulation of NO synthesis is promising in the future treatment of liver diseases, especially with the emergence of selective NO synthase inhibitors and cell-specific NO donors.
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Affiliation(s)
- Wei Min Hon
- Department of Medicine, National University of Singapore, Singapore.
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Abstract
The genetic mechanisms that are complementary in predisposing and then establishing disease are yet to be fully elucidated. During a lifetime, the genetic composition of the host is not only hereditary but undergoes rearrangements, integrations, and more subtle single-base pair alterations. These changes can be inconsequential or lead to aberrant and deleterious pathologic changes. In a complex multifactorial disease such as RA, the relative roles of the dynamic versus germline elements of the disease have yet to be fully determined. Further studies of large populations are likely to segregate out factors affecting specific ethnic, clinical, and genetic subgroups.
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Affiliation(s)
- Maripat Corr
- Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, School of Medicine, La Jolla, California, USA.
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Tesana S, Takahashi Y, Sithithaworn P, Ando K, Sakakura T, Yutanawiboonchai W, Pairojkul C, Ruangjirachuporn W. Ultrastructural and immunohistochemical analysis of cholangiocarcinoma in immunized Syrian golden hamsters infected with Opisthorchis viverrini and administered with dimethylnitrosamine. Parasitol Int 2000; 49:239-51. [PMID: 11426579 DOI: 10.1016/s1383-5769(00)00052-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Utilizing the experimental model in Syrian golden hamsters, we explored the role of immunization in carcinogenesis. The animals, which were infected with liver flukes (Opisthorchis viverrini), and administered a subcarcinogenic dose of dimethylnitrosamine, developed cancer. Pre-immunizing with a crude somatic antigen did not reduce cancer development, but accelerated carcinogenesis. Histopathological analysis of the cancer tissues was done once at week 30 and again at week 39 using H and E staining, immunostaining for the p53 tumor suppressor phosphoprotein, and electron microscopy. Thirty weeks after immunization, the immunized hamsters developed tubular adenocarcinoma at a higher rate (71.43%) than the non-immunized group (20.00%). This rate (20.00%) increased to 63.64% by week 39. The small foci cancer in the non-immunized group decreased in frequency from 80.00% (at week 30) to 36.36% (by week 39), suggesting the small foci cancer progressed to tubular adenocarcinoma during the 9-week interval. Most of the observed tubular adenocarcinoma was well differentiated. Nearly all hamsters that tested positive for cancer also tested positive for p53 immunostaining in the epithelia of the small bile ducts. The positive reaction for p53-immunostaining was localized in the rough endoplasmic reticulum, Golgi apparatus and perinuclear membranes. The electron micrographs of these positive p53-immunostained cells showed characteristics of early cancer. The detection of p53 in early cancer development makes it a candidate as a tumor marker.
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Affiliation(s)
- S Tesana
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Thailand
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Mamone G, Sannolo N, Malorni A, Ferranti P. In vitro formation of S-nitrosohemoglobin in red cells by inducible nitric oxide synthase. FEBS Lett 1999; 462:241-5. [PMID: 10622703 DOI: 10.1016/s0014-5793(99)01527-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The present study demonstrates that NO produced in vitro by inducible nitric oxide synthase in red cells can convert hemoglobin contained in the red cells to S-nitrosohemoglobin. Experiments carried out either in the absence or in the presence of a low molecular weight thiol, such as cysteine, showed that in the first case the target of NO is heme-Fe2+. On the contrary, in the presence of cysteine, the first step is the formation of S-nitrosocysteine, followed by transfer of the NO group to a particular cysteine residue of beta-globin, cysteine 93. These results confirm previous data indicating the preferential formation of S-nitrosohemoglobin at that site by chemical methods [Ferranti et al. (1997) FEBS Lett. 400, 17-24], and the existence of a physiological mechanism of inactivation for NO circulating in blood. The analysis of S-nitrosohemoglobin can also allow the quantification of the NO levels in blood to be applied for in vitro and in vivo measurements.
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Affiliation(s)
- G Mamone
- Centro Internationale di Servizi di Spettrometria di Massa, CNR, Naples, Italy
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Ohshima H, Bartsch H. Quantitative estimation of endogenous N-nitrosation in humans by monitoring N-nitrosoproline in urine. Methods Enzymol 1999; 301:40-9. [PMID: 9919552 DOI: 10.1016/s0076-6879(99)01067-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Affiliation(s)
- H Ohshima
- Unit of Endogenous Cancer Risk Factors, International Agency for Research on Cancer, Lyon, France
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