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Inoue H.,Kyoto University | Maeda-Yamamoto M.,Japan National Agriculture and Food Research Organization | Nesumi A.,Japan National Agriculture and Food Research Organization | Tanaka T.,Tohkai Cytopathology Institute | Murakami A.,Kyoto University
Bioscience, Biotechnology and Biochemistry | Year: 2013

Our previous study indicated that a diet containing a high dose (1%) of green tea polyphenols (GTPs) disrupted liver and kidney function via a reduction in antioxidant enzyme and heat shock protein (HSP) levels in both colitis and non-treated ICR mice. In the present study, we assessed the effects of 0.01%, 0.1%, and 1% dietary GTPs on liver and kidney physiological functioning in dextran sulfate sodium (DSS)-exposed and normal mice. GTPs at 0.01% and 0.1% significantly suppressed DSS-increased serum aspartate 2-oxoglutarate aminotransferase (AST) and alanine aminotransferase (ALT) levels. In contrast, GTPs at 1% increased kidney weight, serum creatinine levels, and thiobarbituric acid-reactive substances (TBARs) in both the kidney and the liver in normal mice, as compared with DSS-exposed mice. GTPs at 0.01% and 0.1% remarkably upregulated the expression of heme oxygenase-1 (HO-1) and heat shock protein 70 (HSP70) mRNA in the liver and kidney of mice exposed to DSS, whereas GTPs at 1% abolished it. Our results indicate that low and medium doses of GTPs have beneficial effects on DSS-induced hepatotoxicity and nephrotoxicity via upregulation of self-protective enzymes, while these effects disappeared at a high dose.


Hata K.,Gifu University | Hata K.,Sunplanet Co | Kubota M.,Gifu University | Shimizu M.,Gifu University | And 7 more authors.
International Journal of Molecular Sciences | Year: 2011

The numbers of obese people and diabetic patients are ever increasing. Obesity and diabetes are high-risk conditions for chronic diseases, including certain types of cancer, such as colorectal cancer (CRC). The aim of this study was to develop a novel animal model in order to clarify the pathobiology of CRC development in obese and diabetic patients. We developed an animal model of obesity and colorectal cancer by breeding the C57BL/KsJ-db/db (db/db) mouse, an animal model of obesity and type II diabetes, and the C57BL/6J-Apc Min/+(Min/+) mouse, a model of familial adenomatous polyposis. At 15 weeks of age, the N9 backcross generation of C57BL/KsJ-db/db-Apc Min/+(db/db-Min/+) mice developed an increased incidence and multiplicity of adenomas in the intestinal tract when compared to the db/m-Min/+ and m/m-Min/+ mice. Blood biochemical profile showed significant increases in insulin (8.3-fold to 11.7-fold), cholesterol (1.2-fold to 1.7-fold), and triglyceride (1.2-fold to 1.3-fold) in the db/db-Min/+ mice, when compared to those of the db/m-Min/+ and m/m-Min/+ mice. Increases (1.4-fold to 2.6-fold) in RNA levels of insulin-like growth factor (IGF)-1, IRF-1R, and IGF-2 were also observed in the db/db-Min/+ mice. These results suggested that the IGFs, as well as hyperlipidemia and hyperinsulinemia, promoted adenoma formation in the db/db-Min/+ mice. Our results thus suggested that the db/db-Min/+ mice should be invaluable for studies on the pathogenesis of CRC in obese and diabetes patients and the therapy and prevention of CRC in these patients. © 2011 by the authors; licensee MDPI, Basel, Switzerland.


Tanaka T.,Clin ToxPath C Top Consulting | Tanaka T.,Tohkai Cytopathology Institute | Tanaka T.,Gifu University | Shimizu M.,Gifu University | And 2 more authors.
Journal of Experimental and Clinical Medicine(Taiwan) | Year: 2013

Historically, evidence of chemical carcinogenesis has played a significant role in verifying conclusions draw from epidemiological studies. Chemical agents that were suspected to have a certain role in human chronic diseases, such as cancers, have been tested in animals to establish firmly a causative risk or link to risk. The three best examples are: (1) tobacco smoke and lung cancer; (2) asbestos and mesothelioma; and (3) aflatoxin and hepatic cancer. New chemical compounds are synthesized every day, and a number of natural or synthetic compounds are incorporated in foods either as a result of their processing or to preserve or enhance them. Chemical carcinogenesis studies using model animals have greatly contributed to understanding the mechanisms underlying the development and prevention of carcinogenesis. The carcinogenesis process is generally considered to include three steps: initiation, promotion, and progression. Each step is characterized by morphological and biochemical alterations resulting from genetic and epigenetic changes, including mutations in proto-oncogenes and tumor suppressor genes that control proliferation, cell death, and cellular repair. Long-term invivo assays using laboratory animals enable the identification of carcinogenic compounds and their modes of action. Based on these findings, we should be able to establish effective strategies to treat and prevent malignancies resulting from exposure to potentially carcinogenic chemicals. © 2013 .


Tanaka T.,Tohkai Cytopathology Institute | Tanaka T.,Gifu University
Cancers | Year: 2012

Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn's disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described. © 2012 by the authors; licensee MDPI, Basel, Switzerland.


