PKuEG8npVpVrefs.MYD ?HDuBois, RAYMOND N Radhika, ARAMANDALA Reddy, BANDARU S Entingh, AMELIA J1996JIncreased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors 1259-1262Gastroenterology1104 0016-50854|45WRefaat, B. El-Shemi, A. G. Kensara, O. A. Mohamed, A. M. Idris, S. Ahmad, J. Khojah, A.2015Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer71J Exp Clin Cancer Res341 2015/07/25e BACKGROUND: Vitamin D3 and its analogues have recently been shown to enhance the anti-tumour effects of 5- Fluorouracil (5-FU) both in vitro and in xenograft mouse model of colon cancer. This study measured the potential mechanism(s) by which vitamin D3 could synergise the tumouricidal activities of 5-FU in azoxymethane (AOM) rat model of colon cancer. METHODS: Seventy-five male Wistar rats were divided equally into 5 groups: Control, AOM, AOM-treated by 5-FU (5-FU), AOM-treated by vitamin D3 (VitD3), and AOM-treated by 5-FU + vitamin D3 (5-FU/D). The study duration was 15 weeks. AOM was injected subcutaneously for 2 weeks (15 mg/kg/week). 5-FU was injected intraperitoneally in the 9th and 10th weeks post AOM (8 total injections were given: 12 mg/kg/day for 4 successive days, then 6 mg/kg every other day for another 4 doses) and oral vitamin D3 (500 IU/rat/day; 3 days/week) was given from week 7 post AOM till the last week of the study. The colons were collected following euthanasia for gross and histopathological examination. The expression of beta-catenin, transforming growth factor-beta1 (TGF-beta1), TGF-beta type 2 receptor (TGF-betaR2), smad4, inducible nitric oxide synthase (iNOS), and heat shock protein-90 (HSP-90) proteins was measured by immunohistochemistry. In colonic tissue homogenates, quantitative RT-PCR was used to measure the mRNA expression of Wnt, beta-catenin, Dickkopf-1 (DKK-1) and cyclooxygenase-2 (COX-2) genes, while ELISA was used to measure the concentrations of TGF-beta1, HSP-90 and COX-2 proteins. RESULTS: Monotherapy with 5-FU or vitamin D3 significantly decreased the number of grown tumours induced by AOM (P < 0.05); however, their combination resulted in more significant tumouricidal effects (P < 0.05) compared with mon '|<5MLubin, F. Rozen, P. Arieli, B. Farbstein, M. Knaani, Y. Bat, L. Farbstein, H.1997[Nutritional and lifestyle habits and water-fiber interaction in colorectal adenoma etiology79-85 Cancer Epidemiol Biomarkers Prev62 1997/02/01Adenoma/*epidemiology/etiology Adult Aged Colorectal Neoplasms/*epidemiology/etiology Dietary Fiber Exercise Female Humans *Life Style Logistic Models Male Middle Aged Multivariate Analysis *Nutritional Physiological Phenomena Questionnaires Risk Factors Smoking Water Weight GainFeb/Adenomatous polyps are neoplasms that may progress to colorectal cancer. The role of diet and other lifestyle habits in their etiology is now being elucidated. The aim of this study was to evaluate effects of nutritional habits, weight and weight gain, tobacco smoking, and physical activity in adenoma etiology. A quantified dietary history questionnaire was designed to evaluate long-term dietary habits in addition to more recent ones. The study population comprised 196 adenoma patients and matched asymptomatic, screened controls. Statistical analysis used multivariate conditional logistic models, adjusting for total energy intake and physical activity. Odds ratios (ORs) and 95% confidence intervals (CIs) for adenoma associated with highest versus lowest tertiles of mean daily intake were as follows: for energy, OR 3.7 and CI 2.1-6.7; for animal fat, OR 2.4 and CI 1.2-4.7; for tobacco smoking, OR 3.1 and CI 1.1-2.8; and for weight gain, OR 2.2 and CI 1.2-4.1 (P for linear trend for all, < or = 0.01). Significant negative associations were found with intake of total carbohydrates (OR, 0.3; CI, 0.1-0.7) and fluids (OR, 0.4; CI, 0.2-0.8) (P for both < 0.01) as well as for physical activity (OR, 0.6; CI, 0.3-0.9; P = 0.03). Increased risk for adenoma was observed with decreased intake of carotene (OR, 0.6; CI, 0.3-1.0; P = 0.06), vitamin E (OR, 0.6; CI, 0.3-1.0; P = 0.07), and dietary fiber (OR, 0.6; CI, 0.3-1.3; not significant). The OR of interaction between water and dietary fiber was significant (OR, 0.7; CI, 0.6-0.9; P = 0.01), suggesting a synergistic protective effect. Specific dietary and lifestyle habits were identified as independent factors associated with colorectal adenomas; of special interest is the interaction between water and fiber intake. Avoiding these factors might delay or prevent neoplasia.4http://cebp.aacrjournals.org/content/6/2/79.full.pdfLubin, F Rozen, P Arieli, B Farbstein, M Knaani, Y Bat, L Farbstein, H Journal Article Research Support, Non-U.S. Gov't United states Cancer Epidemiol Biomarkers Prev. 1997 Feb;6(2):79-85.1055-9965 (Print) 1055-9965Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology9037557=Gastroen f|<5zReichl, F. X. Walther, U. I. Durner, J. Kehe, K. Hickel, R. Kunzelmann, K. H. Spahl, W. Hume, W. R. Benschop, H. Forth, W.2001OCytotoxicity of dental composite components and mercury compounds in lung cells95-101 Dent Mater172 2001/02/138Animals Anti-Infective Agents, Local/toxicity Biocompatible Materials/*toxicity Cell Line Composite Resins/*toxicity Dental Materials/*toxicity Epithelial Cells/drug effects Humans L-Lactate Dehydrogenase/drug effects Linear Models Lung/cytology/*drug effects Lung Neoplasms/pathology Mercuric Chloride/toxicity Mercury Compounds/*toxicity Methacrylates/toxicity Methylmercury Compounds/toxicity Polyethylene Glycols/toxicity Polymethacrylic Acids/toxicity Pulmonary Alveoli/cytology/drug effects Rats Statistics as Topic Temperature Time Factors Tumor Cells, CulturedMarOBJECTIVE: The effect of dental composite components triethyleneglycoldimethacrylate (TEGDMA) and hydroxyethylmethacrylate (HEMA), as well as mercuric chloride (HgCl2) and methylmercury chloride (MeHgCl) was investigated on the release of lactatedehydrogenase (LDH) from alveolar epithelial lung cell lines in vitro. METHODS: The confluent cell layers from the A549 (human, malignant) and the L2 cells (rat) were incubated with various concentrations of HEMA, TEGDMA, MeHgCl and HgCl2 at 37 degrees C in 2% (v/v) CO2 atmosphere for 8h. In further experiments the L2 cells were incubated with the same compounds for 6-48 h. LDH release was measured and the values were expressed as percentage of the LDH content. The values were plotted on a concentration log-scale and the substance concentration at the maximum slope was assessed as effective concentration (EC50). RESULTS: A significant (p<0.05) increase in the LDH release was found in the L2 cells after 8-h incubation with HEMA (4 mmol/l), TEGDMA (2 mmol/l), MeHgCl (0.01 mmol/l) and HgCl2 (0.015 mmol/l), and in A549 cells with HEMA (14 mmol/l), TEGDMA (15 mmol/l), MeHgCl (0.15 mmol/l) and HgCl2 (0.05 mmol/l), compared to controls. The EC50 values from compounds in the L2 cells are shown in the following table (mean; sem in parentheses; n=3-6; #n=1): [see text]. SIGNIFICANCE: The toxic effect of HgCl2 and MeHgCl from the L2 cells was about 100-700-fold higher than of the dental composite components. A significant (p<0.05) time dependent increase of toxicity was observed with TEGDMA, HEMA and MeHgCl.Reichl, F X Walther, U I Durner, J Kehe, K Hickel, R Kunzelmann, K H Spahl, W Hume, W R Benschop, H Forth, W Journal Article Research Support, Non-U.S. Gov't England Dent Mater. 2001 Mar;17(2):95-101.0109-5641 (Print) 0109-5641JDental materials : official publication of the Academy of Dental Materials11163377Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University of Munich, Nussbaumstr. 26, 80336, Munich, Germany. f.x.reichl@lrz.uni-muenchen.deNLMeng  o|45Sangvanich, T. Morry, J. Fox, C. Ngamcherdtrakul, W. Goodyear, S. Castro, D. Fryxell, G. E. Addleman, R. S. Summers, A. O. Yantasee, W.2014]Novel oral detoxification of mercury, cadmium, and lead with thiol-modified nanoporous silica5483-93ACS Appl Mater Interfaces68 2014/03/26Apr 23~We have developed a thiol-modified nanoporous silica material (SH-SAMMS) as an oral therapy for the prevention and treatment of heavy metal poisoning. SH-SAMMS has been reported to be highly efficient at capturing heavy metals in biological fluids and water. Herein, SH-SAMMS was examined for efficacy and safety in both in vitro and in vivo animal models for the oral detoxification of heavy metals. In simulated gastrointestinal fluids, SH-SAMMS had a very high affinity (Kd) for methyl mercury (MeHg(I)), inorganic mercury (Hg(II)), lead (Pb(II)), and cadmium (Cd(II)) and was superior to other SAMMS with carboxylic acid or phosphonic acid ligands or commercially available metal chelating sorbents. SH-SAMMS also effectively removed Hg from biologically digested fish tissue with no effect on most nutritional minerals found in fish. SH-SAMMS could hold Hg(II) and MeHg(I) tightly inside the nanosize pores, thus preventing bacteria from converting them to more absorbable forms. Rats fed a diet containing MeHg(I), Cd(II), and Pb(II) and SH-SAMMS for 2 weeks had blood Hg levels significantly lower than rats fed the metal-rich diet only. Upon cessation of the metal-rich diet, continued administration of SH-SAMMS for 2 weeks facilitated faster and more extensive clearance of Hg than in animals not continued on oral SH-SAMMS. Rats receiving SH-SAMMS also suffered less weight loss as a result of the metal exposure. Retention of Hg and Cd in major organs was lowest in rats fed with SH-SAMMS throughout the entire four weeks. The reduction of blood Pb by SH-SAMMS was significant. SH-SAMMS was safe to intestinal epithelium model (Caco-2) and common intestinal bacteria (Escherichia coli). Altogether, it has great potential as a new oral drug for the treatment of heavy metal poisoning. This new application is enabled by the installation of tailored interfacial chemistry upon nontoxic nanoporous materials.Ehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004256/pdf/am5007707.pdf1944-8252 Sangvanich, Thanapon Morry, Jingga Fox, Cade Ngamcherdtrakul, Worapol Goodyear, Shaun Castro, David Fryxell, Glen E Addleman, Raymond S Summers, Anne O Yantasee, Wassana R01GM089918/GM/NIGMS NIH HHS/United States R21ES015620/ES/NIEHS NIH HHS/United States R41DK094571/DK/NIDDK NIH HHS/United States Journal Article Research Support, N.I.H., Extramural United States ACS Appl Mater Interfaces. 2014 Apr 23;6(8):5483-93. doi: 10.1021/am5007707. Epub 2014 Apr 4. 1944-8244 Pmc4004256"ACS applied materials & interfaces24660651rDepartment of Biomedical Engineering, Oregon Health & Science Univ 3|<5.Abd El-Aziz, G. S. El-Fark, M. M. Saleh, H. A.2012The prenatal toxic effect of methylmercury on the development of the appendicular skeleton of rat fetuses and the protective role of vitamin E939-49Anat Rec (Hoboken)2956 2012/05/03Abnormalities, Drug-Induced/etiology/*prevention & control Animals Antioxidants/*pharmacology Bone and Bones/abnormalities/*drug effects Crown-Rump Length Drug Antagonism Extremities Female Fetal Weight/drug effects Head/embryology Maternal Exposure/*adverse effects Mercury Poisoning/*drug therapy/physiopathology/prevention & control Methylmercury Compounds/*toxicity Osteogenesis/drug effects Pregnancy Rats Rats, Sprague-Dawley Vitamin E/*pharmacologyJunMethylmercury (MeHg) is an environmental contaminant that is found in many ecosystems. Many studies reported that MeHg toxicity is accompanied by increased lipid peroxidation that may lead to oxidative damage to DNA, RNA, and proteins. Vitamin E is considered as the most effective antioxidant preventing lipid peroxidation. The aim of this study was to evaluate the effects of MeHg exposure during pregnancy on the development of the appendicular skeleton in rat fetuses and whether vitamin E administration could reduce this toxicity. Positively mated adult female Sprague-Dawley rats were used and divided into the following experimental groups: control group, received only deionized water, and four MeHg treated groups received 1 mg of MeHg/kg/d, 2 mg of MeHg/kg/d, 1 mg of MeHg/kg/d plus 150 mg of vitamin E/kg/d, and 2 mg of MeHg/kg/d, plus 150 mg of vitamin E/kg/d starting from Day 0 of gestation. On Day 20 of gestation, the fetuses from the pregnant rats were extracted and the fetal growth parameters were evaluated. Skeletal evaluation of ossification of both fore- and hind-limbs, and coxal bones were undertaken. Results showed that treatment with MeHg caused adverse effects on fetal growth parameters and ossification of the bones. The coadministration of vitamin E with MeHg revealed an improvement in these parameters. These results suggest that vitamin E may ameliorate some aspects of MeHg developmental toxicity. The underlying and human health implications warrant further investigations.http://onlinelibrary.wiley.com/store/10.1002/ar.22485/asset/22485_ftp.pdf?v=1&t=id1nlt3j&s=591e194a002f64d63330287febea932c0633d092 http://onlinelibrary.wiley.com/store/10.1002/ar.22485/asset/22485_ftp.pdf?v=1&t=id3kdpxd&s=d63dacf2b00b4f281c22cd25d8e05954499256541932-8494 Abd El-Aziz, Gamal S El-Fark, Magdy M O Saleh, Hamid A M Journal Article United States An|<50Perez, H. Sullivan, E. C. Michael, K. Harris, R.2012]Fish consumption and advisory awareness among the Philadelphia Asian community: a pilot study24-8J Environ Health748 2012/04/27Animals Asia/ethnology Diet Female *Fishes *Food Contamination *Information Dissemination Male Mercury Poisoning/etiology/*prevention & control Philadelphia/epidemiology Pilot Projects Questionnaires *SeafoodAprDifficulties in the risk communication of fish consumption arise from the concept that this consumption can have both harmful and beneficial effects. This is particularly an issue among populations for which seafood is a major dietary and cultural component. Fish advisories are an important tool in preventing overconsumption of fish that have elevated concentrations of toxic contaminants. The exploratory pilot study described in this article examined fish consumption patterns and knowledge of the potential health risks associated with overconsumption of mercury-contaminated fish within a limited (N = 34) sample of the Philadelphia Asian-American population. Study data were used to evaluate the efficacy of state-issued advisories designed to encourage safe levels of fish consumption within the study population. Results indicate that while advisory awareness levels among study participants were greater than previously observed in Asian-American populations, consumption levels remained high. The limited findings of the authors' study, in combination with existing evidence, suggest the need for the development of more effective methods of disseminating advisory information.Perez, Hernando Sullivan, Erin C Michael, Karen Harris, Reginald Journal Article United States J Environ Health. 2012 Apr;74(8):24-8.0022-0892 (Print) 0022-0892Journal of environmental health22533121Drexel University School of Public Health, Department of Environmental and Occupational Health, Philadelphia, PA 19012, USA. hrp22@drexel.eduNLMengA(~45pSilbernagel, S. M. Carpenter, D. O. Gilbert, S. G. Gochfeld, M. Groth, E., 3rd Hightower, J. M. Schiavone, F. M.2011vRecognizing and preventing overexposure to methylmercury from fish and seafood consumption: information for physicians983072 J Toxicol2011 2011/07/26Fish is a valuable source of nutrition, and many people would benefit from eating fish regularly. But some people eat a lot of fish, every day or several meals per week, and thus can run a significant risk of overexposure to methylmercury. Current advice regarding methylmercury from fish consumption is targeted to protect the developing brain and nervous system but adverse health effects are increasingly associated with adult chronic low-level methylmercury exposure. Manifestations of methylmercury poisoning are variable and may be difficult to detect unless one considers this specific diagnosis and does an appropriate test (blood or hair analysis). We provide information to physicians to recognize and prevent overexposure to methylmercury from fish and seafood consumption. Physicians are urged to ask patients if they eat fish: how often, how much, and what kinds. People who eat fish frequently (once a week or more often) and pregnant women are advised to choose low mercury fish.Ihttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139210/pdf/JT2011-983072.pdf1687-8205 Silbernagel, Susan M Carpenter, David O Gilbert, Steven G Gochfeld, Michael Groth, Edward 3rd Hightower, Jane M Schiavone, Frederick M Journal Article Egypt J Toxicol. 2011;2011:983072. doi: 10.1155/2011/983072. Epub 2011 Jul 13. 1687-8191 Pmc3139210Journal of toxicology21785592GStony Brook UniversitySp|45Pierre, F. H. Martin, O. C. Santarelli, R. L. Tache, S. Naud, N. Gueraud, F. Audebert, M. Dupuy, J. Meunier, N. Attaix, D. Vendeuvre, J. L. Mirvish, S. S. Kuhnle, G. C. Cano, N. Corpet, D. E.2013Calcium and alpha-tocopherol suppress cured-meat promotion of chemically induced colon carcinogenesis in rats and reduce associated biomarkers in human volunteers1255-62Am J Clin Nutr985 2013/09/13,Acetylcysteine/urine Adult Aged Animals Biological Markers/blood Blood Glucose/analysis C-Reactive Protein/analysis/metabolism Calcium, Dietary/*administration & dosage Carcinogenesis/chemically induced/*pathology Carcinogens/toxicity Cholesterol/blood Colon/*drug effects/pathology Colorectal Neoplasms/drug therapy/prevention & control Creatinine/blood Cross-Over Studies Dimethylhydrazines/administration & dosage/adverse effects Diphosphates/administration & dosage Diterpenes, Abietane/administration & dosage Feces/chemistry Female Healthy Volunteers Humans Inulin/administration & dosage Meat Products/*adverse effects Middle Aged Rats Rats, Inbred F344 Rutin/administration & dosage Single-Blind Method Thiobarbituric Acid Reactive Substances/analysis/metabolism alpha-Tocopherol/*administration & dosageNov)BACKGROUND: Processed meat intake has been associated with increased colorectal cancer risk. We have shown that cured meat promotes carcinogen-induced preneoplastic lesions and increases specific biomarkers in the colon of rats. OBJECTIVES: We investigated whether cured meat modulates biomarkers of cancer risk in human volunteers and whether specific agents can suppress cured meat-induced preneoplastic lesions in rats and associated biomarkers in rats and humans. DESIGN: Six additives (calcium carbonate, inulin, rutin, carnosol, alpha-tocopherol, and trisodium pyrophosphate) were added to cured meat given to groups of rats for 14 d, and fecal biomarkers were measured. On the basis of these results, calcium and tocopherol were kept for the following additional experiments: cured meat, with or without calcium or tocopherol, was given to dimethylhydrazine-initiated rats (47% meat diet for 100 d) and to human volunteers in a crossover study (180 g/d for 4 d). Rat colons were scored for mucin-depleted foci, putative precancer lesions. Biomarkers of nitrosation, lipoperoxidation, and cytotoxicity were measured in the urine and feces of rats and volunteers. RESULTS: Cured meat increased nitroso compounds and lipoperoxidation in human stools (both P < 0.05). Calcium normalized both biomarkers in rats and human feces, whereas tocopherol only decreased nitro compounds in rats and lipoperoxidation in feces of volunteers (all P < 0.05). Last, calcium and tocopherol reduced the number of mucin-depleted foci per colon in rats compared with nonsupplemented cured meat (P = 0.01). CONCLUSION: Data suggest that the addition of calcium carbonate to the diet or alpha-tocopherol to cured meat may reduce colorectal cancer risk associated with cured-meat intake. This trial was registered at clinicaltrials.gov as NCT00994526.Ghttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798078/pdf/ajcn9851255.pdf1938-3207 Pierre, Fabrice H F Martin, Oceane C B Santarelli, Raphaelle L Tache, Sylviane Naud, Nathalie Gueraud, Francoise Audebert, Marc Dupuy, Jacques Meunier, Nathalie Attaix, Didier Vendeuvre, Jean-Luc Mirvish, Sidney S Kuhnle, Gunter C G Cano, Noel Corpet, Denis E R01-CA-1434600/CA/NCI NIH HHS/United States Journal Article Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Am J Clin Nutr. 2013 Nov;98(5):1255-62. doi: 10.3945/ajcn.113.061069. Epub 2013 Sep 11. 0002-9165 Pmc3798078*The American journal of clinical nutrition24025632Universite de Toulouse, French National Institute For Agricultural Research, Joint Research Unit 1331 Xenobiotiques, Toulouse, France (FHFP, OCBM, RLS, ST, NN, FG, MA, JD, and DEC); the French Pork and Pig Institute-Institut du Porc, Paris, France (RLS and J-LV); the INRA, UMR 1019, Human Nutrition Unit, Research Center for Human Nutrition Auvergne, Clermont-Ferrrand, France (NM, DA, and NC); the University hospital Clermont-Ferrand, Service de Nutrition, Clermont-Ferrrand, France (NM and NC); the Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE (SSM); and the Department of Food and Nutritional Sciences, Universit[4|<5 9Liu, Y. Yu, Q. Zhu, Z. Zhang, J. Chen, M. Tang, P. Li, K.2015tVitamin and multiple-vitamin supplement intake and incidence of colorectal cancer: a meta-analysis of cohort studies434 Med Oncol321 2014/12/11JanThis paper systematically evaluated the association of intake of different vitamins and multiple-vitamin supplements and the incidence of colorectal cancer. Relevant studies were identified in MEDLINE via PubMed (published up to April 2014). We extracted data from articles on vitamins A, C, D, E, B9 (folate), B2, B3, B6, and B12 and multiple-vitamin supplements. We used multivariable-adjusted relative risks (RRs) and a random-effects model for analysis and random effects. With heterogeneity, we looked for the source of heterogeneity or performed sensitivity and stratified analyses. We found 47 articles meeting the inclusion criteria. The multivariable-adjusted RR for pooled studies for the association between the highest versus lowest vitamin B9 (folate) intake and colorectal cancer was 0.88 [95 % confidence interval (95 % CI) 0.81-0.95]. Vitamin D was 0.87 (95 % CI 0.77-0.99); vitamin B6, 0.88 (95 % CI 0.79-0.99); vitamin B2, 0.86 (95 % CI, 0.76-0.97); vitamin A, 0.87 (95 % CI, 0.75-1.03); vitamin C, 0.92 (95 % CI, 0.80-1.06); vitamin E, 0.94 (95 % CI, 0.82-1.07); vitamin B12, 1.10 (95 % CI, 0.92-1.32); vitamin B3, 1.18 (95 % CI, 0.76-1.84). Vitamin B9 (folate), D, B6, and B2 intake was inversely associated with risk of colorectal cancer, but further study is needed. Our study featured unacceptable heterogeneity for studies of multiple-vitamin supplements, so findings were inconclusive.<http://link.springer.com/article/10.1007%2Fs12032-014-0434-51559-131x Liu, Yan Yu, Qiuyan Zhu, Zhenli Zhang, Jun Chen, Meilan Tang, Pingyi Li, Ke Journal Article Research Support, Non-U.S. Gov't United States Med Oncol. 2015 Jan;32(1):434. doi: 10.1007/s12032-014-0434-5. Epub 2014 Dec 10. 1357-0560-Medical oncology (Northwood, London, England)25491145Department of Public Health, Shantou University Medical College, No. 22 Xinling Road, Shantou, 515041, Guangdong,  f |<5 Heine-Broring, R. C. Winkels, R. M. Renkema, J. M. Kragt, L. van Orten-Luiten, A. C. Tigchelaar, E. F. Chan, D. S. Norat, T. Kampman, E.2015vDietary supplement use and colorectal cancer risk: a systematic review and meta-analyses of prospective cohort studies2388-401 Int J Cancer13610 2014/10/23fAdult Aged Aged, 80 and over Calcium, Dietary/*administration & dosage Colorectal Neoplasms/*epidemiology/prevention & control Databases as Topic *Dietary Supplements Female Humans Male Middle Aged Prospective Studies Risk Factors Vitamins/*administration & dosage Young Adult colorectal cancer dietary supplements epidemiology meta-analysis nutrition reviewMay 15$Use of dietary supplements is rising in countries where colorectal cancer is prevalent. We conducted a systematic literature review and meta-analyses of prospective cohort studies on dietary supplement use and colorectal cancer risk. We identified relevant studies in Medline, Embase and Cochrane up to January 2013. Original and peer-reviewed papers on dietary supplement use and colorectal cancer, colon cancer, or rectal cancer incidence were included. "Use-no use"(U-NU), "highest-lowest"(H-L) and "dose-response"(DR) meta-analyses were performed. Random-effects models were used to estimate summary estimates. In total, 24 papers were included in the meta-analyses. We observed inverse associations for colorectal cancer risk and multivitamin (U-NU: RR = 0.92; 95% CI: 0.87,0.97) and calcium supplements (U-NU: RR = 0.86; 95% CI: 0.79,0.95; H-L: RR = 0.80; 95% CI: 0.70,0.92; DR: for an increase of 100 mg/day, RR = 0.96; 95% CI: 0.94,0.99). Inconsistent associations were found for colon cancer risk and supplemental vitamin A and vitamin C, and for colorectal cancer risk and supplemental vitamin D, vitamin E, garlic and folic acid. Meta-analyses of observational studies suggest a beneficial role for multivitamins and calcium supplements on colorectal cancer risk, while the association with other supplements and colorectal cancer risk is inconsistent. Residual confounding of lifestyle factors might be present. Before recommendations can be made, an extensive assessment of dietary supplement use and a better understanding of underlying mechanisms is needed.Uhttp://onlinelibrary.wiley.com/doi/10.1002/ijc.29277/abstract?systemMessage=Wiley+Online+Library+will+have+intermittent+access+on+8th+August+2015+from+10%3A00-16%3A00+BST+%2F+05%3A00-11%3A00+EDT+%2F+17%3A00-23%3A00+SGT+for+essential+maintenance.