Yoshimi K.,Kyoto University | Tanaka T.,Tohkai Cytopathology Institute | Serikawa T.,Kyoto University | Kuramoto T.,Kyoto University
American Journal of Pathology | Year: 2013

Mucosal repair after acute colonic inflammation is central to maintaining mucosal homeostasis. Failure of mucosal repair often leads to chronic inflammation, sometimes associated with inflammatory bowel disease (IBD). The adenomatous polyposis coli (APC) tumor suppressor gene regulates the Wnt signaling pathway, which is essential for epithelial development, and inactivation of APC facilitates colorectal cancer. Our previous study suggested that APC is involved in pathogenesis of colonic inflammation; however, its role in mucosal repair remains unknown. In this article, we report that colitis induced by dextran sodium sulfate persisted with delayed mucosal repair in Kyoto Apc Delta (KAD) rats lacking the APC C terminus. Defects in the repair process were accompanied by an absence of a fibrin layer covering damaged mucosa and reduced microvessel angiogenesis. APC was up-regulated in vascular endothelial cells (VECs) in inflamed mucosa in KAD and F344 (control) rats. The VECs of KAD rats revealed elevated cell adhesion and low-branched and short-length tube formation. We also found that DLG5, which is associated with IBD pathogenesis, was up-regulated in VECs in inflamed mucosa and interacted with the C terminus of APC. This finding suggests that loss of interaction between the APC C terminus and DLG5 affects VEC morphology and function and leads to persistence of colitis. Therefore, APC is essential for maintenance of intestinal mucosal homeostasis and can consequently contribute to IBD pathogenesis. Copyright © 2013 American Society for Investigative Pathology.


Nakanishi M.,University of Connecticut Health Center | Menoret A.,University of Connecticut Health Center | Tanaka T.,Tohkai Cytopathology Institute | Miyamoto S.,University of Connecticut Health Center | And 3 more authors.
Cancer Prevention Research | Year: 2011

Prostaglandin E 2 (PGE 2) is a bioactive lipid that mediates a wide range of physiologic effects and plays a central role in inflammation and cancer. PGE 2 is generated from arachidonic acid by the sequential actions of the COX and terminal synthases (PGES). Increased levels of COX-2, with a concomitant elevation of PGE 2, are often found in colorectal cancers (CRC), providing the rationale for the use of COX-2 inhibitors for chemoprevention. Despite their proven efficacy in cancer prevention, however, COX-2 inhibitors exhibit dose-dependent toxicities that are mediated in part by their nonspecific reduction of essential prostanoids, thus limiting their chemopreventive benefit. To achieve enhanced specificity, recent efforts have been directed toward targeting the inducible terminal synthase in the production of PGE 2, microsomal PGES (mPGES-1). In the present study, we show that genetic deletion of mPGES-1 affords significant protection against carcinogen-induced colon cancer. mPGES-1 gene deletion results in an about 80% decrease in tumor multiplicity and up to a 90% reduction in tumor load in the distal colon of azoxymethane (AOM)-treated mice. Associated with the striking cancer suppression, we have identified a critical role for PGE 2 in the control of immunoregulatory cell expansion (FoxP3-positive regulatory T cells) within the colon-draining mesenteric lymph nodes, providing a potential mechanism by which suppression of PGE 2may protect against CRC. These results provide new insights into how PGE 2 controls antitumor immunity. ©2011 AACR.


PubMed | Tohkai Cytopathology Institute
Type: Journal Article | Journal: Cancers | Year: 2013

Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohns disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.


PubMed | Tohkai Cytopathology Institute
Type: Journal Article | Journal: Molecules (Basel, Switzerland) | Year: 2012

Carotenoids are natural fat-soluble pigments that provide bright coloration to plants and animals. Dietary intake of carotenoids is inversely associated with the risk of a variety of cancers in different tissues. Preclinical studies have shown that some carotenoids have potent antitumor effects both in vitro and in vivo, suggesting potential preventive and/or therapeutic roles for the compounds. Since chemoprevention is one of the most important strategies in the control of cancer development, molecular mechanism-based cancer chemoprevention using carotenoids seems to be an attractive approach. Various carotenoids, such as -carotene, a-carotene, lycopene, lutein, zeaxanthin, -cryptoxanthin, fucoxanthin, canthaxanthin and astaxanthin, have been proven to have anti-carcinogenic activity in several tissues, although high doses of -carotene failed to exhibit chemopreventive activity in clinical trials. In this review, cancer prevention using carotenoids are reviewed and the possible mechanisms of action are described.


PubMed | Tohkai Cytopathology Institute
Type: Journal Article | Journal: Current drug targets | Year: 2013

Inflammation is a risk factor for cancer development in several tissues. In the colorectum, inflammatory bowel disease (ulcerative colitis and Crohns disease) is a longstanding inflammatory disease with increased risk for colorectal cancer (CRC). Several molecular events involving in chronic inflammatory process contribute to multi-stage carcinogenesis of CRC in the inflamed colon. They include alterations in production of reactive oxygen and nitrogen species, upregulation of pro-inflammatory cytokines and inflammatory enzymes, and intestinal immune system. In this short review, experimental animal models of inflammation-associated CRC are described. Also, some preclinical data on chemoprevention of inflammation-associated CRC by astaxanthin and a specific inhibitor of nitric oxide synthase using these inflammation-related CRC models is briefly introduced.

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