++Apologies+for+the+inconvenience. http://onlinelibrary.wiley.com/doi/10.1002/ijc.29277/abstract]1097-0215 Heine-Broring, Renate C Winkels, Renate M Renkema, Jacoba M S Kragt, Lea van Orten-Luiten, Anne-Claire B Tigchelaar, Ettje F Chan, Doris S M Norat, Teresa Kampman, Ellen Journal Article Meta-AnJ|<5 Pais, R. Dumitrascu, D. L.2013:Do antioxidants prevent colorectal cancer? A meta-analysis152-63Rom J Intern Med513-4 2014/03/14Adenomatous Polyps/*mortality/prevention & control Antioxidants/administration & dosage/*therapeutic use Ascorbic Acid/administration & dosage Colorectal Neoplasms/*mortality/prevention & control Humans Incidence Neoplasm Recurrence, Local/*mortality/prevention & control Oxidative Stress/drug effects Randomized Controlled Trials as Topic Risk Assessment Risk Factors Romania/epidemiology Selenium/administration & dosage/*therapeutic use Survival Rate Treatment Outcome Vitamin E/administration & dosage beta Carotene/administration & dosageJul-Decd BACKGROUND: Oxidative stress is the first step involved in mutagenesis, carcinogenesis and aging. There has been great interest in recent years in potentially health benefits of dietary and antioxidant supplements in cancer prevention. OBJECTIVES: Our primary objectives were to estimate the global effect of antioxidants on colorectal cancer incidence, adenomatous polyp recurrence, overall mortality and cancer related mortality. A secondary aim was to evaluate these effects across specific antioxidant compounds, dose and duration of antioxidant supplementation. METHODS: Using Cochrane Collaboration methodology we searched for all randomized controlled trials (RCTs) from 1966 till May 2009 (MEDLINE, Cochrane Controlled Clinical Trials Registry), comparing antioxidant supplements with placebo or no intervention on the occurrence of colorectal cancer or adenoma. The results expressed as relative risk (RR) and 95% confidence intervals (95% CI) were obtained using random and fixed effect meta-analysis. RESULTS: Twenty RCTs, including 26 8590 participants, were eligible: 12 analyzing the colorectal cancer incidence included 25 0676 participants and 8 analyzing colorectal adenoma recurrence included 17914 participants. Antioxidant supplements had no significant effect on colorectal cancer incidence or colorectal adenoma recurrence (RR = 0. 94, 95% CI, 0.84-1.06, p = 0.32) in a random-effect meta-analysis. The antioxidant supplements had no significant effect on overall mortality (RR = 1.03, 95% CI, 0.99-1.07, p = 0.12) or cancer related mortality (RR = 1.05, 95% CI, 0.94-1.16, p = 0.38) in a random effect meta-analysis. Selenium supplementation was associated with a trend in reducing colorectal cancer incidence, (RR = 0.88, 95% CI, 0.55-1.40, p = 0.59), colorectal adenoma recurrence (RR = 0.70, 95% CI, 0.43-1.14, p = 0.16) and overall mortality (RR = 0.91, 95% CI, 0.82-1.02, p = 0.09). Beta carotene alone was associated with a slight increase in colorectal cancer incidence (RR = 1.09, 95% CI, 0.92-1.29, p = 0.34) and in combination with other antioxidants it was associated with an increase in mortality (RR = 1.05, 95% CI, 0.99-1.11, p = 0.10). For both selenium and beta carotene, the effect was not statistically significant. Vitamin C and Vitamin E combination slightly reduced colorectal cancer incidence with no effect on overall mortality. CONCLUSIONS: This meta-analysis found no evidence in favor of a protective effect of the studied antioxidant supplements in the prevention of colorectal cancer or cancer related mortality. Only selenium supplementation might have anticarcinogenic effects and requires further research.Pais, Raluca Dumitrascu, D L Journal Article Meta-Analysis Research Support, Non-U.S. Gov't Romania Rom J Intern Med. 2013 Jul-Dec;51(3-4):152-63.1220-4749 (Print) 1220-4749JRomanian journal of internal medicine = Revue roumaine de medecine interne24620628NLMeng N|<5 ?Xu, X. Yu, E. Liu, L. Zhang, W. Wei, X. Gao, X. Song, N. Fu, C.2013sDietary intake of vitamins A, C, and E and the risk of colorectal adenoma: a meta-analysis of observational studies529-39Eur J Cancer Prev226 2013/09/26Adenoma/*etiology/prevention & control Ascorbic Acid/*administration & dosage Clinical Trials as Topic Colorectal Neoplasms/*etiology/prevention & control *Diet Humans Prognosis Risk Factors Vitamin A/*administration & dosage Vitamin E/*administration & dosageNov*To comprehensively summarize the association between dietary intake of vitamins A, C, and E and the risk of colorectal adenoma (CRA), the precursor of colorectal cancer, relevant studies were identified in MEDLINE and EMBASE up to 31 October 2012. Summary relative risks (SRRs) with 95% confidence intervals (CIs) were pooled with a random-effects model. Between-study heterogeneity was assessed using Cochran's Q and I statistics. A total of 13 studies with 3832 CRA cases were included in this meta-analysis. On the basis of the highest versus lowest analysis, dietary intake of vitamin C reduced the risk of CRA by 22% (SRRs 0.78, 95% CIs: 0.62-0.98). Subgroup analyses showed that this relation was not modified by BMI, smoking status, and dietary energy intake. Further, dietary intake of beta-carotene was also inversely associated with the risk of CRA. However, dietary intake of vitamins A and E was not associated with the risk of CRA in overall and subgroup analyses (vitamin A: SRRs 0.87, 95% CIs: 0.67-1.14; vitamin E: SRRs 0.87, 95% CIs: 0.69-1.10). Our results indicate that dietary intake of vitamin C and beta-carotene, but not vitamins A and E, could reduce the risk of CRA. However, these associations seem to be limited. Further investigation using large samples and a rigorous methodology is warranted.1473-5709 Xu, Xiaodong Yu, Enda Liu, Lianjie Zhang, Wei Wei, Xubiao Gao, Xianhua Song, Ning Fu, Chuangang Journal Article Meta-Analysis Observational Study England Eur J Cancer Prev. 2013 Nov;22(6):529-39. doi: 10.1097/CEJ.0b013e328364f1eb. 0959-8278qEuropean journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP)24064545kDepartment of Colorectal Surgery, Changhai Hospital of Second Military Medical University, Shanghai, China.10.1097/CEJ.0b013e328364f1ebNLMeng ?$|<5 RRosato, V. Bosetti, C. Levi, F. Polesel, J. Zucchetto, A. Negri, E. La Vecchia, C.2013.Risk factors for young-onset colorectal cancer335-41Cancer Causes Control242 2012/12/12Adult Age of Onset Case-Control Studies Colorectal Neoplasms/*epidemiology Diet Female Humans Italy/epidemiology Male Middle Aged Risk Factors Switzerland/epidemiologyFebPURPOSE: We investigated risk factors for colorectal cancer in early-onset cancers, to provide quantitative estimates for major selected risk factors. METHODS: We analyzed data from three Italian and Swiss case-control studies conducted between 1985 and 2009, including 329 colorectal cancer cases and 1,361 controls aged /=14 drinks/week of alcohol, 1.56 for the highest tertile of processed meat, 0.40 for vegetables, 0.75 for fruit, and 0.78 for fish intake. Among micronutrients, the ORs were 0.52 for beta-carotene, 0.68 for vitamin C, 0.38 for vitamin E, and 0.59 for folate. No significant associations emerged for physical activity, overweight, and diabetes. CONCLUSIONS: This study-the largest on young-onset colorectal cancer-confirms that several recognized risk factors for colorectal cancer are also relevant determinants of young-onset colorectal cancer. Family history of colorectal cancer in particular is a stronger risk factor in young subjects, as compared to middle age and elderly ones.<http://link.springer.com/article/10.1007%2Fs10552-012-0119-31573-7225 Rosato, Valentina Bosetti, Cristina Levi, Fabio Polesel, Jerry Zucchetto, Antonella Negri, Eva La Vecchia, Carlo Journal Article Research Support, Non-U.S. Gov't Netherlands Cancer Causes Control. 2013 Feb;24(2):335-41. doi: 10.1007/s10552-012-0119-3. Epub 2012 Dec 8. 0957-5243Cancer causes & control : CCC23224326zDepartment of Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri, Via Giuseppe o# |<5 Corpet, D. E.2011SRed meat and colon cancer: should we become vegetarians, or can we make meat safer?310-6Meat Sci893 2011/05/12`Animals Calcium, Dietary/therapeutic use Cattle Colonic Neoplasms/etiology/*prevention & control *Diet Diet, Vegetarian Food Additives/*therapeutic use Food Handling Humans Iron, Dietary/*adverse effects Lipid Peroxidation Meat/*adverse effects Meta-Analysis as Topic Nitrites Nitrosation Oxidation-Reduction Rats Swine alpha-Tocopherol/therapeutic useNovThe effect of meat consumption on cancer risk is a controversial issue. However, recent meta-analyses show that high consumers of cured meats and red meat are at increased risk of colorectal cancer. This increase is significant but modest (20-30%). Current WCRF-AICR recommendations are to eat no more than 500 g per week of red meat, and to avoid processed meat. Moreover, our studies show that beef meat and cured pork meat promote colon carcinogenesis in rats. The major promoter in meat is heme iron, via N-nitrosation or fat peroxidation. Dietary additives can suppress the toxic effects of heme iron. For instance, promotion of colon carcinogenesis in rats by cooked, nitrite-treated and oxidized high-heme cured meat was suppressed by dietary calcium and by alpha-tocopherol, and a study in volunteers supported these protective effects in humans. These additives, and others still under study, could provide an acceptable way to prevent colorectal cancer.Bhttp://www.sciencedirect.com/science/article/pii/S03091740110014581873-4138 Corpet, Denis E Journal Article Research Support, Non-U.S. Gov't Review England Meat Sci. 2011 Nov;89(3):310-6. doi: 10.1016/j.meatsci.2011.04.009. Epub 2011 Apr 17. 0309-1740 Meat science21558046SUniversite de Toulouse, ENVT, INRA, UMR Toxalim, Ca v ~<5HStone, W. L. Krishnan, K. Campbell, S. E. Qui, M. Whaley, S. G. Yang, H.2004-Tocopherols and the treatment of colon cancer223-33Ann N Y Acad Sci1031 2005/03/09Animals Chemoprevention Colon/chemistry Colonic Neoplasms/*drug therapy/prevention & control Diet Gene Expression/drug effects Humans Iron, Dietary/administration & dosage Oxidative Stress/drug effects PPAR gamma/genetics Proto-Oncogene Proteins p21(ras)/analysis Rats Tocopherols/*therapeutic use Tumor Cells, Cultured alpha-Tocopherol/administration & dosage gamma-Tocopherol/administration & dosageDecColorectal cancer is the second most common cause of cancer deaths in the United States. Vitamin E (VE) and other antioxidants may help prevent colon cancer by decreasing the formation of mutagens arising from the free radical oxidation of fecal lipids or by "non-antioxidant" mechanisms. VE is not a single molecule, but refers to at least eight different molecules, that is, four tocopherols and four tocotrienols. METHODS: Both animal models and human colon cancer cell lines were used to evaluate the chemopreventive potential of different forms of VE. Rats were fed diets deficient in tocopherols or supplemented with either alpha-tocopherol or gamma-tocopherol. Half the rats in each of these groups received normal levels of dietary Fe and the other half Fe at eight times the normal level. In our cell experiments, we looked at the role of gamma-tocopherol in upregulating peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in the SW 480 human cell line. RESULTS: Rats fed the diets supplemented with alpha-tocopherol had higher levels of VE in feces, colonocytes, plasma, and liver than did rats fed diets supplemented with gamma-tocopherol. Dietary Fe levels did not influence tocopherol levels in plasma, liver, or feces. For colonocytes, high dietary Fe decreased tocopherol levels. Rats fed the gamma-tocopherol-supplemented diets had lower levels of fecal lipid hydroperoxides than rats fed the alpha-tocopherol-supplemented diets. Ras-p21 levels were significantly lower in rats fed the gamma-tocopherol-supplemented diets compared with rats fed the alpha-tocopherol-supplemented diets. High levels of dietary Fe were found to promote oxidative stress in feces and colonocytes. Our data with the SW480 cells suggest that both alpha- and gamma-tocopherol upregulate PPAR-gamma mRNA and protein expression. gamma-tocopherol was, however, found to be a better enhancer of PPAR-gamma expression than alpha-tocopherol at the concentrations tested.ahttp://onlinelibrary.wiley.com/doi/10.1196/annals.1331.022/abstract?systemMessage=Wiley+Online+Library+will+have+intermittent+access+on+8th+August+2015+from+10%3A00-16%3A00+BST+%2F+05%3A00-11%3A00+EDT+%2F+17%3A00-23%3A00+SGT+for+essential+maintenance.++Apologies+for+the+inconvenience. http://onlinelibrary.wiley.com/doi/10.1196/annals.1331.022/abstractStone, William L Krishnan, Koyamangalath Campbell, Sharon E Qui, Min Whaley, Sarah G Yang, Hongsong Journal Article Research Support, Non-U.S. Gov't Resea|<5zYou, J. Huang, S. Huang, G. Q. Zhu, G. Q. Ma, R. M. Liu, W. Y. Shi, K. Q. Guo, G. L. Chen, Y. P. Braddock, M. Zheng, M. H.2015XNonalcoholic fatty liver disease: a negative risk factor for colorectal cancer prognosise479Medicine (Baltimore)945 2015/02/06Aged Aged, 80 and over Body Mass Index Colorectal Neoplasms/*epidemiology/mortality Disease-Free Survival Female Humans Kaplan-Meier Estimate Liver Function Tests Male Middle Aged Non-alcoholic Fatty Liver Disease/*epidemiology Prognosis Proportional Hazards Models Risk FactorsFebNonalcoholic fatty liver disease (NAFLD) is known to be associated with an increased risk of colorectal cancer (CRC). However, the relationship between NAFLD and the prognosis of CRC remains unclear. The primary objective of this study was to evaluate the overall survival (OS) and disease-free survival (DFS) rates in patients with CRC and the secondary objective was to compare clinicopathologic variables which were stratified by NAFLD. We performed a large cohort study of 1314 patients who were first diagnosed with CRC between January 2006 and April 2011. Postoperative follow-up data were collected from out-patient medical records, telephone consultations, and social security death indices. The Kaplan-Meier method was used to calculate the cumulative survival rate. Clinicopathologic variables were analyzed by univariate analysis and multivariate analysis through a Cox proportional hazard regression model. The mean follow-up time was 52.7 +/- 25.3 months. Upon baseline comparison, the NAFLD group had significantly higher values of body mass index, triglycerides, and uric acid and significantly lower values of high-density lipoprotein, compared with the non-NAFLD group (P < 0.05 for all). There were no significant differences between the 2 groups with regard to tumor location, TNM staging, tumor differentiation, carcinoembryonic antigen, and vascular invasion. The cumulative 1-, 3-, and 5-year OS rates were 96.1%, 85.2%, and 80.6%, respectively, in the NAFLD group, which were statistically significantly higher than the OS rates of 91.6%, 76.2%, and 67.8%, respectively, in the non-NAFLD group (P = 0.075, P = 0.002, P = 0.030, respectively). There was no difference in DFS rates between the CRC patients with and without NAFLD (P = 0.267). Multivariate analysis showed that the presence of NAFLD was an independent negative risk factor for OS after adjusting for clinicopathologic covariates (hazard ratio = 0.593; 95% confidence interval 0.442, 0.921; P = 0.020), but not for DFS (P = 0.270). NAFLD may play a protective role in OS for CRC patients. Further studies are needed to elucidate the molecular mechanisms of putative protective effects in CRC patients with NAFLD.*1536-5964 You, Jie Huang, Sha Huang, Gui-Qian Zhu, Gui-Qi Ma, Rui-Min Liu, Wen-Yue Shi, Ke-Qing Guo, Gui-Long Chen, Yong-Ping Braddock, Martin Zheng, Ming-Hua Journal Article Research Support, Non-U.S. Gov't United States Medicine (Baltimore). 2015 Feb;94(5):e479. doi: 10.1097/MD.0000000000000479. 0025-7974Medicine25654388xFrom the Department of Oncological Surgery (JY, R-MM,G-LG); Department of Infection and Liver Diseases, Liver Research Center, the First Affiliated Hospital of Wenzhou Medical University (SH, G-QH, G-QZ, W-YL, K-QS, Y-PC, M-HZ); School of the First Clinical Medical Sciences, Wenzhou Medical University (SH, G-QZ); Renji School of Wenzhou Medical University (G-QH); Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University (W-YL); Institute of Hepatology, Wenzhou Medical University, Wenzhou, China (K-QS, Y-PC, M-HZ); Global Medicines Development, AstraZeneca R&D, Loughborough, United Kingdom (MB).10.1097/md.0000000000000479NLMeng |45+Shen, H. Lipka, S. Kumar, A. Mustacchia, P.2014pAssociation between nonalcoholic fatty liver disease and colorectal adenoma: a systemic review and meta-analysis440-6J Gastrointest Oncol56 2014/12/02SNonalcoholic fatty liver disease (NAFLD) colorectal adenoma colorectal cancer (CRC)DecBACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome (MetS) and the most common chronic liver disease worldwide. The association between NAFLD and colorectal adenoma has been investigated in multiples studies but the results have been conflicting. We performed a systematic review and meta-analysis to evaluate this in asymptomatic patients who underwent screening colonoscopy. METHODS: We searched the literatures of all languages from PubMed, EMBASE and the Cochrane library from January 1, 1980 through July 15, 2014. Combined and subgroup analyses stratified by study designs, study locations, characteristics of adenoma (location, size, number, and advanced adenoma) were performed. RESULTS: Four cross-sectional and one cohort studies with a total of 6,263 subjects were included in the meta-analysis. NAFLD was significantly associated with colorectal adenoma [pooled odds ratio (OR) 1.74, 95% confidence interval (CI): 1.53-1.97]. The association was more significant in Asian population (pooled OR =1.77, 95% CI: 1.52-2.05, n=3 studies), compared to European/North American population (pooled OR =1.42, 95% CI: 0.75-2.67, n=2 studies). NAFLD was significantly associated with the number of colorectal adenoma (pooled OR =1.78, 95% CI: 1.10-2.86, n=2 studies), but not the location, size, or presence of advanced adenoma. CONCLUSIONS: Our results suggest NAFLD is significantly associated with the presence of colorectal adenoma in asymptomatic patients undergoing screening colonoscopy. This finding provides additional risk stratifications for applying colorectal cancer (CRC) screening strategies. However, more studies of western population are needed to further investigate the ethnic disparity.Ihttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226833/pdf/jgo-05-06-440.pdfShen, Huafeng Lipka, Seth Kumar, Ambuj Mustacchia, Paul Journal Article China J Gastrointest Oncol. 2014 Dec;5(6):440-6. doi: 10.3978/j.issn.2078-6891.2014.061.2078-6891 (Print) 2078-6891 Pmc4226833$Journal of gastrointestinal oncology25436123A1 Department of Medicine, Nassau University Medical Center, East Meadow, New York, USA ; 2 Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA ; 3 Division of Gastroenterology, Department of Medicine, Nassau University Medica  p|<5Girotti, A. W.1998SLipid hydroperoxide generation, turnover, and effector action in biological systems1529-42 J Lipid Res398 1998/08/26BAnimals Apoptosis Cell Survival Chromatography, High Pressure Liquid Electrons Humans Lipid Peroxidation Lipid Peroxides/*biosynthesis/metabolism/pharmacology Models, Biological Oxidation-Reduction Oxidative Stress Phospholipases/metabolism Protein Kinases/metabolism Reactive Oxygen Species/metabolism Signal TransductionAugLipid peroxidation is a well known example of oxidative damage in cell membranes, lipoproteins, and other lipid-containing structures. Peroxidative modification of unsaturated phospholipids, glycolipids, and cholesterol can occur in reactions triggered by i) free radical species such as oxyl radicals, peroxyl radicals, and hydroxyl radicals derived from iron-mediated reduction of hydrogen peroxide or ii) non-radical species such as singlet oxygen, ozone, and peroxynitrite generated by the reaction of superoxide with nitric oxide. Lipid hydroperoxides (LOOHs) are prominent non-radical intermediates of lipid peroxidation whose identification can often provide valuable mechanistic information, e.g., whether a primary reaction is mediated by singlet oxygen or oxyradicals. Certain cholesterol-derived hydroperoxides (ChOOHs) have been used very effectively in this regard, both in model systems and cells. Being more polar than parent lipids, LOOHs perturb membrane structure/function and can be deleterious to cells on this basis alone. However, LOOHs can also participate in redox reactions, the nature and magnitude of which often determines whether peroxidative injury is exacerbated or prevented. Exacerbation may reflect iron-catalyzed one-electron reduction of LOOHs, resulting in free radical-mediated chain peroxidation, whereas prevention may reflect selenoperoxidase-catalyzed two-electron reduction of LOOHs to relatively non-toxic alcohols. LOOH partitioning between these two pathways in an oxidatively stressed cell is still poorly understood, but recent cell studies involving various ChOOHs have begun to shed light on this important question. An aspect of related interest that is under intensive investigation is lipid peroxidation/LOOH-mediated stress signaling, which may evoke a variety of cellular responses, ranging from induction of antioxidant enzymes to apoptotic death. Ongoing exploration of these processes will have important bearing on our understanding of disease states associated with peroxidative stress.-http://www.jlr.org/content/39/8/1529.full.pdfGirotti, A W CA49089/CA/NCI NIH HHS/United States CA70823/CA/NCI NIH HHS/United States CA72630/CA/NCI NIH HHS/United States Journal Article Research Support, U.S. Gov't, P.H.S. Review United states J Lipid Res. 1998 Aug;39(8):1529-42.0022-2275 (Print) 0022-2275Journal of lipid research9717713eDepartment of Biochemistry, Medical College of Wisconsin |<59Bishak, Y. K. Payahoo, L. Osatdrahimi, A. Nourazarian, A.2015CMechanisms of cadmium carcinogenicity in the gastrointestinal tract9-21Asian Pac J Cancer Prev161 2015/02/03Cancer, a serious public health problem in worldwide, results from an excessive and uncontrolled proliferation of the body cells without obvious physiological demands of organs. The gastrointestinal tract, including the esophagus, stomach and intestine, is a unique organ system. It has the highest cancer incidence and cancer- related mortality in the body and is influenceed by both genetic and environmental factors. Among the various chemical elements recognized in the nature, some of them including zinc, iron, cobalt, and copper have essential roles in the various biochemical and physiological processes, but only at low levels and others such as cadmium, lead, mercury, arsenic, and nickel are considered as threats for human health especially with chronic exposure at high levels. Cadmium, an environment contaminant, cannot be destroyed in nature. Through impairment of vitamin D metabolism in the kidney it causes nephrotoxicity and subsequently bone metabolism impairment and fragility. The major mechanisms involved in cadmium carcinogenesis could be related to the suppression of gene expression, inhibition of DNA damage repair, inhibition of apoptosis, and induction of oxidative stress. In addition, cadmium may act through aberrant DNA methylation. Cadmium affects multiple cellular processes, including signal transduction pathways, cell proliferation, differentiation, and apoptosis. Down-regulation of methyltransferases enzymes and reduction of DNA methylation have been stated as epigenetic effects of cadmium. Furthermore, increasing intracellular free calcium ion levels induces neuronal apoptosis in addition to other deleterious influence on the stability of the genome.Bishak, Yaser Khaje Payahoo, Laleh Osatdrahimi, Alireza Nourazarian, Alireza Journal Article Thailand Asian Pac J Cancer Prev. 2015;16(1):9-21.1513-7368 (Print) 1513-73682Asian Pacific journal of cancer prevention : APJCP25640397Student Research Committee, Nutrition Research Center, Department of Nutrition, Tabriz University of Medical sciences, Tabriz, Iran E-mail : nourazariana@tbzmed.ac.ir.NLMeng ;|<5+Koedrith, P. Kim, H. Weon, J. I. Seo, Y. R.2013oToxicogenomic approaches for understanding molecular mechanisms of heavy metal mutagenicity and carcinogenicity587-98Int J Hyg Environ Health2165 2013/04/02Animals Carcinogens/*toxicity Environmental Exposure/adverse effects Genomics Humans Metals, Heavy/*toxicity Mutagens/*toxicity Neoplasms/chemically induced/*genetics Carcinogenicity Environment Heavy metal Mutagenicity ToxicogenomicsAugIHeavy metals that are harmful to humans include arsenic, cadmium, chromium, lead, mercury, and nickel. Some metals or their related compounds may even cause cancer. However, the mechanism underlying heavy metal-induced cancer remains unclear. Increasing data show a link between heavy metal exposure and aberrant changes in both genetic and epigenetic factors via non-targeted multiple toxicogenomic technologies of the transcriptome, proteome, metabolome, and epigenome. These modifications due to heavy metal exposure might provide a better understanding of environmental disorders. Such informative changes following heavy metal exposure might also be useful for screening of biomarker-monitored exposure to environmental pollutants and/or predicting the risk of disease. We summarize advances in high-throughput toxicogenomic-based technologies and studies related to exposure to individual heavy metal and/or mixtures and propose the underlying mechanism of action and toxicant signatures. Integrative multi-level expression analysis of the toxicity of heavy metals via system toxicology-based methodologies combined with statistical and computational tools might clarify the biological pathways involved in carcinogenic processes. Although standard in vitro and in vivo endpoint testing of mutagenicity and carcinogenicity are considered a complementary approach linked to disease, we also suggest that further evaluation of prominent biomarkers reflecting effects, responses, and disease susceptibility might be diagnostic. Furthermore, we discuss challenges in toxicogenomic applications for toxicological studies of metal mixtures and epidemiological research. Taken together, this review presents toxicogenomic data that will be useful for improvement of the knowledge of carcinogenesis and the development of better strategies for health risk assessment.Bhttp://www.sciencedirect.com/science/article/pii/S14384639130003701618-131x Koedrith, Preeyaporn Kim, Hyelim Weon, Jong-Il Seo, Young Rok Journal Article Research Support, Non-U.S. Gov't Review Germany Int J Hyg Environ Health. 2013 Aug;216(5):587-98. doi: 10.1016/j.ijheh.2013.02.010. Epub 2013 Mar 13. 1438-46399International journal of hygiene and environmental health23540489Department of Life Science, Institute of Environmental Medicine for Green Chemistry, Dongguk University, 30 Pildong-ro 1-gil, Jung-g aotherapy groups. Mechanistically, vitamin D3/5-FU co-therapy significantly decreased the expression of Wnt, beta-catenin, iNOS, COX-2 and HSP-90 and significantly increased the expression of DKK-1, TGF-beta1, TGF-betaR2, smad4 (P < 0.05), in comparison with their corresponding monotherapy groups. CONCLUSIONS: Vitamin D3 and 5-FU synergise together and exhibit better anticancer effects by modulating Wnt/beta-catenin pathway, TGF-beta1 signals, iNOS, COX-2 and HSP-90. Further studies are required to illustrate the clinical value of vitamin D supplementation during the treatment of colon cancer with 5-FU in human patients.Rhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513788/pdf/13046_2015_Article_187.pdf1756-9966 Refaat, Bassem El-Shemi, Adel Galal Kensara, Osama Adnan Mohamed, Amr Mohamed Idris, Shakir Ahmad, Jawwad Khojah, Athar Journal Article England J Exp Clin Cancer Res. 2015 Jul 25;34(1):71. doi: 10.1186/s13046-015-0187-9. 0392-9078 Pmc45137887Journal of experimental & clinical cancer research : CR26205949Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia. bassem.refaat@yahoo.co.uk. Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia. dr_adel_elshemy2006@yahoo.com. Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt. dr_adel_elshemy2006@yahoo.com. Clinical Nutrition Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia. o.kensara@gmail.com. Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia. amrmohamed2004@yahoo.com. Clinical Laboratory Diagnosis, Department of Animal Medicine, Faculty of Veterinary Medicine, Assiut University, Assiut, 71526, Egypt. amrmohamed2004@yahoo.com. Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia. shakir_sust@hotmail.com. Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia. jawad7776@gmail.com. Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia. athar.h.k@hotmail.com.10.1186/s13046-015-0187-9internal-pdf://0156708813/Refaat-2015-Vitamin D3 enhances the tumouricid.pdf int {~<5]Hayde, V. C. Ramon, G. G. Lorenzo, G. O. Dave, O. B. Rosalia, R. C. Paul, W. Guadalupe, L. P.2012Non-digestible fraction of beans (Phaseolus vulgaris L.) modulates signalling pathway genes at an early stage of colon cancer in Sprague-Dawley ratsS145-54 Br J Nutr 108 Suppl 1 2012/08/25Animals Anticarcinogenic Agents/pharmacology Apoptosis/genetics Azoxymethane Cell Cycle/genetics Colon/metabolism Colonic Neoplasms/chemically induced/*metabolism/prevention & control DNA Repair/genetics Diet Dietary Fiber/*administration & dosage Digestion Gene Expression/*drug effects Gene Expression Profiling Male Phaseolus/*chemistry Plant Extracts/administration & dosage Polymerase Chain Reaction Rats Rats, Sprague-Dawley Seeds/*chemistry Signal Transduction/*geneticsAugColorectal cancer is one of the most common causes of morbidity and mortality in Western countries, the second cause of cancer mortality in the USA and a major public health problem in Mexico. A diet rich in legumes is directly related to the prevention of colon cancer, showing an inverse relationship with the development of colorectal adenomas in human subjects. The present study shows the results of molecular changes involved in the Tp53 pathway at an early stage in the distal colon tissue of azoxymethane (AOM)-induced colon cancer in rats evaluated by PCR array after exposure to diets containing the non-digestible fraction (NDF) of cooked bean (cultivar Bayo Madero). Significant differences were detected in seventy-two genes of the Tp53-mediated signalling pathway involved in apoptosis, cell-cycle regulation and arrest, inhibition of proliferation and inflammation, and DNA repair. Tp53, Gadd45a, Cdkn1a and Bax were highly expressed (9.3-, 18.3-, 5.5- and 3.5-fold, respectively) in the NDF+AOM group, whereas Cdc25c, Ccne2, E2f1 and Bcl2 were significantly suppressed ( - 9.2-, - 2.6-, - 18.4- and - 3.5-fold, respectively), among other genes, compared with the AOM group, suggesting that chemoprevention of aberrant crypt foci results from a combination of cell-cycle arrest in G1/S and G2/M phases and cell death by apoptotic induction. We demonstrate that the NDF from common bean modulates gene expression profiles in the colon tissue of AOM-induced rats, contributing to the chemoprotective effect of common bean on early-stage colon cancer.http://journals.cambridge.org/download.php?file=%2FBJN%2FBJN108_S1%2FS0007114512000785a.pdf&code=afd5f9603909e3d55d1724b76fbc7feb 1475-2662 Hayde, Vergara-Castaneda Ramon, Guevara-Gonzalez Lorenzo, Guevara-Olvera Dave, Oomah B Rosalia, Reynoso-Camacho Paul, Wiersma Guadalupe, Loarca-Pina Journal Article Research Support, Non-U.S. Gov't England Br J Nutr. 2012 Aug;108 Suppl 1:S145-54. doi: 10.1017/S0007114512000785. 0007-1145 The British journal of nutrition22916810Programa de Posgrado en Alimentos del Centro de Republica, Research and Graduate Studies in Food Science, School of Chemistry, Queretaro State University, Cerro de Campanas S/N Col. Las Campanas, Queretaro, Qro. 76010, Mexico.10.1017/s0007114512000785Linternal-pdf://1784001202/Hayde-2012-Non-digestible fraction of beans (P.pdfNLMeng Lpelles, France. d.corpet@envt.fr10.1016/j.meatsci.2011.04.009NLMeng , Milwaukee 53226-4801, USA. agirotti@mcw.eduLinternal-pdf://1759860873/Girotti-1998-Lipid hydroperoxide generation, t.pdfNLMeng !rch Support, U.S. Gov't, Non-P.H.S. Review United States Ann N Y Acad Sci. 2004 Dec;1031:223-33.0077-8923 (Print) 0077-8923*Annals of the New York Academy of Sciences15753148East Tennessee State University, James H. Quillen College of Medicine, Department of Pediatrics, Johnson , 167 Dana Hall, Stony Brook, NY 11794-5000, USA.10.1155/2011/983072Linternal-pdf://2129356623/Silbernagel-2011-Recognizing and preventing ov.pdfNLMeng Nu, Seoul 100-715, Republic of Korea.10.1016/j.ijheh.2013.02.010NLMeng HLa Masa 19, 20156, Milan, Italy.10.1007/s10552-012-0119-3NLMeng y of Reading, Reading, United Kingdom (GCGK).10.3945/ajcn.113.061069Linternal-pdf://1472387316/Pierre-2013-Calcium and alpha-tocopherol suppr.pdfNLMeng at Rec (Hoboken). 2012 Jun;295(6):939-49. doi: 10.1002/ar.22485. Epub 2012 May 2. 1932-8486(Anatomical record (Hoboken, N.J. : 2007)22549941\Department of Anatomy, Faculty of Medicine, King Abdulaziz Univ terology Department, Tel Aviv Medical Center, Israel.Linternal-pdf://2006189427/Lubin-1997-Nutritional and lifestyle habits an.pdfNLMeng `l Center, East Meadow, New York, USA.!10.3978/j.issn.2078-6891.2014.061internal-pdf://1628377168/Shen-2014-Association between nonalcoholic fat.pdf inte FChina, huajianrui6666@126.com.10.1007/s12032-014-0434-5NLMeng halysis Research Support, Non-U.S. Gov't Review United States Int J Cancer. 2015 May 15;136(10):2388-401. doi: 10.1002/ijc.29277. Epub 2014 Nov 11. 0020-7136@International journal of cancer. Journal international du cancer25335850PDivision of Human Nutrition, Wageningen Un ersity (OHSU) , Portland, Oregon, United States.10.1021/am5007707Linternal-pdf://4146200919/Sangvanich-2014-Novel oral detoxification of m.pdfNLMeng F<5Byun, S. Y. Kim, D. B. Kim, E.2015Curcumin ameliorates the tumor-enhancing effects of a high-protein diet in an azoxymethane-induced mouse model of colon carcinogenesisNutr Res 2015/06/22=Colorectal cancer Curcumin Dietary protein Inflammation MouseJun 1An increasing number of reports suggest that a high-protein diet (HPD) is associated with an increased risk for colorectal cancer (CRC). One of the proposed mechanisms is that an HPD increases the delivery of protein to the colon and generates various toxic metabolites that contribute to colon carcinogenesis. Curcumin was shown to exert significant preventive properties against CRC. We therefore hypothesized that curcumin can reverse the tumor-enhancing effects of an HPD. This study examined the effects of curcumin on the development of azoxymethane (AOM)-induced colorectal tumors in HPD-fed mice. A total of 30 female Balb/c mice were randomly divided into 3 groups: those fed a normal diet (20% casein), those fed an HPD (HPD; 50% casein), and those fed an HPD supplemented with curcumin (HPDC; 0.02% curcumin). The mice were subjected to an AOM-dextran sodium sulfate colon carcinogenesis protocol. Mice in the HPDC group exhibited a significant (40%) reduction in colorectal tumor multiplicity when compared with those in the HPD group. The expression of colonic inflammatory proteins (cyclooxygenase-2 and inducible nitric oxide synthase), the levels of plasma inflammatory markers (nitric oxide and tumor necrosis factor-alpha), fecal ammonia, short- and branched-chain fatty acid levels, and the rate of colonocyte proliferation were significantly lower in the HPDC than the HPD group. In conclusion, curcumin inhibited the development of colorectal tumors in an AOM-induced mouse model of colon carcinogenesis by attenuating colonic inflammation, proliferation, and toxic metabolite production. Curcumin might be useful in the chemoprevention of CRC in individuals consuming an HPD.1879-0739 Byun, So-Young Kim, Dan-Bi Kim, Eunjung Journal article Nutr Res. 2015 Jun 1. pii: S0271-5317(15)00128-1. doi: 10.1016/j.nutres.2015.05.016. 0271-5317#Nutrition research (New York, N.Y.)26094212Department of Food Science and Nutrition, Catholic University of Daegu, Gyeongsan, Korea. Department of Food Science and Nutrition, Catholic University of Daegu, Gyeongsan, Korea. Electronic address: kimeunj@cu.ac.kr.10.1016/j.nutres.2015.05.016NLMEng WX|<52Zhang, M. Fan, X. Fang, B. Zhu, C. Zhu, J. Ren, F.2015Effects of Lactobacillus salivarius Ren on cancer prevention and intestinal microbiota in 1, 2-dimethylhydrazine-induced rat model398-405 J Microbiol536 2015/05/31JunProbiotics have been suggested as a prophylactic measure in colon cancer. The aim of this study was to investigate the impact of Lactobacillus salivarius Ren (Ren) in modulating colonic microbiota structure and colon cancer incidence in a rat model after injection with 1,2-dimethyl hydrazine (DMH). The results indicated that oral administration of Ren could effectively suppress DMH-induced colonic carcinogenesis. A significant decrease in cancer incidence (87.5% to 25%) was detected in rats fed with a dose of 5 x 10(10) CFU/kg bodyweight per day. Using denaturing gradient gel electrophoresis and Real-time PCR combined with multivariate statistical methods, we demonstrated that injection with DMH significantly altered the rat gut microbiota, while Ren counteracted these DMH-induced adverse effects and promoted reversion of the gut microbiota close to the healthy state. Tvalue biplots followed by band sequencing identified 21 bacterial strains as critical variables affected by DMH and Ren. Injection of DMH significantly increased the amount of Ruminococcus species (sp.) and Clostridiales bacteria, as well as decreasing the Prevotella sp. Administration of Ren reduced the amount of Ruminococcus sp., Clostridiales bacteria, and Bacteroides dorei, and increased the amount of Prevotella. Real-time PCR results were consistent with the results derived by t-value biplots. These findings suggested that Ren is a potential agent for colon cancer prevention. In conclusion, the results in the present study suggest a potential therapeutic approach based on the modulation of intestinal microflora by probiotics may be beneficial in the prevention of colorectal carcinogenesis.<http://link.springer.com/article/10.1007%2Fs12275-015-5046-z1976-3794 Zhang, Ming Fan, Xing Fang, Bing Zhu, Chengzhen Zhu, Jun Ren, Fazheng Journal Article Research Support, Non-U.S. Gov't Korea (South) J Microbiol. 2015 Jun;53(6):398-405. doi: 10.1007/s12275-015-5046-z. Epub 2015 May 30. 1225-8873&Journal of microbiology (Seoul, Korea)26025172rSchool of Food and Chemical Engineering, Beijing Technology and Business University F<5Liu, N. Sun, B. Wu, P. Wei, X.2015Chemopreventive Effects of Azadirachta indica on Cancer Marker Indices and Ultrastructural Changes During 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis in RatsCell Biochem Biophys 2015/02/24Feb 20 The present study elucidated the prospective of Azadirachta indica supplementation, if any, in affording chemoprevention by modulating the altered cancer markers and ultrastructural changes in DMH-induced colorectal carcinogenesis in rats. The rats were segregated into four groups viz., normal control, DMH treated, A. indica treated, and DMH+AI treated. Initiation and induction of colon carcinogenesis were achieved through weekly subcutaneous injections of DMH (30 mg/kg body weight) for both 10 and 20 weeks. A. indica extract was supplemented to rats at a dose rate of 100 mg/kg body weight of animals thrice a week on alternative days, ad libitum for two different time durations of 10 and 20 weeks. The study observed a significant increase in the number of aberrant crypt foci in colons of DMH-treated rats at both the time intervals which were decreased significantly upon AI supplementation. Also, a significant increase was seen in the enzyme activity of alkaline phosphatase, which, however, was moderated upon AI administration to DMH-treated rats. Changes in the ultrastructural architecture of colonic cells were apparent following both the treatment schedules of DMH; however, the changes were prominent following 20 weeks of DMH treatment. The most obvious changes were seen in the form of altered nuclear shape and disruption of cellular integrity, which were appreciably improved upon AI supplementation. In conclusion, the study shows the chemopreventive abilities of AI against DMH-induced colorectal carcinogenesis in rats.<http://link.springer.com/article/10.1007%2Fs12013-015-0621-9a1559-0283 Liu, Ning Sun, Bo Wu, Peiwei Wei, Xi Journal article Cell Biochem Biophys. 2015 Feb 20. 1085-9195 Cell biochemistry and biophysics25697750Department of Emergency Surgery, The First People's Hospital of Xuzhou, No. 19, Zhongshanbei Road, Xuzhou, 221000, Jiangsu, People's Republ 0|<5Reynoso-Camacho, R. Guerrero-Villanueva, G. Figueroa Jde, D. Gallegos-Corona, M. A. Mendoza, S. Loarca-Pina, G. Ramos-Gomez, M.2015Anticarcinogenic Effect of Corn Tortilla Against 1,2-Dimethylhydrazine (DMH)-Induced Colon Carcinogenesis in Sprague-Dawley Rats146-52Plant Foods Hum Nutr702 2015/02/15JunSMexico has the highest per capita consumption of corn in the world, which is consumed mainly as tortilla. However, only a few in vivo studies have demonstrated the anticarcinogenic potential of some maize components against colon cancer, but not as a whole food product. Therefore, our objective was to evaluate the protective effect of corn tortillas against the development of colon cancer. First, blue, red, yellow and white corn grains were lime-cooked and processed to elaborate tortillas. Then, tortillas were administered into the diet (27% w/w) to male Sprague-Dawley rats induced with the colon carcinogen 1,2-dimethylhydrazine (DMH). Our results indicated that consumption of tortillas, particularly from white and blue corns, significantly decreased adenocarcinoma incidence (up to 77.5%) and mean number compared to DMH-treated animals. In addition, an inhibition of beta-glucuronidase activity, and induction of detoxifying enzymes in liver and colon, as well as a decrease in the expression of the two most important proliferative proteins (K-ras and beta-catenin) involved in colon carcinogenesis, were also observed. These results highlight some of the molecular mechanisms related to the chemopreventive effect of tortillas, thus indicating that corn products retain their biological properties even after nixtamalization and tortilla processing.<http://link.springer.com/article/10.1007%2Fs11130-015-0471-z71573-9104 Reynoso-Camacho, Rosalia Guerrero-Villanueva, Guadalupe Figueroa, Juan de Dios Gallegos-Corona, Marco A Mendoza, Sandra Loarca-Pina, Guadalupe Ramos-Gomez, Minerva Journal Article Research Support, Non-U.S. Gov't Netherlands Plant Foods Hum Nutr. 2015 Jun;70(2):146-52. doi: 10.1007/s11130-015-0471-z. 0921-96688Plant foods for human nutrition (Dordrecht, Netherlands)25680741Departamento de Investigacion y Posgrado en Alimentos (PROPAC), Facultad de Quimica, Universidad Autonoma de Queretaro, Queretaro, 76010, Mexico.10.1007/s11130-015-0471-zNLMengIic of China, manuautho@gmail.com.10.1007/s12013-015-0621-9NLMEng G, Beijing, 100048, P. R. China.10.1007/s12275-015-5046-zNLMeng|<5"Boffetta, P. Merler, E. Vainio, H.19930Carcinogenicity of mercury and mercury compounds1-7Scand J Work Environ Health191 1993/02/01.Animals Carcinogenicity Tests Humans Mercury/*adverse effects Mercury Poisoning/*complications Neoplasms/*chemically induced Neoplasms, Experimental/*chemically induced Occupational Diseases/*chemically induced Occupational Exposure/*adverse effects Organomercury Compounds/adverse effects Risk FactorsFebMercury and mercury compounds are widely used in modern society, but only sparse data are available on their carcinogenicity. Methylmercury chloride causes kidney tumors in male mice. Mercury chloride has shown some carcinogenic activity in male rats, but the evidence for female rats and male mice is equivocal. Other mercury compounds and metallic mercury have not been tested adequately in experimental animals. Epidemiologic data are available for chloralkali workers, dentists and dental nurses, and nuclear weapons workers, three groups occupationally exposed to low levels of mercury and its compounds, but those highly exposed in the past, such as miners, or populations which have suffered massive environmental exposure have not been adequately studied. However, the sparse epidemiologic data point toward the possibility of a risk of lung, kidney, and central nervous system tumors. Better data are needed on the carcinogenicity of mercury and mercury compounds in humans and experimental animals.oBoffetta, P Merler, E Vainio, H Journal Article Review Finland Scand J Work Environ Health. 1993 Feb;19(1):1-7.0355-3140 (Print) 0355-31402Scandinavian journal of work, environment & health8465166[Unit of Analytical Epidemiology, International Agency for Research on Cancer, Lyon, France.NLMeng |<5.Schurz, F. Sabater-Vilar, M. Fink-Gremmels, J.2000gMutagenicity of mercury chloride and mechanisms of cellular defence: the role of metal-binding proteins525-30 Mutagenesis156 2000/11/153T3 Cells Animals Antimetabolites, Antineoplastic/metabolism Buthionine Sulfoximine/pharmacology Cell Nucleus/metabolism DNA Damage/drug effects Dose-Response Relationship, Drug Free Radicals Genes, Reporter Glutathione/metabolism Hydrogen Peroxide/pharmacology Lac Operon *Mercuric Chloride Mercury/metabolism Metallothionein/metabolism Mice Mutagenicity Tests *Mutagens Mutation Oxygen/metabolism Plasmids/metabolismNovThe mechanisms of toxicity and, particularly, the potential carcinogenicity of inorganic mercury are still under debate. Results of mutagenicity and genotoxicity testing with mercury have been inconsistent: mercury induces DNA single-strand breaks at low concentrations in mammalian cells but has not proved mutagenic in several bacterial mutagenicity assays. We investigated the mutagenicity of subtoxic concentrations of inorganic mercury and the role of metal-binding proteins and free radicals in this process. A mutagenicity assay using NIH 3T3 cells, transfected with a vector containing lacZ' as a reporter for mutational events, was applied. In this model, inorganic mercury significantly increased the mutation frequency in the lacZ gene, even at the lowest concentration tested. The mutation frequency was greatest at an Hg(2+) concentration of 0.5 microM. To identify the mechanisms involved, different cellular responses to non-cytotoxic concentrations of HgCl(2) were measured. Hg(2+) increased the intracellular amount of reactive oxygen species. This induction of oxidative stress was observed, although the intracellular glutathione (GSH) and metallothionein (MT) concentrations were increased significantly. Mercury-induced MT expression was even more pronounced after GSH depletion. Correspondingly, radical formation was more evident in the presence of the GSH-depleting agent L-buthioneine-[S:,R:]-sulfoximine. These findings suggest that the observed mutations might be a consequence of oxidative processes, rather than due to a direct interaction of mercury with nuclear DNA. The results also indicate that the auto-induction of MT by Hg(2+) fails to prevent these mutational events.Schurz, F Sabater-Vilar, M Fink-Gremmels, J Journal Article Research Support, Non-U.S. Gov't England Mutagenesis. 2000 Nov;15(6):525-30.0267-8357 (Print) 0267-8357 Mutagenesis11077005`Department of Analytical and Molecular Pharmacology, TNO Pharma Zeist, Utrecht, The Netherlands.<internal-pdf://2818185487/Mutagenesis-2000-Schurz-525-30.pdfNLMeng Z ~<5'Garcia-Nino, W. R. Pedraza-Chaverri, J.2014GProtective effect of curcumin against heavy metals-induced liver damage182-201Food Chem Toxicol69 2014/04/23Animals Arsenic/toxicity Cadmium/toxicity Copper/toxicity Curcumin/*pharmacology Humans Intracellular Signaling Peptides and Proteins/metabolism Lead/toxicity Liver/*drug effects/metabolism/pathology Mercury/toxicity Metals, Heavy/*toxicity NF-E2-Related Factor 2/metabolism Oxidative Stress/drug effects Protective Agents/*pharmacology Curcumin Heavy metals Hepatoprotective Mitochondrial dysfunction Nrf2 Oxidative stressJulOccupational or environmental exposures to heavy metals produce several adverse health effects. The common mechanism determining their toxicity and carcinogenicity is the generation of oxidative stress that leads to hepatic damage. In addition, oxidative stress induced by metal exposure leads to the activation of the nuclear factor (erythroid-derived 2)-like 2/Kelch-like ECH-associated protein 1/antioxidant response elements (Nrf2/Keap1/ARE) pathway. Since antioxidant and chelating agents are generally used for the treatment of heavy metals poisoning, this review is focused on the protective role of curcumin against liver injury induced by heavy metals. Curcumin has shown, in clinical and preclinical studies, numerous biological activities including therapeutic efficacy against various human diseases and anti-hepatotoxic effects against environmental or occupational toxins. Curcumin reduces the hepatotoxicity induced by arsenic, cadmium, chromium, copper, lead and mercury, prevents histological injury, lipid peroxidation and glutathione (GSH) depletion, maintains the liver antioxidant enzyme status and protects against mitochondrial dysfunction. The preventive effect of curcumin on the noxious effects induced by heavy metals has been attributed to its scavenging and chelating properties, and/or to the ability to induce the Nrf2/Keap1/ARE pathway. However, additional research is needed in order to propose curcumin as a potential protective agent against liver damage induced by heavy metals.Bhttp://www.sciencedirect.com/science/article/pii/S02786915140019871873-6351 Garcia-Nino, Wylly Ramses Pedraza-Chaverri, Jose Journal Article Research Support, Non-U.S. Gov't Review England Food Chem Toxicol. 2014 Jul;69:182-201. doi: 10.1016/j.fct.2014.04.016. Epub 2014 Apr 18. 0278-6915|Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association24751969*Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), University City, 04510 D.F., Mexico. Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), University City, 04510 D.F., Mexic `|45Koedrith, P. Seo, Y. R.2011GAdvances in carcinogenic metal toxicity and potential molecular markers9576-95 Int J Mol Sci1212 2012/01/25 Animals Carcinogens/chemistry/*toxicity Humans Metals/chemistry/*toxicity Neoplasms/*chemically induced/diagnosis/metabolism Oxidative Stress Oxidoreductases/genetics/*metabolism Tumor Markers, Biological/genetics/*metabolism DNA damage DNA repair carcinogenicity genotoxicity heavy metalMetal compounds such as arsenic, cadmium, chromium, cobalt, lead, mercury, and nickel are classified as carcinogens affecting human health through occupational and environmental exposure. However, the underlying mechanisms involved in tumor formation are not well clarified. Interference of metal homeostasis may result in oxidative stress which represents an imbalance between production of free radicals and the system's ability to readily detoxify reactive intermediates. This event consequently causes DNA damage, lipid peroxidation, protein modification, and possibly symptomatic effects for various diseases including cancer. This review discusses predominant modes of action and numerous molecular markers. Attention is paid to metal-induced generation of free radicals, the phenomenon of oxidative stress, damage to DNA, lipid, and proteins, responsive signal transduction pathways with major roles in cell growth and development, and roles of antioxidant enzymatic and DNA repair systems. Interaction of non-enzymatic antioxidants (carotenoids, flavonoids, glutathione, selenium, vitamin C, vitamin E, and others) with cellular oxidative stress markers (catalase, glutathione peroxidase, and superoxide dismutase) as well as certain regulatory factors, including AP-1, NF-kappaB, Ref-1, and p53 is also reviewed. Dysregulation of protective pathways, including cellular antioxidant network against free radicals as well as DNA repair deficiency is related to oncogenic stimulation. These observations provide evidence that emerging oxidative stress-responsive regulatory factors and DNA repair proteins are putative predictive factors for tumor initiation and progression.Ihttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257147/pdf/ijms-12-09576.pdf1422-0067 Koedrith, Preeyaporn Seo, Young Rok Journal Article Research Support, Non-U.S. Gov't Review Switzerland Int J Mol Sci. 2011;12(12):9576-95. doi: 10.3390/ijms12129576. Epub 2011 Dec 20. 1422-0067 Pmc3257147+International journal of molecular sciences22272150Department of Life Science, Dongguk University, 30 Pildong-ro 1-gil (26 Pildong 3-ga), D|45 Holmes, A. L. Wise, J. P.20104Mechanisms of metal-induced centrosome amplification1687-90Biochem Soc Trans386 2010/12/02Animals Arsenic/*toxicity Carcinogens/toxicity Cell Line Centrosome/*drug effects/*metabolism Chromium/*toxicity Environmental Exposure Humans Mercury/*toxicity Nanostructures/toxicity Titanium/chemistry/*toxicityDecbExposure to toxic and carcinogenic metals is widespread; however, their mechanisms of action remain largely unknown. One potential mechanism for metal-induced carcinogenicity and toxicity is centrosome amplification. Here we review the mechanisms for metal-induced centrosome amplification, including arsenic, chromium, mercury and nano-titanium dioxide.Ahttp://www.biochemsoctrans.org/content/ppbiost/38/6/1687.full.pdf'1470-8752 Holmes, Amie L Wise, John Pierce ES016893/ES/NIEHS NIH HHS/United States R01 ES016893/ES/NIEHS NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review England Biochem Soc Trans. 2010 Dec;38(6):1687-90. doi: 10.1042/BST0381687. 0300-5127 Pmc4086844 Biochemical Society transactions21118148 Nihms605658Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 7 |45!!Hong, Y. S. Kim, Y. M. Lee, K. E.2012)Methylmercury exposure and health effects353-63J Prev Med Public Health456 2012/12/12bAnimals *Environmental Exposure Fishes/metabolism Food Chain Humans Mercury Poisoning, Nervous System/etiology Methylmercury Compounds/chemistry/*metabolism/toxicity Neurons/drug effects Oxidative Stress/drug effects Public Health Reproduction/drug effects Thymocytes/cytology/drug effects Epidemiology Health effect Human exposure Methylmercury ToxicityNovMethylmercury is a hazardous substance that is of interest with regard to environmental health, as inorganic mercury circulating in the general environment is dissolved into freshwater and seawater, condensed through the food chain, ingested by humans, and consequently affects human health. Recently, there has been much interest and discussion regarding the toxicity of methylmercury, the correlation with fish and shellfish intake, and methods of long-term management of the human health effects of methylmercury. What effects chronic exposure to a low concentration of methylmercury has on human health remains controversial. Although the possibility of methylmercury poisoning the heart and blood vessel system, the reproductive system, and the immune system is continuously raised and discussed, and the carcinogenicity of methylmercury is also under discussion, a clear conclusion regarding the human health effects according to exposure level has not yet been drawn. The Joint FAO/WHO Expert Committee on Food Additives proposed to prepare additional fish and shellfish intake recommendations for consumers based on the quantified evaluation of the hazardousness of methylmercury contained in fish and shellfish, methylmercury management in the Korea has not yet caught up with this international trend. Currently, the methylmercury exposure level of Koreans is known to be very high. The starting point of methylmercury exposure management is inorganic mercury in the general environment, but food intake through methylation is the main exposure source. Along with efforts to reduce mercury in the general environment, food intake management should be undertaken to reduce the human exposure to methylmercury in Korea.Hhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514465/pdf/jpmph-45-353.pdf2233-4521 Hong, Young-Seoub Kim, Yu-Mi Lee, Kyung-Eun Journal Article Research Support, Non-U.S. Gov't Review Korea (South) J Prev Med Public Health. 2012 Nov;45(6):353-63. doi: 10.3961/jpmph.2012.45.6.353. Epub 2012 Nov 29. 1975-8375 Pmc3514465FJournal of preventive medicine and public health = Yebang Uihakhoe chi23230465WDepartment of Preventive Medicine, Dong-A Un|<5"%Koizumi, A. Dobashi, Y. Tachibana, Y.1979F[Chromosome changes induced by industrial chemicals (author's transl)]3-10 Sangyo Igaku211 1979/01/01Adult Animals Benzene/*toxicity *Chromosome Aberrations Cytogenetics Environmental Exposure Female Humans Male Metals/toxicity Mice Occupational Diseases/*chemically induced/genetics Occupational Medicine Rabbits Rats Styrenes/toxicity Vinyl Chloride/toxicityJanURadiation-induced chromosome damage has been widely recognized and intensively studied. Recently, attention is placed on chromosome changes induced by various industrial chemicals. In case of occupational exposure to ionizing radiation, chromosome breaks are characterized as one of the most sensitive biological effects. Chromosome breaks among industrial workers who dealt with benzene, vinyl chloride monomer or styrene have also been reported. Moreover, relationship between chromosome changes and exposure to environmental lead, cadmium and mercury compounds have been studied. Ionizing radiation, benzene and vinyl chloride monomer are known also as industrial carcinogens and attention is now placed on carcinogenicity of clastogens or chromosome breaking agents. In the present paper, our studies on in vitro chromosome breakage induced by benzene and its metabolites as well as cadmium, lead, and chromium compounds are reviewed. Also, inhibition of repair of radiation-induced chromosome breaks by clastogens is reported. Significance of cytogenetic studies in industrial medicine is also discussed.sKoizumi, A Dobashi, Y Tachibana, Y English Abstract Journal Article Review Japan Sangyo Igaku. 1979 Jan;21(1):3-10.0047-1879 (Print) 0047-18793Sangyo igaku. Japanese journal of industrial health381735NLMjpn '~45# Kazantzis, G.1981bRole of cobalt, iron, lead, manganese, mercury, platinum, selenium, and titanium in carcinogenesis143-61Environ Health Perspect40 1981/08/01,Animals Cobalt/adverse effects Environmental Exposure Humans Iron/adverse effects Lead/adverse effects Manganese/adverse effects Mercury/adverse effects Metals/*adverse effects Mutagenicity Tests Neoplasms/*chemically induced Platinum/adverse effects Selenium/adverse effects Titanium/adverse effectsAuguThe possible carcinogenicity of cobalt, iron, lead, manganese, mercury, platinum, selenium, and titanium is reviewed, taking into account epidemiological data, the results of animal experimental studies, data on mutagenic effects and on other in vitro test systems. Of the great variety of occupations where exposure to one of these metals may occur, only haematite mining has been clearly shown to involve an increased human cancer risk. While the possibility that haematite might in some way act as a carcinogen has to be taken into consideration it is more likely that other carcinogens are responsible. Certain platinum coordination complexes are used in cancer chemotherapy, are mutagenic, and likely to be carcinogenic. Cobalt, its oxide and sulfide, certain lead salts, one organomanganese, and one organotitanium compound have been shown to have a limited carcinogenic effect in experimental animal studies, and except for titanium appear to be mutagenic. Certain mercury compounds are mutagenic but none have been shown to be carcinogenic. The presently available data are inadequate to assess the possible carcinogenicity of selenium compounds, but a few observations suggest that selenium may suppress the effect of other carcinogens administered to experimental animals and may even be associated with lower cancer mortality rates in man. Epidemiological observations are essential for the assessment of a human cancer risk, but the difficulty in collecting past exposure data in occupational groups and the complexity of multiple occupational exposures with changes over time, limits the usefulness of retrospective epidemiological studies.Mhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1568837/pdf/envhper00467-0145.pdf^Kazantzis, G Journal Article Review United states Environ Health Perspect. 1981 Aug;40:143-61.0091-6765 ~<5$ Boffetta, P.1993wCarcinogenicity of trace elements with reference to evaluations made by the International Agency for Research on Cancer67-70Scand J Work Environ Health 19 Suppl 1 1993/01/01hHumans International Agencies Neoplasms/*chemically induced/epidemiology Trace Elements/*adverse effectskThe monograph program of the International Agency for Research of on Cancer has evaluated many trace elements for their carcinogenicity to humans. Five groups of compounds were considered human carcinogens: arsenic and arsenic compounds, beryllium and beryllium compounds, cadmium and cadmium compounds, hexavalent chromium compounds, and nickel compounds. Antimony trioxide, cobalt and cobalt compounds, lead and inorganic lead compounds, methylmercury compounds, and metallic nickel were considered possibly carcinogenic to humans. Antimony trisulfide, trivalent chromium compounds, metallic chromium, ferric oxide, organolead compounds, metallic mercury, inorganic mercury compounds, selenium and selenium compounds, and titanium dioxide were not classifiable. Trace elements studied to a limited extent include copper, manganese, tin, vanadium, and zinc. Among the problems are the lack of relevant data, the definition of active species, the extrapolation of the results of experimental studies to humans, the methodological problems of epidemiologic studies, and the possible anticarcinogenic activity of some trace elements.^Boffetta, P Journal Article Review Finland Scand J Work Environ Health. 1993;19 Suppl 1:67-70.0355-3140 (Print) 0355-31402Scandinavian journal of work, environment & health8159977:International Agency for Research on Cancer, Lyon, France.NLMeng [|<5%FDieter, M. P. Boorman, G. A. Jameson, C. W. Eustis, S. L. Uraih, L. C.1992tDevelopment of renal toxicity in F344 rats gavaged with mercuric chloride for 2 weeks, or 2, 4, 6, 15, and 24 months319-40J Toxicol Environ Health364 1992/08/019Acid Phosphatase/urine Alkaline Phosphatase/urine Animals Aspartate Aminotransferases/urine Body Weight/drug effects Brain Chemistry Dose-Response Relationship, Drug Drug Administration Routes Female Hyperparathyroidism/chemically induced Kidney/anatomy & histology/chemistry/drug effects Kidney Diseases/*chemically induced/enzymology/metabolism Leucyl Aminopeptidase/urine Liver/chemistry Male Mercuric Chloride/pharmacokinetics/*toxicity Mercury/analysis Organ Size/drug effects Rats Rats, Inbred F344 Time Factors Tissue Distribution gamma-Glutamyltransferase/urineAuglBoth sexes of F344 rats were gavaged with maximal tolerated doses of mercuric chloride for periods from 2 wk to up to 2 yr to investigate chronic nephrotoxicity and potential carcinogenicity. The toxicity of mercuric chloride was excessive after 2 wk of exposure to doses ranging from 1.25 to 20 mg/kg, compromising renal function by selectively destroying cells of the proximal tubules, and eliciting marked elevations in urinary biomarker enzymes diagnostic for acute renal tubule necrosis. In the 2-wk studies, urinary alkaline phosphatase and aspartate amino-transferase were most sensitive to renal mercury toxicity among a panel of six enzymes, exhibiting twofold increases above controls at the 5.0 mg/kg dose, before changes in the other enzymes occurred. Urinary lactate dehydrogenase was the most responsive enzyme, with up to 11-fold increases in activity above controls. In response to mercuric chloride exposure of 5.0 mg/kg for 2-6 mo, the greatest and most persistent increases in elevation of urinary enzyme activities were exhibited by alkaline phosphatase and gamma-glutamyl transferase, which increased two-to threefold above controls. At this interval, the maximal severity of the renal lesions in both sexes of rats was graded as minimal to mild. Beyond 6 mo none of the urinary enzymes measured in this study was adequate as biomarkers of nephrotoxicity, although the severity of the renal lesions had progressed. Mercury accumulated in a dose-related fashion primarily in the kidney, and to a lesser extent in the liver. The severity of the renal lesions was increased by continued exposure to mercuric chloride, as tissue concentrations of mercury rose in proportion to dose. Mercuric chloride treatment for 2 yr clearly exacerbated the severity of the spontaneous nephrotoxicity prevalent in aging F344 rats. The excessive mortality that occurred in the male rats was probably due to a combination of these factors. No renal tumors were detected in rats, possibly because the potential for their development was reduced; however, direct tissue contact with mercury induced squamous-cell papillomas of the forestomach in both sexes.<http://www.tandfonline.com/doi/abs/10.1080/15287399209531642Dieter, M P Boorman, G A Jameson, C W Eustis, S L Uraih, L C Comparative Study Journal Article United states J Toxicol Environ Health. 1992 Aug;36(4):319-40.0098-4108 (Print) 0098-4108.Journal of toxicology and environmental health1354752National Institutes of Health, National Institute of Environmental Health Sciences, Research Triang|<5&(De Flora, S. Bennicelli, C. Bagnasco, M.1994+Genotoxicity of mercury compounds. A review57-79 Mutat Res3171 1994/02/01=Animals Humans Mercury Compounds/*toxicity Mutagens/*toxicityFebThis article reviews literature data concerning the genotoxicity of 29 mercury-containing agents, including laboratory compounds as well as ingredients of preparations used as fungicides, dyes, disinfectants and drugs. A variety of genetic end-points were investigated in bacteria, yeasts, moulds, plants, insects, cultured cells from fishes, rodents or humans, aquatic organisms, amphibians, mammalia and exposed humans. The overall evaluation is quite complex. Mercury compounds failed to induce point mutations in bacteria but often exerted clastogenic effects in eukaryotes, especially by binding SH groups and acting as spindle inhibitors, thereby causing c-mitosis and consequently aneuploidy and/or polyploidy. Inorganic mercury compounds were also found to induce the generation of reactive oxygen species and glutathione depletion in cultured mammalian cells. Although different mercury compounds tended to produce qualitatively comparable genetic effects, which suggests the involvement of a common toxic entity, methylmercury derivatives and other ionizable organomercury compounds were more active in short-term tests than either non-ionizable mercury compounds (e.g., dimethylmercury) or inorganic mercury salts (e.g., mercuric chloride). The results of cytogenetic monitoring in peripheral blood lymphocytes of individuals exposed to elemental mercury or mercury compounds from accidental, occupational or alimentary sources were either negative or borderline or uncertain as to the actual role played by mercury in some positive findings. Both genotoxic and non-genotoxic mechanisms may contribute to the renal carcinogenicity of mercury, which so far has been convincingly demonstrated only in male rodents treated with methylmercury chloride.jDe Flora, S Bennicelli, C Bagnasco, M Journal Article Review Netherlands Mutat Res. 1994 Feb;317(1):57-79.0027-5107 (Print) 0027-5107Mutation research7507573IInstitute of Hygiene and Preventive Medicine, University of Genoa, Italy.NLMeng |<5'Moszczynski, P.19971Mercury compounds and the immune system: a review247-58Int J Occup Med Environ Health103 1997/01/01Animals Environmental Exposure/adverse effects Immune System/*drug effects Leukocytes, Mononuclear Mercury Compounds/*adverse effects_This article reviews the literature data concerning the immunologic monitoring of animals and cell cultures exposed to mercury compounds. Mercury is present in nature as metallic mercury, mono- and bivalent inorganic compounds, and organic alkyl, aryl and alloxy-alkyl compounds. Methylmercury is most important in terms of environmental exposure while metallic mercury is the most common form to which workers are exposed. The database on immune function disturbances in human induced by mercury compounds is limited. Immunotoxicity assessment in animals, mainly in rodents, with subsequent extrapolation to man, is the basis of human risk assessment. The strength of in vitro immunotoxicity testing lies in studies aimed at unravelling mechanisms of immunotoxicity. These experimental investigations show clearly that mercury compounds can have immunomodulating activity. Mercuric chloride and methylmercury inhibit most of animal and human lymphocyte functions including proliferation, expression of cell activation markers on cell surface and cytokine production. These cells exhibit a greater sensitivity to the immunotoxic effects of methylmercury than to mercuric chloride. Repeated administration of mercuric chloride to rats, mice and rabbits can induce autoimmune response and a membranous nephropathy. In contrast, Lewis rats injected with mercuric chloride do not develop autoimmunity but exhibit immunosuppression. The immunosuppressive effects associated with exposure to chemical substances are often accompanied by increased susceptibility to challenge with infectious agents or tumour cells. Only few reports are available on animal studies of increased mortality connected with exposure to mercury compounds and challenge with infectious agents. It is difficult to establish a relationship between the observed immunomodulatory properties of mercury compounds and their possible carcinogenicity. In fact, the epidemiological studies performed so far failed to bring any conclusive evidence of carcinogenicity of mercury in animal experiments. The induction of renal tumours in male rodents by methylmercury was observed only._Moszczynski, P Journal Article Review Poland Int J Occup Med Environ Health. 1997;10(3):247-58.1232-1087 (Print) 1232-1087GInternational journal of occupational medicine and environmental health9524402<Regional Hospital Immunological Laboratory, Brzesko, Poland.NLMeng |<5(Boffetta, P. Garcia-Gomez, M. Pompe-Kirn, V. Zaridze, D. Bellander, T. Bulbulyan, M. Caballero, J. D. Ceccarelli, F. Colin, D. Dizdarevic, T. Espanol, S. Kobal, A. Petrova, N. Sallsten, G. Merler, E.1998/Cancer occurrence among European mercury miners591-9Cancer Causes Control96 1999/04/03Carcinogens/*adverse effects Cohort Studies Europe/epidemiology Female Follow-Up Studies Humans Male Mercury/*adverse effects *Mining Neoplasms/chemically induced/*mortality Occupational Diseases/chemically induced/*mortality Occupational Exposure/*adverse effectsDec`OBJECTIVES: To study the carcinogenicity of inorganic mercury in humans. METHODS: We studied the mortality from cancer among 6784 male and 265 female workers of four mercury mines and mills in Spain, Slovenia, Italy and the Ukraine. Workers were employed between the beginning of the century and 1990; the follow-up period lasted from the 1950s to the 1990s. We compared the mortality of the workers with national reference rates. RESULTS: Among men, there was no overall excess cancer mortality; an increase was observed in mortality from lung cancer (standardized mortality ratio [SMR] 1.19, 95 percent confidence interval [CI] 1.03-1.38) and liver cancer (SMR 1.64, CI 1.18-2.22). The increase in lung cancer risk was restricted to workers from Slovenia and the Ukraine: no relationship was found with duration of employment or estimated mercu ry exposure. The increase in liver cancer risk was present both among miners and millers and was stronger in workers from Italy and Slovenia: there was a trend with estimated cumulative exposure but not with duration of employment, and the excess was not present in a parallel analysis of cancer incidence among workers from Slovenia. No increase was observed for other types of cancer, including brain and kidney tumours. Among female workers (Ukraine only), three deaths occurred from ovarian cancer, likely representing an excess. CONCLUSIONS: Exposure to inorganic mercury in mines and mills does not seem strongly associated with cancer risk, with the possible exception of liver cancer; the increase in lung cancer may be explained by co-exposure to crystalline silica and radon. Boffetta, P Garcia-Gomez, M Pompe-Kirn, V Zaridze, D Bellander, T Bulbulyan, M Caballero, J D Ceccarelli, F Colin, D Dizdarevic, T Espanol, S Kobal, A Petrova, N Sallsten, G Merler, E Journal Article Research Support, Non-U.S. Gov't Netherlands Cancer Causes Control. 1998 Dec;9(6):591-9.0957-5243 (Print) 0957-5243Cancer causes & control : CCC10189044vUnit of Environmental Cancer Epidemiology, International Agency for Research on Cancer, Lyon, France. boffetta@iarc.frNLMeng Fle Park, North Carolina 27709.10.1080/15287399209531642NLMeng Oo. Electronic address: pedraza@unam.mx.10.1016/j.fct.2014.04.016NLMeng  Falmouth Street, Portland, ME 04104, USA.10.1042/bst0381687Linternal-pdf://2100525670/Holmes-2010-Mechanisms of metal-induced centro.pdfNLMeng iversity College of Medicine, Busan, Korea.10.3961/jpmph.2012.45.6.353Linternal-pdf://3638200197/Hong-2012-Methylmercury exposure and health ef.pdfNLMeng ersity, Jeddah, Saudi Arabia.10.1002/ar.22485internal-pdf://3645637691/Abd El-Aziz-2012-The prenatal toxic effect of.pdf internal-pdf://0008888428/Abd El-Aziz-2012-The prenatal toxic effect of1.pdfNLMeng Fiversity, Wageningen, The Netherlands.10.1002/ijc.29277NLMeng (Print) 0091-6765 Pmc1568837!Environmental health perspectives7023929Linternal-pdf://1087334293/Kazantzis-1981-Role of cobalt, iron, lead, man.pdfNLMeng Jung-gu, Seoul 100-715, Korea. pkoedrith@gmail.com10.3390/ijms12129576Linternal-pdf://2221577954/Koedrith-2011-Advances in carcinogenic metal t.pdfNLMengUernal-pdf://0664104597/Refaat-2015-Vitamin D3 enhances the tumourici1.pdfNLMeng Trnal-pdf://0112642797/Shen-2014-Association between nonalcoholic fa1.pdfNLMeng J City, TN 37614, USA. stone@etsu.edu10.1196/annals.1331.022NLMeng4|<5)$Zhang, X. Wang, Y. Zhao, Y. Chen, X.2008CExperimental study on the estrogen-like effect of mercuric chloride143-50 Biometals212 2007/06/26 Animals Cell Line, Tumor Cell Proliferation Cyanides Estradiol/*metabolism Estrogen Receptor Modulators/*metabolism Female Humans Mercury Compounds Organ Size Ovariectomy Peroxidase/metabolism Rats Rats, Sprague-Dawley Receptors, Estrogen/*metabolism Uterus/anatomy & histology/enzymologyApr)Although mercuric chloride has toxicity on reproductive system, it is uncertain if such toxicity is induced by estrogen-like effect. To study whether mercuric chloride has the estrogen-like effect and its relevant mechanism, proliferation assay of MCF-7 human breast cancer cells, uterotrophic assay, peroxidase activity assay and estrogen receptor competitive binding assay were conducted to screen the estrogen-like effect of mercuric chloride. The MCF-7 cells proliferated in the stimulation of mercuric chloride and got to the peak at 10(-7) mol/l concentration. And this proliferation could be completely blocked by estrogenic antagonist ICI182.780. In addition, mercuric chloride could increase the weight of uterus of ovariectomized SD rats and the peroxidase activity of uterus complying with dose-effect relationship. However, mercuric chloride could not affect the binding of estradiol (E(2)) to estrogen receptor (ER). So mercuric chloride exhibits the estrogen-like effect through binding and activating ER rather than bind to ER by competing with E(2).<http://link.springer.com/article/10.1007%2Fs10534-007-9102-yZhang, Xiaojuan Wang, Yadong Zhao, Yingzheng Chen, Xiaoyu Journal Article Research Support, Non-U.S. Gov't Netherlands Biometals. 2008 Apr;21(2):143-50. Epub 2007 Jun 23.0966-0844 (Print) 0966-0844eBiometals : an international journal on the role of metal ions in biology, biochemistry, and medicine17588195MDepartment of Toxicology, Zhengzhou Universi|<5*(Wang, Y. D. Chen, X. Y. Wu, Y. M. Xu, D.2005^[Experiment study on the estrogen-like effect of compounds of mercury, chromium and manganese]49-51Wei Sheng Yan Jiu341 2005/05/03Animals Binding, Competitive Breast Neoplasms/metabolism/pathology Cell Line, Tumor Cell Proliferation/drug effects Chlorides/*pharmacology Chromium Compounds/*pharmacology Endocrine Disruptors/*pharmacology Environmental Pollutants/pharmacology Female Humans Manganese Compounds/*pharmacology Mercuric Chloride/*pharmacology Rats Rats, Sprague-Dawley Receptors, Estrogen/metabolism Sulfates/*pharmacologyJanOBJECTIVE: In order to study estrogen-like effect of compounds of Mercury, Chromium and Manganese. METHODS: Mercury Chloride, Manganese Sulfate, Chromium Chloride and Chromium trioxide were selected to perform proliferation assay of MCF-7 human breast cancer cells and binding assay of estrogen receptor for rat uterine. RESULTS: Mercury Chloride could stimulate the proliferation of MCF-7 cell, the maximal increase of MCF-7 cells was measured by Mercury Chloride at 10(-7) mol/L. The effect was blocked completely by a pure antigestrogen ICI182, 780; but Mercury Chloride could not bind to ER by competing with E2. Chromium Chloride, Chromium Trioxide and Manganese Sulfate were not able to stimulate the proliferation of MCF-7 cell and bind to ER through competing against 3H-E2 in vitro. CONCLUSION: Mercury Chloride exhibited the estrogenicity through binding and activating ER; Chromium Chloride, Chromium trioxide and Manganese Sulfate did not show any estrogenicity.Wang, Ya-Dong Chen, Xiao-Yu Wu, Yi-Ming Xu, Dong English Abstract Journal Article Research Support, Non-U.S. Gov't China Wei Sheng Yan Jiu. 2005 Jan;34(1):49-51.1000-8020 (Print) 1000-8020/Wei sheng yan jiu = Journal of hygiene research15862022GSchool of Public Health, Zhengzhou University, Zhengzhou 450052, China.NLMchi-~<5+1993|Toxicology and Carcinogenesis Studies of Mercuric Chloride (CAS No. 7487-94-7) in F344 Rats and B6C3F1 Mice (Gavage Studies)1-260!Natl Toxicol Program Tech Rep Ser408 1993/02/01Feb7,Mercuric chloride is an inorganic compound that has been used in agriculture as a fungicide, in medicine as a topical antiseptic and disinfectant, and in chemistry as an intermediate in the production of other mercury compounds. The widespread use of mercury has resulted in increased levels of mercury in rivers and lakes. Mercuric chloride was evaluated in toxicity and carcinogenicity studies because of its extensive use and its occurrence as an environmental pollutant, and because of the lack of adequate long-term rodent studies. Toxicology and carcinogenesis studies were conducted by administering mercuric chloride (greater than 99% pure) in deionized water by gavage to groups of F344 rats or B6C3F1 mice for 16 days, 6 months, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium (strains TA98, TA100, TA1535, and TA1537), in mouse lymphoma L5178Y cells, in Chinese hamster ovary cells, and in Drosophila melanogaster. 16-DAY STUDIES: Groups of five rats of each sex received 0, 1.25, 2.5, 5, 10, or 20 mg mercuric chloride/kg body weight and groups of five mice of each sex received 0, 5, 10, 20, 40, or 80 mg/kg in deionized water by gavage for 12 dose days. Two male rats in the 20 mg/kg group died in the first week, as did all male and four female mice from the 80 mg/kg group and one male mouse from the 40 mg/kg group. The final mean body weight of male rats receiving 20 mg/kg was 10% lower than that of the controls; the final mean body weight of 20 mg/kg females was 9% lower than that of the controls. Final mean body weights and body weight gains of dosed mice were similar to those of the controls. Absolute and relative kidney weights of male rats receiving 2.5 mg/kg or greater doses and of female rats administered 5 mg/kg or more were significantly greater than those of the controls. Absolute kidney weights of mice were significantly increased in all male dose groups and in the 40 mg/kg female dose group; relative kidney weights of dosed male and female mice were significantly greater than the controls. Analysis of kidney, liver, and brain tissues for mercury residues revealed that the highest mercury concentration was in the kidneys of rats and mice. Acute renal tubule nephropathy occurred in dosed rats and was slightly more severe in males than in females. Chemical-related lesions in mice included renal tubule necrosis, inflammation and necrosis of the forestomach, and necrosis of the glandular stomach. 6-MONTH STUDIES: Groups of 10 rats of each sex received 0, 0.312, 0.625, 1.25, 2.5, or 5 mg mercuric chloride/kg body weight in deionized water by gavage for 26 weeks. Groups of 10 mice of each sex received 0, 1.25, 2.5, 5, 10, or 20 mg/kg in deionized water by gavage for 26 weeks (males) or 27 weeks (females). No deaths related to mercuric chloride administration occurred in rats or mice. Mean body weight gains of male rats that received 5 mg/kg and all female rat dose groups that received 0.625 mg/kg or greater were significantly lower than the controls. The final mean body weight and body weight gain of male mice in the 20 mg/kg group were significantly lower than those of the controls; final mean body weights and body weight gains of other dosed male mice and all dosed female mice were similar to those of the controls. Absolute and relative kidney weights of all dosed male rats and of female rats that received 0.625 mg/kg or greater were significantly greater than those of the controls. In male mice, absolute kidney weights in the three highest dose groups were significantly increased; no biologically significant differences in organ weights occurred in female mice. Analysis of kidney, liver, and brain tissues for mercury residues revealed the highest mercury concentration in the kidneys of rats and mice. The severity of chronic nephropathy increased with dose in male rats. Cytoplasmic vacuolation of renal tubule epithelial cells was observed in male mice in the 5, 10, and 20 mg/kg groups. No histopathologic changes in female mice were related to chemical exposure. 2-YEAR STUDIES: Groups YEAR STUDIES: Groups of 60 rats of each sex received 0, 2.5, or 5 mg mercuric chloride/kg body weight and groups of 60 mice of each sex received 0, 5, or 10 mg/kg in deionized water by gavage 5 days per week for 2 years. The doses were based on decreased weight gains in rats receiving 10 and 20 mg/kg and the decreased weight in male mice receiving 40 mg/kg during the 16-day studies, and on the decreased weight gains and toxicity results seen in the 6-month studies. Increased absolute and relative kidney weights in rats and male mice in the 6-month studies and degenerative renal changes suggested that higher dose levels would result in inadequate survival rates for a 2-year study. 15-Month Interim Evaluations: Relative kidney weights were significantly increased in dosed rats and female mice. The severity of nephropathy was increased in male rats, but not in females. High-dose male and female rats had minimal to mild hyperplasia of the basal cell layer in the forestomach epithelium (diagnosed as acanthosis); this lesion was not found in control or low-dose rats. Male mice had an increased severity of vacuolation of the renal tubule epithelium; no chemical-related lesions occurred in the kidneys of females. The incidence of inflammation of the olfactory epithelium lining the nasal cavity increased in male and female high-dose mice. Survival, Body Weights, and Clinical Signs: Survival of dosed male rats was lower than that of the controls (26/50, 10/50, 5/50); survival of dosed female rats was similar to that of the controls (35/50, 28/49, 30/50). Although more than 60% of the mice in each dose group survived to study end, survival rates of high-dose male mice and dosed female mice were lower than those of the controls (males: 36/50, 36/50, 31/50; females: 41/50, 35/50, 31/50). The final mean body weights of high-dose male and female rats were 15% and 14% lower than controls, respectively. The mean body weight of low-dose female rats was generally similar to controls throughout the 2-year study; the mean body weight of low-dose male rats was similar to that of the control through week 89. In mice, mean body weights of all male and female dose groups were similar to those of the controls throughout the studies. Pathology Findings: Chronic nephropathy appeared to develop at an accelerated rate and led to decreased survival in both dosed male rat groups. Secondary effects of renal dysfunction in dosed male rats resulted in increased incidences of fibrous osteodystrophy of the bone, mineralization of various tissues, and parathyroid gland hyperplasia. Based on evaluations of single and step sections, the incidence of renal tubule hyperplasia was increased in high-dose male rats (control, 3/50; high-dose, 10/50), but the incidences of renal tubule adenoma in high-dose and control males were similar (4/50, 5/50). Renal tubule hyperplasia was also slightly increased in high-dose female rats (2/50, 5/50) and adenomas were seen in high-dose females, but not in controls (0/50, 2/50). Incidences of forestomach hyperplasia in rats were markedly increased in dosed males (3/49, 16/50, 35/50) and high-dose females (5/50, 5/49, 20/50). Squamous cell papillomas of the forestomach were found in 3 low-dose and 12 high-dose males and in 2 high-dose females. No squamous cell carcinomas were found. The incidence of thyroid follicular cell carcinoma was marginally increased in high-dose male rats (1/50, 2/50, 6/50). However, a corresponding increased incidence in follicular cell adenomas (1/50, 4/50, 0/50) or hyperplasia (2/50, 4/50, 2/50) in males did not occur, and the overall incidence of follicular cell neoplasms was not significantly increased (2/50, 6/50, 6/50). The incidence of nasal mucosa inflammation in male and female rats was increased in the high-dose groups (male: 9/50, 8/47, 18/50; female: 0/49, 5/49, 15/50) and may have been related to chemical administration. The incidences of mammary gland fibroadenomas were significantly decreased in dosed female rats (15/50, 5/48, 2/50). The incidence and severity of nephropathy were increased in dosed mice; secondary effects of renal dysfunction did not occur. Renal tubule hyperplasia was found in one control and two high-dose male mice. Two renal tubule adenomas and one renal tubule adenocarcinoma were seen in high-dose male mice. Additional step sections revealed focal hyperplasia in another control male; no additional renal tubule neoplasms were found in high-dose or control males. Proliferative lesions of the renal tubule epithelium were not found in female mice. The incidence of metaplasia of the olfactory epithelium increased with dose in male and female mice. No other biologically significant lesions were found. GENETIC TOXICOLOGY: Mercuric chloride was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without exogenous metabolic activation (S9). Induction of sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster did not occur when mercuric chloride was administered in feed or by injection. However, positive results were obtained in mutagenicity tests with mammalian cells. In the absence of S9, mercuric chloride induced trifluorothymidine resistance in mouse L5178Y cells and chromosomal aberrations in Chinese hamster ovary cells. In the Chinese hamster ovary cell test for induction of sister chromatid exchanges, mercuric chloride produced a negative response without S9 and a weakly positive response in the presence of S9. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of mercuric chloride in male F344 rats based on the increased incidence of squamous cell papillomas of the forestomach. Marginally increased incidences of thyroid follicular cell adenomas and carcinomas may have been related to mercuric chloride exposure. There was equivocal evidence of carcinogenic activity of mercuric chloride in female F344 rats based on two squamous cell papillomas of the forestomach. There was equivocal evidence of carcinogenic activity of mercuric chloride in male B6C3F1 mice based on the occurrences of two renal tubule adenomas and one renal tubule adenocarcinoma. There was no evidence of carcinogenic activity of mercuric chloride in female B6C3F1 mice receiving 5 or 10 mg/kg. Nonneoplastic lesions associated with exposure to mercuric chloride included increased severity of nephropathy in male rats and male and female mice. There was an increased incidence of renal tubule hyperplasia in male rats. The incidence of forestomach hyperplasia was increased in dosed male and female rats. Increased incidences of nasal mucosa inflammation were associated with mercuric chloride administration in rats. Increased incidences of olfactory epithelial metaplasia in mice were also associated with mercuric chloride administration. Synonyms: Abavit B, calochlor, corrosive sublimate, dichloromercury, mercuric bichloride, mercury chloride, mercury (II) chloride, mercury bichloride, mercury perchloride, sublimate, sulem, bichloride of mercury, corrosive mercury chloride, perchloride of mercury, mercury dichloride Trade name: Fungchexl0888-8051 National Toxicology Program Journal article Natl Toxicol Program Tech Rep Ser. 1993 Feb;408:1-260. 0888-80513National Toxicology Program technical report series12621522NLMEngIty of Henan, Zhengzhou, PR China.10.1007/s10534-007-9102-yNLMeng |<5,'Liu, L. B. Duan, C. N. Ma, Z. Y. Xu, G.2015b[Curcumin inhibited rat colorectal carcinogenesis by activating PPAR-gamma: an experimental study]471-5"Zhongguo Zhong Xi Yi Jie He Za Zhi354 2015/06/06AprOBJECTIVE: To explore the chemopreventive effect of curcumin on DMH induced colorectal carcinogenesis and the underlining mechanism. METHODS: Totally 40 Wistar rats were divided into the model group and the curcumin group by random digit table, 20 in each group. Meanwhile, a normal control group was set up (n =10). A colorectal cancer model was induced by subcutaneously injecting 20 mg/kg DMH. The tumor incidence and the inhibition rate were calculated. The effect of curcumin on the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in rat colon mucosal tissues was observed using immunohistochemistry and Western blot. HT 29 cell line were cultured and divided into a control group, the curcumin + GW9662 (2-chloro-5-nitro-N-4-phenylbenzamide) intervention group, and the curcumin group. The inhibition of different concentrations curcumin on HT29 cell line was detected using MTT. The expression of curcumin on PPARy was also detected using Western blot. RESULTS: The tumor incidence was 80. 00% (12/15 cases) in the model group, obviously higher than that of the curcumin group (58. 82%, 10/17 cases, P <0. 05). The inhibition rate of curcumin on DMH induced colorected carcinoma reached 26. 46%. Compared with the normal control group, the expression of PPARgamma protein was significantly increased in the curcumin group and the model group (P <0. 01). Compared with the model group at the same time point, the expression of PPARy protein was significantly enhanced in the curcumin group (P <0. 05). MTT analysis showed that curcumin could inhibit the proliferation of in vitro HT 29 cells in dose and time dependent manners. The expression of PPARy protein was significantly increased in the GW9662 group and the curcumin group, showing statistical difference when compared with the normal control group (P <0. 01). Compared with the GW9662 group, the expression of PPARgamma protein was significantly increased in the curcumin group (P <0. 01). CONCLUSION: Curcumin could inhibit DMH-induced rat colorectal carcinogenesis and the growth of in vitro cultured HT 29 cell line, which might be achieved by activating PPARy signal transduction pathway.Liu, Liu-bin Duan, Chang-nong Ma, Zeng-yi Xu, Gang English Abstract Journal Article China Zhongguo Zhong Xi Yi Jie He Za Zhi. 2015 Apr;35(4):471-5.1003-5370 (Print) 1003-5370Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine / Zhongguo Zhong xi yi jie he xue hui, Zhongguo Zhong yi yan jiu yuan zhu ban26043573NLMchi }  |<5-Lindblom, P. Berg, A. L. Zhang, H. Westerberg, R. Tugwood, J. Lundgren, H. Marcusson-Stahl, M. Sjogren, N. Blomgren, B. Ohman, P. Skanberg, I. Evans, J. Hellmold, H.2012qTesaglitazar, a dual PPAR-alpha/gamma agonist, hamster carcinogenicity, investigative animal and clinical studies18-32Toxicol Pathol401 2011/12/02Alkanesulfonates/*toxicity Animals Area Under Curve Carcinogenicity Tests Cell Proliferation/drug effects Cricetinae Female Gene Expression Profiling Hemangioma/chemically induced Hemangiosarcoma/chemically induced Human Umbilical Vein Endothelial Cells/drug effects Humans Immunohistochemistry Liver/drug effects/metabolism/pathology Liver Neoplasms, Experimental/*chemically induced Male PPAR alpha/*agonists PPAR gamma/*agonists Phenylpropionates/*toxicity Statistics, Nonparametric Vascular Endothelial Growth Factor A/metabolismTesaglitazar was developed as a dual peroxisome proliferator-activated receptor (PPARalpha/gamma). To support the clinical program, a hamster carcinogenicity study was performed. The only neoplastic findings possibly related to treatment with tesaglitazar were low incidences of hemangioma and hemangiosarcoma in the liver of male animals. A high-power, two-year investigative study with interim necropsies was performed to further elucidate these findings. Treatment with tesaglitazar resulted in changes typical for exaggerated PPARalpha pharmacology in rodents, such as hepatocellular hypertrophy and hepatocellular carcinoma, but not an increased frequency of hemangiosarcomas. At the highest dose level, there was an increased incidence of sinusoidal dilatation and hemangiomas. No increased endothelial cell (EC) proliferation was detected in vivo, which was confirmed by in vitro administration to ECs. Immunohistochemistry and gene expression analyses indicated increased cellular stress and vascular endothelial growth factor (VEGF) expression in the liver, which may have contributed to the sinusoidal dilatation. A two-fold increase in the level of circulating VEGF was detected in the hamster at all dose levels, whereas no effect on VEGF was observed in patients treated with tesaglitazar. In conclusion, investigations have demonstrated that tesaglitazar does not produce hemangiosarcomas in hamster despite a slight effect on vascular morphology in the liver./http://tpx.sagepub.com/content/40/1/18.full.pdfE1533-1601 Lindblom, Per Berg, Anna-Lena Zhang, Hui Westerberg, Rolf Tugwood, Jonathan Lundgren, Hanna Marcusson-Stahl, Maritha Sjogren, Niclas Blomgren, Bo Ohman, Peter Skanberg, Inger Evans, John Hellmold, Heike Journal Article United States Toxicol Pathol. 2012;40(1):18-32. doi: 10.1177/0192623311429972. Epub 2011 Nov 30. 0192-6233Toxicologic pathology22131108!AstraZeneca R V  |<5.tLee, H. S. Chang, M. Lee, J. E. Kim, W. Hwang, I. C. Kim, D. H. Park, H. K. Choi, H. J. Jo, W. Cha, S. W. Son, W. C.2014Carcinogenicity study of CKD-501, a novel dual peroxisome proliferator-activated receptors alpha and gamma agonist, following oral administration to Sprague Dawley rats for 94-101 weeks207-16Regul Toxicol Pharmacol692 2014/04/22Administration, Oral Animals Body Weight/drug effects Carcinogenicity Tests Carcinogens/administration & dosage/*toxicity Dose-Response Relationship, Drug Female Lipoma/*chemically induced/pathology Liposarcoma/*chemically induced/pathology Male PPAR alpha/*agonists PPAR gamma/*agonists Platelet Count Pyrimidines/*administration & dosage/*toxicity Rats Rats, Sprague-Dawley Thiazolidinediones/*administration & dosage/*toxicity Time Factors Ckd-501 Carcinogenicity Dual PPARalpha/gamma agonistJulCKD-501 is a peroxisome proliferator-activated receptor (PPAR) agonist. The current study was conducted in Sprague Dawley (SD) rats for 94-101 weeks to investigate the carcinogenic potential of CKD-501. 60 males received 0, 0.03, 0.12, or 1.0mg/kg/day, which was changed after 66 weeks to 0.24 mg/kg/day due to increased mortality, while 60 females received 0, 0.03, 0.06, or 0.12 mg/kg/day throughout the study period. After switching the dosage, no significant changes in the survival rates were observed. Non-neoplastic lesions such as bladder transitional cell hyperplasia and a diminished corpus luteum were observed in females administered 0.12 mg/kg/day and the right chamber dilation and left ventricular hypertrophy were increased dose dependently in both males and females. Non-neoplastic lesions such as bone marrow hypoplasia and fat cell proliferation and neoplastic lesions such as lipomas and liposarcomas observed in males and/or females were considered expected pharmacological effects for this compound. Compared to rosiglitazone, CKD-501 had a 4.4-fold higher margin of safety for tumor induction and did not cause bladder carcinoma as was observed with pioglitazone.Bhttp://www.sciencedirect.com/science/article/pii/S027323001400066X1096-0295 Lee, Hee Su Chang, Minsun Lee, Ji-Eun Kim, Woojin Hwang, In-Chang Kim, Dal-Hyun Park, Hyun-Kyu Choi, Hyun-Ji Jo, Woori Cha, Shin-Woo Son, Woo-Chan Journal Article United States Regul Toxicol Pharmacol. 2014 Jul;69(2):207-16. doi: 10.1016/j.yrtph.2014.04.003. Epub 2014 Apr 18. 0273-2300,Regulatory toxicology and pharmacology : RTP24747398bDepartment of Pathology, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. Department of Medical and Pharmaceutical Science, Sookmyung Women's University, Seoul, Republic of Korea. Department of Pathology, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea; College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea. Chong Kun Dang Research Institute, CKD Pharmaceuticals Inc., Kyunggi-do, Republic of Korea. Division of Non-clinical Studies, Korea Institute of Toxicology (KIT), Daejeon, Republic of Korea. Department of Pathology, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. El #  p|<5/9Long, G. G. Reynolds, V. L. Dochterman, L. W. Ryan, T. E.2009xNeoplastic and non-neoplastic changes in F-344 rats treated with Naveglitazar, a gamma-dominant PPAR alpha/gamma agonist741-53Toxicol Pathol376 2009/08/25Adipose Tissue/drug effects/pathology Analysis of Variance Animals Body Weight/drug effects Carcinogenicity Tests/*methods Dose-Response Relationship, Drug Female Genitalia/pathology Histocytochemistry Hyperplasia/chemically induced Male Neoplasms, Experimental/*chemically induced/pathology PPAR alpha/agonists PPAR gamma/agonists Phenylpropionates/*toxicity Rats Rats, Inbred F344 Sarcoma/chemically induced/pathology Urothelium/pathologyOctrThe carcinogenic potential of naveglitazar, a gamma-dominant peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist, was evaluated in a two-year study in F344 rats (0, 0.3, 1.0, or 3.0 mg/kg, males; 0, 0.1, 0.3, or 1.0 mg/kg, females). Increased mortality in male rats of the high-dose group was related to cardiac-associated lesions, neoplasms, and undetermined causes. Degeneration and hypertrophy of the myocardium occurred with dose-responsive increased incidence and severity. Neoplasms with increased incidence included sarcomas in male rats and urinary bladder neoplasms in female rats. Most sarcomas in male rats occurred in the adipose tissue of the subcutis and were diagnosed as fibrosarcomas, with fewer liposarcomas and other histologic types. Non-neoplastic changes in adipose tissue included expansion of adipose tissue in multiple sites, alterations in cytoplasmic vesicular pattern in brown and white fat, increases in stroma and mesenchymal cells, and fibrosis. The severity of chronic progressive nephropathy was decreased in a dose-responsive manner in males, and hyperplasia and neoplasia of the mammary gland were decreased in incidence in females. The adverse effects of cardiotoxicity and increased incidence of neoplasms occurred with dose-responsive incidence and/or severity, and a no-effect level for these effects was not achieved in this study.0http://tpx.sagepub.com/content/37/6/741.full.pdf1533-1601 Long, Gerald G Reynolds, Vincent L Dochterman, L Wayne Ryan, Thomas E Journal Article United States Toxicol Pathol. 2009 Oct;37(6):741-53. doi: 10.1177/0192623309343775. Epub 2009 Aug 21. 0192-6233Toxicologic pathology19700659QLilly Research Laboratories, Indianapolis, IN 46225, USA. L|<50/Wang, M. S. Chang, C. L. Lee, C. I. Shaw, H. M.2014trans-10,cis-12 conjugated linoleic acid specifically increases tissue alpha-tocopherol mediated by PPARgamma inhibition in mice841-7Int J Food Sci Nutr657 2014/05/21Adiponectin/blood Adipose Tissue/drug effects Animals Carrier Proteins/metabolism Gene Expression Regulation Linoleic Acids, Conjugated/chemistry/*pharmacology Liver/drug effects/metabolism Male Mice Mice, Inbred C57BL PPAR gamma/antagonists & inhibitors/genetics/*metabolism Thiazolidinediones/pharmacology Triglycerides/secretion Vitamin E/metabolism alpha-Tocopherol/*metabolism conjugated linoleic acid rosiglitazone triglyceride alpha-tocopherolNov4C57BL/6J mice were divided into control group (C), CLA, c9t11, or t10c12 groups. CLA and t10c12 significantly increased alpha-tocopherol levels in the plasma and various tissues in experiment 1. The CLA and t10c12 groups also showed a significant increase in hepatic alpha-tocopherol transfer protein (alpha-TTP) levels. In experiment 2, mice were divided into control, CLA, R (rosiglitazone, a PPARgamma agonist), or CLA+R groups. Vitamin E levels in the liver, epididymal fat pad, kidney, and plasma were increased by CLA, and this effect was reduced in the CLA+R group. t10,c12-CLA is the most active isomer in the CLA mixture in the regulation of tissue vitamin E status and alpha-TTP protein levels in mice. The increase in liver vitamin E status in CLA-fed mice is mainly due to the effect of PPARgamma inhibition.Ahttp://informahealthcare.com/doi/abs/10.3109/09637486.2014.9171501465-3478 Wang, Ming-Shyong Chang, Chia-Ling Lee, Chien-I Shaw, Huey-Mei Journal Article Research Support, Non-U.S. Gov't England Int J Food Sci Nutr. 2014 Nov;65(7):841-7. doi: 10.3109/09637486.2014.917150. Epub 2014 May 19. 0963-74864International journal of food sciences and nutrition24840024'Department of Health and Nutrition and.10.3109/09637486.2014.917150NLMeng Oectronic address: wcson@amc.seoul.kr.10.1016/j.yrtph.2014.04.003NLMeng ong_gerald_g@lilly.com10.1177/0192623309343775Linternal-pdf://3669630139/Long-2009-Neoplastic and non-neoplastic change.pdfNLMeng &D, Molndal, Sweden.10.1177/0192623311429972Linternal-pdf://3174532659/Lindblom-2012-Tesaglitazar, a dual PPAR-alpha_.pdfNLMeng"(~451?Campbell, S. E. Stone, W. L. Whaley, S. G. Qui, M. Krishnan, K.2003Gamma (gamma) tocopherol upregulates peroxisome proliferator activated receptor (PPAR) gamma (gamma) expression in SW 480 human colon cancer cell lines25 BMC Cancer3 2003/10/03>Cell Line, Tumor Colonic Neoplasms/*drug therapy/metabolism Humans RNA, Messenger/drug effects/metabolism Receptors, Cytoplasmic and Nuclear/drug effects/genetics/*metabolism Tocopherols/*pharmacology Transcription Factors/drug effects/genetics/*metabolism Tumor Cells, Cultured/drug effects Up-Regulation/drug effectsOct 1c BACKGROUND: Tocopherols are lipid soluble antioxidants that exist as eight structurally different isoforms. The intake of gamma-tocopherol is higher than alpha-tocopherol in the average US diet. The clinical results of the effects of vitamin E as a cancer preventive agent have been inconsistent. All published clinical trials with vitamin E have used alpha-tocopherol. Recent epidemiological, experimental and molecular studies suggest that gamma-tocopherol may be a more potent chemopreventive form of vitamin E compared to the more-studied alpha-tocopherol. Gamma-tocopherol exhibits differences in its ability to detoxify nitrogen dioxide, growth inhibitory effects on selected cancer cell lines, inhibition of neoplastic transformation in embryonic fibroblasts, and inhibition of cyclooxygenase-2 (COX-2) activity in macrophages and epithelial cells. Peroxisome proliferator activator receptor gamma (PPARgamma) is a promising molecular target for colon cancer prevention. Upregulation of PPARgamma activity is anticarcinogenic through its effects on downstream genes that affect cellular proliferation and apoptosis. The thiazolidine class of drugs are powerful PPARgamma ligands. Vitamin E has structural similarity to the thiazolidine, troglitazone. In this investigation, we tested the effects of both alpha and gamma tocopherol on the expression of PPARgamma mRNA and protein in SW 480 colon cancer cell lines. We also measured the intracellular concentrations of vitamin E in SW 480 colon cancer cell lines. RESULTS: We have discovered that the alpha and gamma isoforms of vitamin E upregulate PPARgamma mRNA and protein expression in the SW480 colon cancer cell lines. gamma-Tocopherol is a better modulator of PPARgamma expression than alpha-tocopherol at the concentrations tested. Intracellular concentrations increased as the vitamin E concentration added to the media was increased. Further, gamma-tocopherol-treated cells have higher intracellular tocopherol concentrations than those treated with the same concentrations of alpha-tocopherol. CONCLUSION: Our data suggest that both alpha and gamma tocopherol can upregulate the expression of PPARgamma which is considered an important molecular target for colon cancer chemoprevention. We show that the expression of PPARgamma mRNA and protein are increased and these effects are more pronounced with gamma-tocopherol. Gamma-tocopherol's ability to upregulate PPARgamma expression and achieve higher intracellular concentrations in the colonic tissue may be relevant to colon cancer prevention. We also show that the intracellular concentrations of gamma-tocopherol are several fold higher than alpha-tocopherol. Further work on other colon cancer cell lines are required to quantitate differences in the ability of these forms of vitamin E to induce apoptosis, suppress cell proliferation and act as PPAR ligands as well as determine their effects in conjunction with other chemopreventive agents. Upregulation of PPARgamma by the tocopherols and in particular by gamma-tocopherol may have relevance not only to cancer prevention but also to the management of inflammatory and cardiovascular disorders.Ihttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC222914/pdf/1471-2407-3-25.pdf1471-2407 Campbell, Sharon E Stone, William L Whaley, Sarah G Qui, Min Krishnan, Koyamangalath Journal Article Research Support, Non-U.S. Gov't England BMC Cancer. 2003 Oct 1;3:25. 1471-2407 Pmc222914 BMC cancer14521714Division of Hematology-Oncology, Department of Internal Medicine, East Tennessee State University and James H, Quillen VA Medical Center, f|<52EDavies, G. F. Khandelwal, R. L. Wu, L. Juurlink, B. H. Roesler, W. J.2001Inhibition of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by troglitazone: a peroxisome proliferator-activated receptor-gamma (PPARgamma)-independent, antioxidant-related mechanism1071-9Biochem Pharmacol628 2001/10/13Animals Antioxidants/*pharmacology Chromans/*pharmacology Gene Expression/*drug effects Hepatocytes/drug effects/metabolism Male Oxidative Stress/drug effects Phosphoenolpyruvate Carboxykinase (ATP)/*genetics Rats Rats, Sprague-Dawley Receptors, Cytoplasmic and Nuclear/*metabolism Thiazoles/*pharmacology *Thiazolidinediones Transcription Factors/*metabolism Transcription, Genetic/drug effectsOct 15Phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme of gluconeogenesis. Enhanced expression of the PEPCK gene in liver is present in most models of diabetes, and is thought to contribute to the increased hepatic glucose output seen in this disease. Recently, we showed that troglitazone, the first thiazolidinedione (TZD) used clinically, inhibits expression of the PEPCK gene in isolated hepatocytes. We have pursued the molecular mechanism whereby troglitazone exerts this inhibition. TZDs are known to bind and activate peroxisome proliferator-activated receptor-gamma (PPARgamma), a nuclear receptor, which regulates expression of target genes. Initially, we examined the abilities of three other TZDs (rosiglitazone, englitazone, and ciglitazone) to inhibit expression of the PEPCK gene. Despite the fact that these agents are ligands for PPARgamma, they displayed little if any inhibitory activity on the expression of this gene. GW1929 [N-(2-benzoyl phenyl)-l-tyrosine], another potent PPARgamma ligand that is unrelated structurally to TZDs, had no inhibitory effect on PEPCK gene expression, while a natural PPARgamma ligand, the prostaglandin metabolite 15-PGJ2 (15-deoxy-Delta(12,14)-prostaglandin J2), displayed only modest inhibitory activity. Treatment of hepatocytes with ligands for other isoforms of PPAR also had no significant effect on PEPCK gene expression. Troglitazone has an alpha-tocopherol (vitamin E) moiety that is not present in other TZDs, and treatment of hepatocytes with vitamin E led to an inhibition of PEPCK gene expression. These observations support the conclusion that troglitazone inhibits the expression of the PEPCK gene by a PPARgamma-independent, antioxidant-related mechanism.Bhttp://www.sciencedirect.com/science/article/pii/S000629520100764XDavies, G F Khandelwal, R L Wu, L Juurlink, B H Roesler, W J Journal Article Research Support, Non-U.S. Gov't England Biochem Pharmacol. 2001 Oct 15;62(8):1071-9.0006-2952 (Print) 0006-2952Biochemical pharmacology11597575rDepartment of Biochemistry, University of Saskatchewan, 107 Wiggins Road, Saskatchewan S7N 5E5, Saskatoon, Canada.NLMeng  Johnson City, TN 37614, USA. campbese@etsu.edu10.1186/1471-2407-3-25Linternal-pdf://3210401589/Campbell-2003-Gamma (gamma) tocopherol upregul.pdfNLMeng X~<53HStone, W. L. Krishnan, K. Campbell, S. E. Qui, M. Whaley, S. G. Yang, H.2004-Tocopherols and the treatment of colon cancer223-33Ann N Y Acad Sci1031 2005/03/09Animals Chemoprevention Colon/chemistry Colonic Neoplasms/*drug therapy/prevention & control Diet Gene Expression/drug effects Humans Iron, Dietary/administration & dosage Oxidative Stress/drug effects PPAR gamma/genetics Proto-Oncogene Proteins p21(ras)/analysis Rats Tocopherols/*therapeutic use Tumor Cells, Cultured alpha-Tocopherol/administration & dosage gamma-Tocopherol/administration & dosageDecColorectal cancer is the second most common cause of cancer deaths in the United States. Vitamin E (VE) and other antioxidants may help prevent colon cancer by decreasing the formation of mutagens arising from the free radical oxidation of fecal lipids or by "non-antioxidant" mechanisms. VE is not a single molecule, but refers to at least eight different molecules, that is, four tocopherols and four tocotrienols. METHODS: Both animal models and human colon cancer cell lines were used to evaluate the chemopreventive potential of different forms of VE. Rats were fed diets deficient in tocopherols or supplemented with either alpha-tocopherol or gamma-tocopherol. Half the rats in each of these groups received normal levels of dietary Fe and the other half Fe at eight times the normal level. In our cell experiments, we looked at the role of gamma-tocopherol in upregulating peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in the SW 480 human cell line. RESULTS: Rats fed the diets supplemented with alpha-tocopherol had higher levels of VE in feces, colonocytes, plasma, and liver than did rats fed diets supplemented with gamma-tocopherol. Dietary Fe levels did not influence tocopherol levels in plasma, liver, or feces. For colonocytes, high dietary Fe decreased tocopherol levels. Rats fed the gamma-tocopherol-supplemented diets had lower levels of fecal lipid hydroperoxides than rats fed the alpha-tocopherol-supplemented diets. Ras-p21 levels were significantly lower in rats fed the gamma-tocopherol-supplemented diets compared with rats fed the alpha-tocopherol-supplemented diets. High levels of dietary Fe were found to promote oxidative stress in feces and colonocytes. Our data with the SW480 cells suggest that both alpha- and gamma-tocopherol upregulate PPAR-gamma mRNA and protein expression. gamma-tocopherol was, however, found to be a better enhancer of PPAR-gamma expression than alpha-tocopherol at the concentrations tested.Chttp://onlinelibrary.wiley.com/doi/10.1196/annals.1331.022/abstractStone, William L Krishnan, Koyamangalath Campbell, Sharon E Qui, Min Whaley, Sarah G Yang, Hongsong Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review United States Ann N Y Acad Sci. 2004 Dec;1031:223-33.0077-8923 (Print) 0077-8923*Annals of the New York Academy of Sciences15753148East Tennessee State University, James H. Quillen College of Medicine, Department of Pediatrics, Johnson City, TN 37614, USA. stone@etsu.edu10.1196/annals.1331.022NLMeng?4Cell, B1983iEnterocyte-like differentiation and polarization of the human colon carcinoma cell line Caco-2 in culture323-330 Biol. Cell47?5DO’Brien, Catherine A Pollett, Aaron Gallinger, Steven Dick, John E2007UA human colon cancer cell capable of initiating tumour growth in immunodeficient mice106-110Nature4457123 0028-0836 cu|<56BDreyer, C. Krey, G. Keller, H. Givel, F. Helftenbein, G. Wahli, W.1992`Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors879-87Cell685 1992/03/06Acyl-CoA Oxidase Amino Acid Sequence Animals Base Sequence Enzyme Induction Fatty Acids/*metabolism Gene Expression Regulation/genetics Microbodies/*metabolism Molecular Sequence Data Oxidation-Reduction Oxidoreductases/*biosynthesis/genetics RNA, Messenger/analysis Receptors, Cell Surface/*biosynthesis/drug effects/*genetics *Receptors, Cytoplasmic and Nuclear Sequence Alignment Transcription Factors/biosynthesis/*genetics Xenopus laevis/*geneticsMar 6yThree novel members of the Xenopus nuclear hormone receptor superfamily have been cloned. They are related to each other and similar to the group of receptors that includes those for thyroid hormones, retinoids, and vitamin D3. Their transcriptional activity is regulated by agents causing peroxisome proliferation and carcinogenesis in rodent liver. All three Xenopus receptors activate the promoter of the acyl coenzyme A oxidase gene, which encodes the key enzyme of peroxisomal fatty acid beta-oxidation, via a cognate response element that has been identified. Therefore, peroxisome proliferators may exert their hypolipidemic effects through these receptors, which stimulate the peroxisomal degradation of fatty acids. Finally, the multiplicity of these receptors suggests the existence of hitherto unknown cellular signaling pathways for xenobiotics and putative endogenous ligands.http://www.cell.com/cell/abstract/0092-8674(92)90031-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2F0092867492900317%3Fshowall%3DtrueDreyer, C Krey, G Keller, H Givel, F Helftenbein, G Wahli, W Comparative Study Journal Article Research Support, Non-U.S. Gov't United states Cell. 199|<57Issemann, I. Green, S.1990^Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators645-50Nature3476294 1990/10/18Amino Acid Sequence Animals Base Sequence Binding Sites Cloning, Molecular DNA/metabolism Gene Expression/drug effects Humans Hypolipidemic Agents/adverse effects/*pharmacology Liver/*ultrastructure Liver Neoplasms, Experimental/chemically induced Mice Microbodies/*drug effects/ultrastructure Molecular Sequence Data Nafenopin/pharmacology Receptors, Estrogen/genetics/metabolism Receptors, Glucocorticoid/genetics/metabolism Receptors, Steroid/drug effects/genetics/*metabolism Sequence Homology, Nucleic Acid Tissue DistributionOct 18We have cloned a member of the steroid hormone receptor superfamily of ligand-activated transcription factors. The receptor homologue is activated by a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes. Identification of a peroxisome proliferator-activated receptor should help elucidate the mechanism of the hypolipidaemic effect of these hepatocarcinogens and aid evaluation of their potential carcinogenic risk to man.Ahttp://www.nature.com/nature/journal/v347/n6294/abs/347645a0.htmldIssemann, I Green, S Comparative Study Journal Article England Nature. 1990 Oct 18;347(6294):645-50.0028-0836 (Print) 0028-0836Nature2129546aImperial Chemical Industries PLC, Central Toxicology Laboratory, Alderley Park, Macclesfield, UK.10.1038/347645a0NLMeng '[|458rLiu, S. H. Shen, C. C. Yi, Y. C. Tsai, J. J. Wang, C. C. Chueh, J. T. Lin, K. L. Lee, T. C. Pan, H. C. Sheu, M. L.2010Honokiol inhibits gastric tumourigenesis by activation of 15-lipoxygenase-1 and consequent inhibition of peroxisome proliferator-activated receptor-gamma and COX-2-dependent signals1963-72Br J Pharmacol1608 2010/07/24Animals Antineoplastic Agents, Phytogenic/*pharmacology Apoptosis/drug effects Arachidonate 15-Lipoxygenase/genetics/*metabolism Biphenyl Compounds/*pharmacology Blotting, Western Cell Line, Tumor Cell Survival/drug effects Cyclooxygenase 2/genetics/*metabolism Cyclooxygenase Inhibitors/pharmacology Dose-Response Relationship, Drug Enzyme Activation Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Humans Lignans/*pharmacology Linoleic Acids/metabolism Male Mice Mice, Inbred BALB C Mice, Nude PPAR gamma/genetics/*metabolism RNA Interference Reverse Transcriptase Polymerase Chain Reaction Signal Transduction/*drug effects Stomach Neoplasms/*drug therapy/enzymology/genetics/pathology Time Factors Tumor Burden/drug effects Xenograft Model Antitumor AssaysAugBACKGROUND AND PURPOSE: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), COX-2 and 15-lipoxygenase (LOX)-1 have been shown to be involved in tumour growth. However, the roles of PPAR-gamma, COX-2 or 15-LOX-1 in gastric tumourigenesis remain unclear. Here, we investigate the role of 15-LOX-1 induction by honokiol, a small-molecular weight natural product, in PPAR-gamma and COX-2 signalling during gastric tumourigenesis. EXPERIMENTAL APPROACH: Human gastric cancer cell lines (AGS, MKN45, N87 and SCM-1) were cultured with or without honokiol. Gene and protein expressions were analysed by RT-PCR and Western blotting respectively. Small interfering RNAs (siRNAs) for COX-2, PPAR-gamma and 15-LOX-1 were used to interfere with the expressions of these genes. A xenograft gastric tumour model in mouse was used for in vivo study. KEY RESULTS: PPAR-gamma and COX-2 proteins were highly expressed in gastric cancer cells. Inhibitors, or siRNA for COX-2 or PPAR-gamma, significantly decreased cell viability. Honokiol markedly inhibited PPAR-gamma and COX-2 expressions in gastric cancer cells and tumours of xenograft mice, and induced apoptosis and cell death. Honokiol markedly activated cellular 15-LOX-1 expression and 13-S-hydroxyoctadecadienoic acid (a primary product of 15-LOX-1 metabolism of linoleic acid) production. 15-LOX-1 siRNA could reverse the honokiol-induced down-regulation of PPAR-gamma and COX-2, and cell apoptosis. 15-LOX-1 was markedly induced in tumours of xenograft mice treated with honokiol. CONCLUSIONS AND IMPLICATIONS: These findings suggest that induction of 15-LOX-1-mediated down-regulation of a PPAR-gamma and COX-2 pathway by honokiol may be a promising therapeutic strategy for gastric cancer.Hhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958642/pdf/bph0160-1963.pdf*1476-5381 Liu, Shing Hwa Shen, Chin Chang Yi, Yu Chiao Tsai, Jaw Ji Wang, Chih Chien Chueh, Ju Ting Lin, Keh Liang Lee, Tso Ching Pan, Hung Chuan Sheu, Meei Ling Journal Article Research Support, Non-U.S. Gov't England Br J Pharmacol. 2010 Aug;160(8):1963-72. doi: 10.1111/j.1476-5381.2010.00804.x. 0007-1188 Pmc2958642British journal of pharmacology20649594(In  '\L|4595Aggarwal, B. B. Sundaram, C. Prasad, S. Kannappan, R.2010hTocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases1613-31Biochem Pharmacol8011 2010/08/110Animals Antineoplastic Agents/*therapeutic use Antioxidants/chemistry/pharmacokinetics/therapeutic use Chronic Disease Drug Delivery Systems/trends Humans Neoplasms/metabolism/*prevention & control Tocotrienols/chemistry/pharmacology/*therapeutic use Vitamin E/chemistry/pharmacokinetics/*therapeutic useDec 1^Initially discovered in 1938 as a "fertility factor," vitamin E now refers to eight different isoforms that belong to two categories, four saturated analogues (alpha, beta, gamma, and delta) called tocopherols and four unsaturated analogues referred to as tocotrienols. While the tocopherols have been investigated extensively, little is known about the tocotrienols. Very limited studies suggest that both the molecular and therapeutic targets of the tocotrienols are distinct from those of the tocopherols. For instance, suppression of inflammatory transcription factor NF-kappaB, which is closely linked to tumorigenesis and inhibition of HMG-CoA reductase, mammalian DNA polymerases and certain protein tyrosine kinases, is unique to the tocotrienols. This review examines in detail the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes, and cardiovascular and neurological diseases at both preclinical and clinical levels. As disappointment with the therapeutic value of the tocopherols grows, the potential of these novel vitamin E analogues awaits further investigation.Ghttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956867/pdf/nihms230562.pdf`1873-2968 Aggarwal, Bharat B Sundaram, Chitra Prasad, Seema Kannappan, Ramaswamy CA-124787-01A2/CA/NCI NIH HHS/United States CA-16 672/CA/NCI NIH HHS/United States P01 CA091844/CA/NCI NIH HHS/United States P01 CA091844-010004/CA/NCI NIH HHS/United States P01 CA091844-020004/CA/NCI NIH HHS/United States P01 CA124787/CA/NCI NIH HHS/United States P01 CA124787-01A20002/CA/NCI NIH HHS/United States P01 CA124787-020002/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Review England Biochem Pharmacol. 2010 Dec 1;80(11):1613-31. doi: 10.1016/j.bcp.2010.07.043. Epub 2010 Aug 7. 0006-2952 Pmc2956867Biochemical pharmacology20696139 Nihms230562Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 143, Houst Qvstitute of Toxicology, Taipei, Taiwan. 10.1111/j.1476-5381.2010.00804.xinter Qvon, TX 77030, USA. aggarwal@mdanderson.org10.1016/j.bcp.2010.07.043internal?:3Krishnan, Anand Nair, S Asha Pillai, M Radhakrishna2007BBiology of PPARγ in cancer: a critical review on existing lacunae532-540Current molecular medicine76 1566-5240-?;0Hafner, Christian Reichle, Albrecht Vogt, Thomas2005New indications for established drugs: combined tumor-stroma-targeted cancer therapy with PPARγ agonists, COX-2 inhibitors, mTOR antagonists and metronomic chemotherapy393-419Current cancer drug targets56 1568-0096uF<5<0Bottino, C. Vazquez, M. Devesa, V. Laforenza, U.2015ZImpaired aquaporins expression in the gastrointestinal tract of rat after mercury exposureJ Appl Toxicol 2015/04/10Waquaporins colon inorganic mercury methylmercury small intestine stomach water channelsApr 8%The main route of exposure to mercury in humans is through the diet. Consequently, the gastrointestinal mucosa is exposed to the mercurial forms, where they cause intestinal fluid accumulation, mucosal injuries and diarrhea. The relationship between inorganic mercury (HgCl2 ) and methylmercury (CH3 HgCl) exposure and water movement in the gastrointestinal tract is still unexplored. The leading role of aquaporins (AQPs) in the rapid bidirectional movement of fluid in the gastrointestinal tract of mammals is well established. The present study evaluates the effect of HgCl2 and CH3 HgCl exposure on AQP expression in different portions of the gastrointestinal tract of rats treated by gavage (5 mg kg-1 of mercury species, single dose, 4 days). The results show that mercury species reduce mRNA and protein levels of AQPs in different parts of the gastrointestinal tract. In the stomach, treated rats show a significant reduction of expression of AQP3 (80-90% for mRNA and 50% for protein) and AQP4 (95-99% for mRNA and 20-40% for protein). In the small and large intestine, treated rats experience a significant reduction of AQP3 and AQP7 expression. Protein contents of both AQPs are reduced in similar proportions in jejunum (AQP3: 40-50%; AQP7: 45-50%) and colon (AQP3: 35-40%; AQP7: 45-60%), regardless of the treatment. Our results indicate that some AQPs are downregulated in the rat gastrointestinal tract by mercury exposure, suggesting a possible role of AQPs in the development of mercury gastrointestinal symptoms. Copyright (c) 2015 John Wiley & Sons, Ltd.<http://onlinelibrary.wiley.com/doi/10.1002/jat.3151/abstract1099-1263 Bottino, Cinzia Vazquez, Marta Devesa, Vicenta Laforenza, Umberto Journal article J Appl Toxicol. 2015 Apr 8. doi: 10.1002/jat.3151. 0260-437x#Journal of applied toxicology : JAT25854323[Department of Molecular Medicine, Human Physiolog|<5=@Reddy, G. U. Ramu, V. Roy, S. Taye, N. Chattopadhyay, S. Das, A.2014A specific probe for Hg(2)(+) to delineate even H(+) in pure aqueous buffer/Hct116 colon cancer cells: Hg(II)-eta(2)-arene pi-interaction and a TBET-based fluorescence response14421-4Chem Commun (Camb)5092 2014/10/11Biological Transport Buffers Cell Survival/drug effects Colonic Neoplasms Energy Transfer Fluorescent Dyes/*chemistry/pharmacology HCT116 Cells Humans Hydrogen/chemistry Mercury/*analysis/chemistry/metabolismNov 28A new molecular probe that demonstrates a distinct TBET process, induced by the Hg(II)-eta(2)-arene pi-interaction, in pure aqueous medium with a large pseudo-Stokes shift of 200 nm.1364-548x Reddy G, Upendar Ramu, Vadde Roy, Sovan Taye, Nandaraj Chattopadhyay, Samit Das, Amitava Journal Article Research Support, Non-U.S. Gov't England Chem Commun (Camb). 2014 Nov 28;50(92):14421-4. doi: 10.1039/c4cc06740a. 1359-7345,Chemical communications (Cambridge, England)25300300dOrganic Chemistry Division, CSIR-National Chemical Laboratory, Pune-411008, India. a.das@ncl.res.in.10.1039/c4cc06740aNLMeng 9|<5>Bohme, M. Diener, M. Rummel, W.1992NChloride secretion induced by mercury and cadmium: action sites and mechanisms295-301Toxicol Appl Pharmacol1142 1992/06/01Animals Arachidonic Acid/metabolism Binding Sites Cadmium/*pharmacology Cell Membrane/drug effects/physiology Chlorides/*physiology Colon/cytology/drug effects/physiology Dithiothreitol/pharmacology Epithelium/drug effects/physiology Female In Vitro Techniques Intestinal Mucosa/drug effects/physiology/secretion Membrane Potentials/drug effects Mercury/*pharmacology Neurons/drug effects/metabolism/physiology Rats Rats, Inbred Strains Sulfhydryl Compounds/pharmacologyJunNThe actions of two mercury compounds, HgCl2 and methyl mercury chloride (MeHg), and of CdCl2 on the epithelium of the rat colon were studied with the whole-cell patch-clamp technique and the Ussing chamber. MeHg (50 microM) induced an increase of membrane outward current (I(out)) in enterocytes of isolated crypts patched from the basolateral side. This action was inhibited by a Cl- channel blocker and a K+ channel blocker, indicating an increase of both the Cl- and the K+ conductance. In contrast, HgCl2 (50 microM) did not affect I(out), whereas CdCl2 (50 microM) decreased it slightly. In mucosal preparations all three compounds induced a concentration-dependent increase in short-circuit current (Isc) when administered to the serosal, i.e., contraluminal side. Sensitivity to chloride transport blockers and anion replacement experiments revealed that the increase in Isc represented Cl- secretion. In contrast to the actions of luminally applied mercury compounds, the increase of tissue conductance (Gt) was only small. Tetrodotoxin and indomethacin suppressed the effect of the metal compounds on Isc and Gt, while atropine diminished it only partly. This indicates that the secretory action of these heavy metals has not only a direct effect on epithelial cells but is also mediated by prostaglandins and cholinergic and noncholinergic neurons.Bohme, M Diener, M Rummel, W Journal Article Research Support, Non-U.S. Gov't United states Toxicol Appl Pharmacol. 1992 Jun;114(2):295-301.0041-008X (Print) 0041-008x#Toxicology and applied pharmacology1609422^Institut fur Pharmakologie und Toxikologie, Universitat des Saarlandes, Homburg/Saar, Germany.NLMeng 2 Mar 6;68(5):879-87.0092-8674 (Print) 0092-8674Cell1312391TMax-Planck-Institut fur Entwicklungsbiologie, Tubingen, Federal Republic of Germany.NLMeng Iy Unit, University of Pavia, Pavia, Italy.10.1002/jat.3151NLMEng nal-pdf://2304132476/Liu-2010-Honokiol inhibits gastric tumourigene.pdf internal-pdf://4215833872/Liu-2010-Honokiol inhibits gastric tumourigen1.pdfNLMeng -pdf://2470297638/Aggarwal-2010-Tocotrienols, the vitamin E of t.pdf internal-pdf://4144631813/Aggarwal-2010-Tocotrienols, the vitamin E of 1.pdfNLMeng|<5BASaleem, T. Attya, A. Ahmed, E. Ragab, S. Abdallah, M. A. Omar, H.2015yPossible Protective Effects of Quercetin and Sodium Gluconate Against Colon Cancer Induction by Dimethylhydrazine in Mice5823-8Asian Pac J Cancer Prev1614 2015/09/01Micronutrients in food have been found to have chemopreventive effects, supporting the conclusions from epidemiologie studies that consumption of fresh fruits and vegetables reduces cancer risk. The present study was carried out to evaluate the role of querctin (Q) and sodium gluconate (GNA) supplementation separately or in combination in ameliorating promotion of colon tumor development by dimethyl-hydrazine (DMH) in mice. Histopathological observation of colons in mice treated with DMH showed goblet cell dysplasia with inflammatory cell infiltration. This pathological finding was associated with significant alteration in oxidative stress markers in colon tissues and carcinoembryonic antigen (CEA) levels in plasma. Mice co-treated with GNA and Q showed mild changes of absorptive and goblet cells and inflammatory cell infiltration in lamina properia, with improvement in oxidative stress markers. In conclusion, findings of the present study indicate significant roles for reactive oxygen species (ROS) in pathogenesis of DMH-induced colon toxicity and initiation of colon cancer. Also, they suggest that Q, GNA or the combination of both have a positive beneficial effect against DMH induced colonic cancer induction in mice.Saleem, Th Attya, Am Ahmed, Ea Ragab, Smm Abdallah, Ma Ali Omar, Hm Journal Article Thailand Asian Pac J Cancer Prev. 2015;16(14):5823-8.1513-7368 (Print) 1513-73682Asian Pacific journal of cancer preveg|<5@Whanger, P. D.1992NSelenium in the treatment of heavy metal poisoning and chemical carcinogenesis209-21$J Trace Elem Electrolytes Health Dis64 1992/12/01Animals Anticarcinogenic Agents/*therapeutic use Diet Female Humans Male Metals/*poisoning Neoplasms, Experimental/chemically induced/*prevention & control Poisoning/*drug therapy Selenium/administration & dosage/blood/pharmacology/*therapeutic useDec5Selenium (Se) has been shown to counteract the toxicity of heavy metals such as cadmium, inorganic mercury, methylmercury, thallium and to a limited extent silver. Although not as effective as Se, vitamin E significantly alters methylmercury toxicity and is more effective than Se against silver toxicity. Vitamin E is very effective against lead toxicity but Se has little effect. The presumed protective effect of Se against cadmium and mercury toxicity is through the diversion in their binding from low molecular weight proteins to higher molecular weight ones. Se appears effective in counteracting the chemical carcinogens (3-methyl-4-dimethyl-aminoazobenzene, 2-acetylaminofluorene, diethylnitrosamine, aflatoxin, 7,12-dimethylben (a) anthracene, benzopyrene and 3-methylcholanthrene) used to induce skin, liver and mammary tumors, but much less effective against those (dimethylhydrazine, azoxymethane, methylazoxymethanol, bis (2-oxopropyl) nitrosamine, benzopyrene, 1 methyl-1-nitrosourea and n-methyl-n-nitro-nitrosoguanidine) used to produce tumors in the colon, lungs, trachea and pancreas in laboratory animals. In contrast, Se many even increase pancreatic carcinomas in animals treated with bis (2-oxopropyl) nitrosamine. The health implications in humans of Se and heavy metal toxicities and in cancer are discussed.Whanger, P D 38 306/PHS HHS/United States Journal Article Research Support, U.S. Gov't, P.H.S. Review Germany J Trace Elem Electrolytes Health Dis. 1992 Dec;6(4):209-21.0931-2838 (Print) 0931-2838@Journal of trace elements and electrolytes in health and disease1304229ODepartment of Agricultural Chemistry, Oregon State University, Corvallis 97331.NLMeng |<5A+Bohme, M. Diener, M. Mestres, P. Rummel, W.1992Direct and indirect actions of HgCl2 and methyl mercury chloride on permeability and chloride secretion across the rat colonic mucosa285-94Toxicol Appl Pharmacol1142 1992/06/01Animals Cell Membrane Permeability/drug effects Chlorides/*physiology Colon/*drug effects/ultrastructure Epithelium/drug effects/physiology/ultrastructure Female In Vitro Techniques Intestinal Absorption/drug effects Intestinal Mucosa/*drug effects/physiology/ultrastructure Mannitol/pharmacokinetics Membrane Potentials/drug effects Mercuric Chloride/*pharmacology Methylmercury Compounds/*pharmacology Rats Rats, Inbred StrainsJundThe actions of two mercury compounds, the inorganic HgCl2 and the organic methyl mercury chloride (MeHg), and of CdCl2 on ion transport across the rat colon were studied with the Ussing chamber and the everted sac method. The mercury compounds (5-50 microM), but not CdCl2, administered to the luminal side, induced a large, concentration-dependent increase of tissue conductance (Gt). The transepithelial movement of the extracellular marker, mannitol, was enhanced in the presence of the mercury compounds, indicating that they cause an increase in the permeability of the epithelium. Morphological studies revealed that at least for HgCl2 this increase of the permeability was associated with a loosening of the tight junctions, severe alterations of the enterocytes, and a loss of the continuity of the epithelium. After washing out HgCl2, cells neighboring the altered enterocytes developed lateral processes and in this way restored the continuity of the epithelial layer. In parallel, the mercury compounds induced an increase of short-circuit current (Isc), which is indicative of an induction of Cl- secretion. The increase of Isc, but not that of Gt, was suppressed by indomethacin and, in the case of MeHg, also by tetrodotoxin. These results suggest that MeHg and HgCl2 induce Cl- secretion by an indirect effect on the epithelium, which is mediated by prostaglandins.Ahttp://www.sciencedirect.com/science/article/pii/0041008X92900798Bohme, M Diener, M Mestres, P Rummel, W Journal Article Research Support, Non-U.S. Gov't United states Toxicol Appl Pharmacol. 1992 Jun;114(2):285-94.0041-008X (Print) 0041-008x#Toxicology and applied pharmacology1609421^Institut fur Pharmakologie und Toxikologie, Universitat des Saarlandes, Homburg/Saar, Germany.Linternal-pdf://0945394160/Bohme-1992-Direct and indirect actions of HgCl.pdfNLMeng ntion : APJCP26320457tDepartment of Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt E-mail : hossameldin mo@gmail.com.Linternal-pdf://2798138681/Saleem-2015-Possible Protective Effects of Que.pdfNLMeng U H|<5DIUlger, H. Ertekin, T. Karaca, O. Canoz, O. Nisari, M. Unur, E. Elmali, F.2013aInfluence of gilaburu (Viburnum opulus) juice on 1,2-dimethylhydrazine (DMH)-induced colon cancer824-9Toxicol Ind Health299 2012/05/0231,2-Dimethylhydrazine/*toxicity Animals Beverages/*analysis Body Weight/drug effects Colon/*drug effects/metabolism Colonic Neoplasms/chemically induced/*prevention & control Fruit/chemistry Male Mice Mice, Inbred BALB C Viburnum/*chemistry 1, 2-dimethylhydrazine Gilaburu juice Viburnum opulus cancer colonOctRIn this study, the effects of gilaburu (Viburnum opulus) juice on colon tumorogenesis were investigated. Eight weeks old Balb-C male mice received subcutaneous injections of 1,2-dimethylhydrazine (DMH) (20 mg/kg body weight) once a week for 12 weeks. Both the sham control (group 1) and the DMH control (group 2) groups received drinking water alone, whereas the mice of groups 3 and 4 received gilaburu juice for 30 weeks (started with first DMH injection) and for 18 weeks (started after last DMH injection), respectively. Eighteen weeks after the last DMH injection, all mice were killed and the histogenesis of colon tumors was investigated from the paraffin-embedded sections of colon, which were stained with hematoxylin-eosin. The sites and incidences of tumoral lesions (low-grade dysplasia, high-grade dysplasia, intramucosal carcinoma and invasive carcinoma) were analyzed and compared with control. The results showed that the body weights of the mice were similar in all the groups. No tumoral lesions were found in group 1. Colon tumors developed in all DMH-treated mice (groups 2, 3 and 4). In these groups, the greatest numbers of tumor lesions were detected in the distal colon, followed by the mid-colon and only a few in the proximal colon. There was a reduction in the mean total number of tumor lesion in groups 3 (8.5) and 4 (8.3), when compared to group 2 (11.3). The incidence of invasive carcinoma in group 3 was significantly lower than group 2 (p < 0.05). On the basis of these results, we conclude that gilaburu juice may be useful for the prevention of colon cancer at the initiation stage.'http://tih.sagepub.com/content/29/9/8241477-0393 Ulger, Harun Ertekin, Tolga Karaca, Omur Canoz, Ozlem Nisari, Mehtap Unur, Erdogan Elmali, Ferhan Journal Article Research Support, Non-U.S. Gov't England Toxicol Ind Health. 2013 Oct;29(9):824-9. doi: 10.1177/07482337 \12445049. Epub 2012 Apr 30. 0748-2337 Toxicology and industrial health22546843?1Department of Anatomy, University of Erciyes, Kayser C|<5EyRoscilli, G. Marra, E. Mori, F. Di Napoli, A. Mancini, R. Serlupi-Crescenzi, O. Virmani, A. Aurisicchio, L. Ciliberto, G.2013eCarnitines slow down tumor development of colon cancer in the DMH-chemical carcinogenesis mouse model1665-73J Cell Biochem1147 2013/02/07,1,2-Dimethylhydrazine/*toxicity Acetylcarnitine/therapeutic use Animals Apoptosis/drug effects Carnitine/*therapeutic use Cell Proliferation/drug effects Colonic Neoplasms/chemistry/*drug therapy/metabolism Curcumin/therapeutic use HT29 Cells Humans Immunohistochemistry Male Mice Mice, Inbred BALB CJulfDietary agents are receiving much attention for the chemoprevention of cancer. While curcumin is known to influence several pathways and affect tumor growth in vivo, carnitin and its congeners play a variety of important metabolic functions: are involved in the oxydation of long-chain fatty acids, regulate acyl-CoA levels and influence protein activity and stability by modifying the extent of protein acetylation. In this study we evaluated the efficacy of carnitines in the prevention of cancer development using the 1,2,-dimethylhydrazine (DMH)-induced colon carcinogenesis model. We also assessed whether their combination was able to give rise to increased protection from cancer development. Mice treated with DMH were dosed orally with curcumin and/or carnitine and acylcarnitines for 20 weeks. At the end of the treatment colon samples were collected, and scored for multiple ACF and adenomas. We observed that carnitine and acyl-carnitines had same, if not higher, efficacy than curcumin alone in inhibiting the formation of neoplastic lesions induced by DMH treatment. Interestingly, the combination of curcumin and acetyl-L-carnitine was able to fully inhibit the development of advanced adenoma lesions. Our data unveil the antitumor effects of carnitines and warrant additional studies to further support the adoption of carnitines as cancer chemopreventative agents.1097-4644 Roscilli, Giuseppe Marra, Emanuele Mori, Federica Di Napoli, Arianna Mancini, Rita Serlupi-Crescenzi, Ottaviano Virmani, Ashraf Aurisicchio, Luigi Ciliberto, Gennaro Journal Article United States J Cell Biochem. 2013 Jul;114(7):1665-73. doi: 10.1002/jcb.24508. 0730-2312 Journal of cellular biochemistry23386399Takis srl, Roma, Italy.10.1002/jcb.24508Li U |<5F@Ertekin, T. Ekinci, N. Karaca, O. Nisari, M. Canoz, O. Ulger, H.2013KEffect of angiostatin on 1,2-dimethylhydrazine-induced colon cancer in mice490-7Toxicol Ind Health296 2012/03/07)1,2-Dimethylhydrazine Analysis of Variance Angiogenesis Inhibitors/pharmacology Angiostatins/*pharmacology Animals Colonic Neoplasms/blood supply/chemically induced/*drug therapy/pathology Histocytochemistry Male Mice Mice, Inbred BALB C 1,2 dimethylhydrazine Colon cancer angiogenesis angiostatinJulAntiangiogenic therapy is supposed to be an attractive approach for antitumor treatment. Human plasminogen-derived angiostatin K1-3 is one of the most potent antiangiogenic agents known currently. However, it is unclear whether angiostatin has got protective effects on colon cancer. So we investigated the protective effects of angiostatin on 1,2-dimethylhydrazine (DMH)-induced colon cancer in mice. Thirty Balb/C male mice, weighing 25-30 g and 8 weeks of age, were used. Twenty of the mice were treated with DMH subcutaneously (20 mg/kg) once a week for 12 weeks. Six mice died during the DMH injection and surviving mice were divided into two groups (7 mice in DMH and 7 mice in DMH + angiostatin groups). In the angiostatin group, 6 weeks after the last DMH injection the animals were first treated with angiostatin (20 mug/mouse) intraperitoneally and then subcutaneously every 48 h (5 mug/mouse) throughout a period of 12 weeks. The animals were killed after 30 weeks for histopathological examination. When we look at the distribution of lesions in the colon, they mainly occurred in the distal colon. The incidence of mean colonic lesions in a tumor-bearing mouse was 9.85 +/- 4.91 in those treated with DMH and 8.71 +/- 3.49 in those treated with angiostatin. The incidence of colon tumors was not significantly affected by low dose of angiostatin, and we noticed that the number of lesions decreased by 12% in DMH + angiostatin group compared to the number of the lesions in DMH group, but this decrease was not statistically significant (p > 0.05). The administration period of angiostatin corresponds to the precancerous period and the reduction in the number of lesions could be important for the protective function of angiostatin in DMH + angiostain group. We assume that therapeutic effects of angiostatin are related to its doses, route of administration, frequency and administration period. In addition, we believe that combination of high doses of angiostatin with radiation, gene therapy or chemotherapy might be successful in proper tumor model.'http://tih.sagepub.com/content/29/6/4901477-0393 Ertekin, Tolga Ekinci, Nihat Karaca, Omur Nisari, Mehtap Canoz, Ozlem Ulger, Harun Journal Article Research Support, Non-U.S. Gov't England Toxicol Ind Health. 2013 Jul;29(6):490-7. doi: 10.1177/0748233712440137. Epub 2012 Mar 5. 0748-2337 Toxicology and industrial health22393105fDepartment of Anatomy, University of Erciyes, School of Medicine, Kayseri, Turkey. tol-kin[~<5G\Garcia-Sevillano, M. A. Rodriguez-Moro, G. Garcia-Barrera, T. Navarro, F. Gomez-Ariza, J. L.2015Biological interactions between mercury and selenium in distribution and detoxification processes in mice under controlled exposure. Effects on selenoprotein82-90Chem Biol Interact229 2015/02/11_Animals Chromatography, Gel Chromatography, High Pressure Liquid Kidney/drug effects/metabolism Liver/drug effects/metabolism Male Mercury/analysis/blood/*metabolism/*toxicity Mice Models, Molecular Selenium/analysis/blood/*metabolism/*pharmacology Selenoproteins/*metabolism Mercury Metal interactions Metallomics Mus musculus Selenium SelenoproteinsMar 5Antagonistic interactions between mercury (Hg) and selenium (Se), were evaluated in mouse (Mus musculus), as a mammalian model, in a series of controlled exposure experiments. The beneficial effect of Se against Hg toxicity involves a variety of biochemical and toxicological processes that have not been clarified yet. For this purpose, a metallomic workflow based on the use of size-exclusion chromatography (SEC) with inductively coupled plasma mass spectrometry (ICP-MS) detection was complemented with the speciation of selenoproteins and low molecular mass selenium species in serum and liver cytosolic extracts using a multidimensional approach based on SEC-AF-HPLC-ICPMS, using species-unspecific isotope dilution (SUID)-ICP-MS for selenium quantification. The results showed potential interactions between Hg/Se in organs and serum related to accumulation and detoxification processes, in addition to the effects of mercury on selenoproteins in hepatic cytosolic extracts and bloodstream when both elements are administrated at the same time. These results provide information about elements distribution, interactions and homeostasis and reveal the potential of metallomic approaches in exposure experiments.Bhttp://www.sciencedirect.com/science/article/pii/S00092797150005631872-7786 Garcia-Sevillano, M A Rodriguez-Moro, G Garcia-Barrera, T Navarro, F Gomez-Ariza, J L Journal Article Research Support, Non-U.S. Gov't Ireland Chem Biol Interact. 2015 Mar 5;229:82-90. doi: 10.1016/j.cbi.2015.02.001. Epub 2015 Feb 7. 0009-2797Chemico-biological interactions25665768Department of Chemistry and Materials Science, Faculty of Experimental Sciences, University of Huelva, Campus de El Carmen, 21007 Huelva, Spain; Research Center on Health and Environment (CYSMA), University of Huelva, Spain; International Campus of Excellence on Agrofood (ceiA3), University of Huelva, Spain. Electronic address: mangel.garcia@dqcm.uhu.es. Department of Chemistry and Materials Science, Faculty of Experimental Sciences, University of Huelva, Campus de El Carmen, 21007 Huelva, Spain; Research Center on Health and Environment (CYSMA), University of Huelva, Spain; International Campus of Excellence on Agrofood (ceiA3), University of Huelva, Spain. Electronic address: gema.moro@dqcm.uhu.es. Department of Chemistry and Materials Science, Faculty of Experimental Sciences, University of Huelva, Campus de El Carmen, 21007 Huelva, Spain; Research Center on Health and Environment (CYSMA), University of Huelva, Spain; International Campus of Excellence on Agrofood (ceiA3), University of Huelva, Spain. Electronic address: tamara@dqcm.uhu.es. International Campus of Excellence on Agrofood (ceiA3), University of Huelva, Spain; Department of Environmental Biology and Public Health, Cell Biology, Faculty of Experimental Sciences, University of Huelva, Campus El Carmen, 21007 Huelva, Spain. Electronic address: navarro@uhu.es. Department of Chemistry and Materials Science, Faculty of Experimental Sciences, University of Huelva, Campus de El Carmen, 21007 Huelva, Spain; Research Center on Health and Environment (CYSMA), University of Huelva, Spain; International Campus of Excellence on Agrofood (ceiA3), University of Huelva, Spai ^ |<5HLi, X. Yin, D. Li, J. Wang, R.2014zProtective effects of selenium on mercury induced immunotoxic effects in mice by way of concurrent drinking water exposure104-14Arch Environ Contam Toxicol671 2014/02/13Animals Drinking Water/*chemistry Environmental Monitoring Female Immunotoxins/chemistry/*toxicity Mercury/chemistry/*toxicity Mice Protective Agents/*chemistry Selenium/*chemistry Water Pollutants, Chemical/chemistry/*toxicityJul?Selenium (Se) has been recognized as one key to understanding mercury (Hg) exposure risks. To explore the effects of Se on Hg-induced immunotoxicity, female Balb/c mice were exposed to HgCl2- or MeHgCl-contaminated drinking water (0.001, 0.01, and 0.1 mM as Hg) with coexisting Na2SeO3 at different Se/Hg molar ratios (0:1, 1/3:1, 1:1 and 3:1). The potential immunotoxicity induced by Na2SeO3 exposure alone (by way of drinking water) was also determined within a wide range of concentrations. After 14 days' exposure, the effects of Hg or Se on the immune system of Balb/c mice were investigated by determining the proliferation of T and B lymphocytes and the activity of natural killer cells. Hg exposure alone induced a dose-dependent suppression effect, whereas Se provided promotion effects at low exposure level (<0.01 mM) and inhibition effects at high exposure level (>0.03 mM). Under Hg and Se coexposure condition, the effects on immunotoxicity depended on the Hg species, Se/Hg ratio, and exposure concentration. At low Hg concentration (0.001 mM), greater Se ingestion exhibited stronger protective effects on Hg-induced suppression effect mainly by way of decreasing Hg concentrations in target organs. At greater Hg concentration (0.01 and 0.1 mM), immunotoxicity induced by Se (>0.03 mM) became evident, and the protective effects appeared more significant at an Se/Hg molar ratio of 1:1. The complex antagonistic effects between Se and Hg suggested that both Se/Hg molar ratio and concentration should be considered when evaluating the potential health risk of Hg-contaminated biota.<http://link.springer.com/article/10.1007%2Fs00244-014-0001-21432-0703 Li, Xuan Yin, Daqiang Li, Jiang Wang, Rui Journal Article Research Support, Non-U.S. Gov't United States Arch Environ Contam Toxicol. 2014 Jul;67(1):104-14. doi: 10.1007/s00244-014-0001-2. Epub 2014 Feb 12. 0090-43416Archives of environmental contamination and toxicology24519443State Key Laboratory of Pollution Control and Resources Reuse, College of Environmental Science and Engineering, Tongji University, 1239 Siping G |<5IUYamamoto, M. Yanagisawa, R. Motomura, E. Nakamura, M. Sakamoto, M. Takeya, M. Eto, K.2014JIncreased methylmercury toxicity related to obesity in diabetic KK-Ay mice914-23J Appl Toxicol348 2013/11/19Adipose Tissue/drug effects/metabolism Animals Blood Glucose Body Weight Brain/drug effects/metabolism Diabetes Mellitus, Type 2/*blood/complications/pathology Immunohistochemistry Kidney/drug effects/metabolism Male Methylmercury Compounds/blood/*toxicity Mice Mice, Inbred C57BL Obesity/*blood/chemically induced/pathology Pancreas/drug effects/metabolism Spleen/drug effects/metabolism Cd204 Diabetes Methylmercury Neurotoxicity ObesityAug#We examined the toxic effects of methylmercury (MeHg) in KK-Ay type 2 diabetic mice to clarify how metabolic changes associated with type 2 diabetes mellitus affect MeHg toxicity. MeHg (5 mg Hg kg (-1) day(-1) p.o.) was given to 4-week-old male KK-Ay and C57BL/6J (BL/6) mice three times per week for 6 weeks. Average body weights (BW) of vehicle-treated BL/6 and KK-Ay mice were 16.3 and 16.4 g respectively on the first day, and 24.8 and 42.3 g respectively on the last day of the experiment. MeHg-treated KK-Ay mice began to lose weight about 5 weeks after MeHg administration. Six of seven MeHg-treated KK-Ay mice showed hind-limb clasping in the final stage of the experiment. The mean blood mercury level of MeHg-treated KK-Ay mice reached a maximum of 9.8 microg ml(-1) , whereas that of the MeHg-treated BL/6 mice was 2.8 microg ml(-1) after 10 days of treatment. The average total mercury concentrations in the cerebrum and epididymal fat pad were 7.4 and 0.57 microg g(-1) , respectively, for BL/6 mice and 27 and 1.6 microg g(-1) , respectively, for KK-Ay mice. In MeHg-treated KK-Ay mice with neurological symptoms, CD204-positive macrophages were observed in the brain, kidney and spleen, indicating CD204 could be a marker for injured tissues. BW loss and significant pathological changes were not observed in other groups of mice. These results indicate that body fat gain in type 2 diabetes mellitus and low mercury accumulation in adipose tissue increased MeHg concentrations in organs and enhanced toxicity in KK-Ay mice at the same dose of MeHg per BW.<http://onlinelibrary.wiley.com/doi/10.1002/jat.2954/abstract1099-1263 Yamamoto, Megumi Yanagisawa, Rie Motomura, Eriko Nakamura, Masaaki Sakamoto, Mineshi Takeya, Motohiro Eto, Komyo Journal Article Research Support, Non-U.S. Gov't England J Appl Toxicol. 2014 Aug;34(8):914-23. doi: 10.1002/jat.2954. Epub 2013 Nov 15. 0260-437x#Journal of applied toxicology : JAT24243536Integrated Physiology Section, Department of Basic Medical Science, National Institute for Mi x|<5J/Bellum, S. Thuett, K. A. Bawa, B. Abbott, L. C.2013dThe effect of methylmercury exposure on behavior and cerebellar granule cell physiology in aged mice959-69J Appl Toxicol339 2012/08/14(Age Factors Animals Behavior, Animal/*drug effects Calcium/metabolism Cell Survival/drug effects Cerebellum/*drug effects/metabolism Dose-Response Relationship, Drug Female Male Membrane Potential, Mitochondrial/drug effects Methylmercury Compounds/*toxicity Mice Mice, Inbred C57BL Neurons/cytology/drug effects Reactive Oxygen Species/metabolism aged CNS behavioral assessment cerebellar granule cells intracellular calcium ion concentrations mercury methylmercury mitochondrial membrane potential open field activity reactive oxygen species rota-rodSepDEpidemiology studies have clearly documented that the central nervous system is highly susceptible to methylmercury toxicity, and exposure to this neurotoxicant in humans primarily results from consumption of contaminated fish. While the effects of methylmercury exposure have been studied in great detail, comparatively little is known about the effects of moderate to low dose methylmercury toxicity in the aging central nervous system. We examined the toxic effects of a moderate dose of methylmercury on the aging mouse cerebellum. Male and female C57BL/6 mice at 16-20 months of age were exposed to methylmercury by feeding a total dose of 5.0 mg kg(-1) body weight and assessed using four behavioral tests. Methylmercury-treated aged mice performed significantly worse in open field, footprint analysis and the vertical pole test compared with age-matched control mice. Isolated cerebellar granule cells from methylmercury-treated aged mice exhibited higher levels of reactive oxygen species and reduced mitochondrial membrane potentials, but no differences in basal intracellular calcium ion levels compared with age-matched control mice. When aged mice were exposed to a moderate dose of methylmercury, they exhibited a similar degree of impairment when compared with young adult mice exposed to the same moderate dose of methylmercury, as reported in earlier studies from this laboratory. Thus, at least in mice, exposure of the aged brain to moderate concentrations methylmercury does not pose greater risk compared with the young adult brain exposed to similar concentrations of methylmercury.<http://onlinelibrary.wiley.com/doi/10.1002/jat.2786/abstract1099-1263 Bellum, Sairam Thuett, Kerry A Bawa, Bhupinder Abbott, Louise C P30ES09106/ES/NIEHS NIH HHS/United States Journal Article Research Support, N.I.H., Extramural England J Appl Toxicol. 2013 Sep;33(9):959-69. doi: 10.1002/jat.2786. Epub 2012 Aug 10. 0260-437x#Journal of applied toxicology : JAT22886740JSafety Assessment, Merck Research X|<5K~Zimmermann, L. T. dos Santos, D. B. Colle, D. dos Santos, A. A. Hort, M. A. Garcia, S. C. Bressan, L. P. Bohrer, D. Farina, M.2014fMethionine stimulates motor impairment and cerebellar mercury deposition in methylmercury-exposed mice46-56J Toxicol Environ Health A771-3 2014/02/22Animals Antioxidants/metabolism Biological Markers/metabolism Cerebellum/*chemistry/metabolism Cysteine/administration & dosage/*analogs & derivatives/pharmacokinetics/toxicity Drug Administration Schedule Environmental Pollutants/administration & dosage/pharmacokinetics/*toxicity Glutathione/metabolism Glutathione Peroxidase/metabolism Injections, Intraperitoneal Male Methionine/administration & dosage/*pharmacology Methylmercury Compounds/administration & dosage/pharmacokinetics/*toxicity Mice Motor Activity/*drug effects Neuroprotective Agents/administration & dosage/*pharmacology Psychomotor Performance/*drug effects Random AllocationMethylmercury (MeHg) is a highly toxic environmental contaminant that produces neurological and developmental impairments in animals and humans. Although its neurotoxic properties have been widely reported, the molecular mechanisms by which MeHg enters the cells and exerts toxicity are not yet completely understood. Taking into account that MeHg is found mostly bound to sulfhydryl-containing molecules such as cysteine in the environment and based on the fact that the MeHg-cysteine complex (MeHg-S-Cys) can be transported via the L-type neutral amino acid carrier transport (LAT) system, the potential beneficial effects of L-methionine (L-Met, a well known LAT substrate) against MeHg (administrated as MeHg-S-Cys)-induced neurotoxicity in mice were investigated. Mice were exposed to MeHg (daily subcutaneous injections of MeHg-S-Cys, 10 mg Hg/kg) and/or L-Met (daily intraperitoneal injections, 250 mg/kg) for 10 consecutive days. After treatments, the measured hallmarks of toxicity were mostly based on behavioral parameters related to motor performance, as well as biochemical parameters related to the cerebellar antioxidant glutathione (GSH) system. MeHg significantly decreased motor activity (open-field test) and impaired motor performance (rota-rod task) compared with controls, as well as producing disturbances in the cerebellar antioxidant GSH system. Interestingly, L-Met administration did not protect against MeHg-induced behavioral and cerebellar changes, but rather increased motor impairments in animals exposed to MeHg. In agreement with this observation, cerebellar levels of mercury (Hg) were higher in animals exposed to MeHg plus L-Met compared to those only exposed to MeHg. However, this event was not observed in kidney and liver. These results are the first to demonstrate that L-Met enhances cerebellar deposition of Hg in mice exposed to MeHg and that this higher deposition may be responsible for the greater motor impairment observed in mice simultaneously exposed to MeHg and L-Met.?http://www.tandfonline.com/doi/abs/10.1080/15287394.2014.865582JZimmermann, Luciana T dos Santos, Danubia B Colle, Dirleise dos Santos, Alessandra A Hort, Mariana A Garcia, Solange C Bressan, Lucas Paines Bohrer, Denise Farina, Marcelo Evaluation Studies Journal Article Research Support, Non-U.S. Gov't England J Toxicol Environ Health A. 2014;77(1-3):46-56. doi: 10.1080/15287394.2014.865582.1528-7394 (Print) 0098-41086Journal of toxicology and environmental health. Part A24555646a Departamento de Bioquimica, Centro de Ciencias Biologicas , Universidade Federal de Santa Catarina , Florianopo AtLaboratories, West Point, PA 19486, USA.10.1002/jat.2786Lint G Road, Shanghai, 200092, China.10.1007/s00244-014-0001-2NLMeng Anamata Disease, Minamata, Kumamoto, Japan.10.1002/jat.2954Li1i, Turkey.10.1177/0748233712445049NLMeng Ln. Electronic address: ariza@uhu.es.10.1016/j.cbi.2015.02.001NLMeng -d@hotmail.com10.1177/0748233712440137LintIlis , Santa Catarina , Brazil.10.1080/15287394.2014.865582NLMengUernal-pdf://1279490368/Ertekin-2013-Effect of angiostatin on 1,2-dime.pdfNLMeng Wnternal-pdf://3264321586/Roscilli-2013-Carnitines slow down tumor devel.pdfNLMeng Wnternal-pdf://2309288348/Yamamoto-2014-Increased methylmercury toxicity.pdfNLMengUernal-pdf://3576738068/Bellum-2013-The effect of methylmercury exposu.pdfNLMeng?LNorseth, Tor Clarkson, Thomas W1971=Intestinal transport of 203Hg-labeled methyl mercury chloride568-577:Archives of Environmental Health: An International Journal225 0003-9896?MBerlin, Maths Ullberg, Sven1963Accumulation and retention of mercury in the mouse: I. An autoradiographic study after a single intravenous injection of mercuric chloride589-601:Archives of Environmental Health: An International Journal65 0003-98963(?NStohs, SJ Bagchi, D19952Oxidative mechanisms in the toxicity of metal ions321-336!Free radical biology and medicine182A?OHarada, Masazumi1995TMinamata disease: methylmercury poisoning in Japan caused by environmental pollution1-24Critical reviews in toxicology251<?PPXue, Fei Holzman, Claudia Rahbar, Mohammad Hossein Trosko, Kay Fischer, Lawrence2007GMaternal fish consumption, mercury levels, and risk of preterm delivery42-47!Environmental health perspectives 0091-6765D?Q1Fishbein, Lawrence Furst, Arthur Mehlman, Myron A1987XGenotoxic and carcinogenic metals: environmental and occupational occurence and exposureXGenotoxic and carcinogenic metals: environmental and occupational occurence and exposurePrinceton Scientific0?RIRojas, Emilio Herrera, Luis A Poirier, Lionel A Ostrosky-Wegman, Patricia1999Are metals dietary carcinogens?157-181BMutation Research/Genetic Toxicology and Environmental Mutagenesis4431 ?S.Dallinger, Reinhard Prosi, F Segner, H Back, H1987bContaminated food and uptake of heavy metals by fish: a review and a proposal for further research91-98 Oecologia731 0029-8549Ihttp://www.tandfonline.com/doi/abs/10.3109/10408449509089885 1040-8444 Exhttp://www.sciencedirect.com/science/article/pii/089158499400159H 0|<5T4Manerio, E. Rodas, V. L. Costas, E. Hernandez, J. M.2008@Shellfish consumption: a major risk factor for colorectal cancer409-12Med Hypotheses702 2007/07/04Animals Carcinogens/toxicity Colorectal Neoplasms/*etiology/prevention & control Diet/adverse effects Europe Humans Marine Toxins/toxicity Models, Biological Okadaic Acid/toxicity Risk Factors Shellfish/*toxicityIn the last decades, relevant efforts have been made to reduce the cancer incidence in the European Union. The prevention programmes against cancer have obtained satisfactory results except for colorectal cancer (CRC). Identification of risk factors is primordial to plan preventive strategies for CRC. We hypothesize that shellfish consumption is increasing CRC incidence. DSP toxins, present in some seafood products, seem to behave like tumour agents. There are no relevant studies on real health-risk of consuming DSP toxins, just some experimental and ecological evidence. Preventive interventions for reducing CRC risk must be approached through the collaboration of governmental, health and environmental sectors as a single regulatory agency. Sometimes, shellfish accumulates diarrhetic shellfish poisoning (DSP) toxins (i.e. okadaic acid and its derivatives) which provoke a gastrointestinal illness (DSP syndrome). Furthermore, DSP toxins are tumour promoters that could increase CRC risk. The current regulation about level of DSP toxins in shellfish meat is only centred on reduction of the gastrointestinal symptoms. Unfortunately, legal levels of DSP toxins in shellfish are enough to increase CRC risk. A review of legislation on DSP toxins is urgent.Manerio, Emilia Rodas, Victoria L Costas, Eduardo Hernandez, Juan Martinez Journal Article Scotland Med Hypotheses. 2008;70(2):409-12. Epub 2007 Jul 2.0306-9877 (Print) 0306-9877Medical hypotheses17606330<Genetica, Facultad de Veterinaria, UCM, 28040 Madrid, Spain.10.1016/j.mehy.2007.03.041NLMeng?UEMalekzadeh, Reza Bishehsari, Faraz Mahdavinia, Mahboobeh Ansari, Reza2009JEpidemiology and molecular genetics of colorectal cancer in iran: a review161-9 Arch Iran Med122 U1383-5718Hinternal-pdf://0694878690/Rojas-1999-Are metals dietary carcinogens_.pdf )891-5849Linternal-pdf://1125988467/Stoh .s-1995-Oxidative mechanisms in the toxicit.pdf  DF<5WGKirkpatrick, M. Benoit, J. Everett, W. Gibson, J. Rist, M. Fredette, N.2015bThe effects of methylmercury exposure on behavior and biomarkers of oxidative stress in adult miceNeurotoxicology 2015/07/08F8-OHdG Locomotor behavior Methylmercury Neurotoxicity Oxidative stressJul 4Methylmercury (MeHg) is a widely distributed environmental neurotoxin with established effects on locomotor behaviors and cognition in both human populations and animal models. Despite well-described neurobehavioral effects, the mechanisms of MeHg toxicity are not completely understood. Previous research supports a role for oxidative stress in the toxic effects of MeHg. However, comparing findings across studies has been challenging due to differences in species, methodologies (in vivo or in vitro studies), dosing regimens (acute vs. long-term) and developmental life stage. The current studies assess the behavioral effects of MeHg in adult mice in conjunction with biochemical and cellular indicators of oxidative stress using a consistent dosing regimen. In Experiment 1, adult male C57/BL6 mice were orally administered 5mg/kg/day MeHg or the vehicle for 28 days. Impact of MeHg exposure was assessed on inverted screen and Rotor-Rod behaviors as well as on biomarkers of oxidative stress (thioredoxin reductase (TrxR), glutathione reductase (GR) and glutathione peroxidase (GPx)) in brain and liver. In Experiment 2, brain tissue was immunohistochemically labeled for 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation and an indicator of oxidative stress, following the same dosing regimen. 8-OHdG immunoreactivity was measured in the motor cortex, the magnocellular red nucleus (RMC) and the accessory oculomotor nucleus (MA3). Significant impairments were observed in MeHg-treated animals on locomotor behaviors. TrxR and GPx was significantly inhibited in brain and liver, whereas GR activity decreased in liver and increased in brain tissue of MeHg-treated animals. Significant MeHg-induced alterations in DNA oxidation were observed in the motor cortex, the RMC and the MA3.1872-9711 Kirkpatrick, Meg Benoit, Janina Everett, Wyll Gibson, Jennifer Rist, Michael Fredette, Nicholas Journal article Neurotoxicology. 2015 Jul 4. pii: S0161-813X(15)00096-0. doi: 10.1016/j.neuro.2015.07.001. 0161-813xNeurotoxicology26151194[Psychology Department and Neuroscience Program, Wheaton College, 26 East Main Street, Norton, MA 02766, United States. Electronic address: Kirkpatrick_meg@wheatoncollege.edu. Chemistry Department, Wheaton College, United States. Psychology Department and Neuroscience Program, Wheaton College, 26 East Main Street, Norton, MA 02766, United States.10.1016/j.neuro.2015.07.001KiQ|<5X<Song, X. R. Tan, B. Y. Su, K. Cao, J. Y. Liu, A. J. Qian, J.2015RExposure to Methylmercury Does Not Change the Sexual Preference of C57BL Male Mice748-9CNS Neurosci Ther219 2015/08/11Sep=http://onlinelibrary.wiley.com/doi/10.1111/cns.12440/abstract1755-5949 Song, Xu-Rui Tan, Bing-Yi Su, Kai Cao, Jun-Yu Liu, Ai-Jun Qian, Jiao Letter England CNS Neurosci Ther. 2015 Sep;21(9):748-9. doi: 10.1111/cns.12440. Epub 2015 Aug 8. 1755-5930CNS neuroscience & therapeutics26257387/Department of Pharmacology, Second Military Medical University, Shanghai, China. Department of Spinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China. Department of Pharmacy, Changhai Hospital, Second Milit g 5|45Y{Chen, K. L. Liu, S. H. Su, C. C. Yen, C. C. Yang, C. Y. Lee, K. I. Tang, F. C. Chen, Y. W. Lu, T. H. Su, Y. C. Huang, C. F.2012MMercuric compounds induce pancreatic islets dysfunction and apoptosis in vivo12349-66 Int J Mol Sci1310 2012/12/04@Animals Apoptosis/*drug effects Blood Glucose/analysis Caspase 3/genetics/metabolism Caspase 7/genetics/metabolism Glutathione Peroxidase/genetics/metabolism Insulin/blood Islets of Langerhans/cytology/*drug effects/metabolism Lipid Peroxidation/drug effects Male Malondialdehyde/blood Mercuric Chloride/chemistry/*toxicity Methylmercury Compounds/chemistry/*toxicity Mice Mice, Inbred ICR Proto-Oncogene Proteins c-bcl-2/genetics/metabolism Proto-Oncogene Proteins c-mdm2/genetics/metabolism Reactive Oxygen Species/metabolism Tumor Suppressor Protein p53/genetics/metabolism8Mercury is a toxic heavy metal that is an environmental and industrial pollutant throughout the world. Mercury exposure leads to many physiopathological injuries in mammals. However, the precise toxicological effects of mercury on pancreatic islets in vivo are still unclear. Here, we investigated whether mercuric compounds can induce dysfunction and damage in the pancreatic islets of mice, as well as the possible mechanisms involved in this process. Mice were treated with methyl mercuric chloride (MeHgCl, 2 mg/kg) and mercuric chloride (HgCl(2), 5 mg/kg) for more than 2 consecutive weeks. Our results showed that the blood glucose levels increased and plasma insulin secretions decreased in the mice as a consequence of their exposure. A significant number of TUNEL-positive cells were revealed in the islets of mice that were treated with mercury for 2 consecutive weeks, which was accompanied by changes in the expression of the mRNA of anti-apoptotic (Bcl-2, Mcl-1, and Mdm-2) and apoptotic (p53, caspase-3, and caspase-7) genes. Moreover, plasma malondialdehyde (MDA) levels increased significantly in the mice after treatment with mercuric compounds for 2 consecutive weeks, and the generation of reactive oxygen species (ROS) in the pancreatic islets also markedly increased. In addition, the mRNA expression of genes related to antioxidation, including Nrf2, GPx, and NQO1, were also significantly reduced in these islets. These results indicate that oxidative stress injuries that are induced by mercuric compounds can cause pancreatic islets dysfunction and apoptosis in vivo.-http://www.mdpi.com/1422-0067/13/10/12349/pdf01422-0067 Chen, Kuo-Liang Liu, Shing-Hwa Su, Chin-Chuan Yen, Cheng-Chieh Yang, Ching-Yao Lee, Kuan-I Tang, Feng-Cheng Chen, Ya-Wen Lu, Tien-Hui Su, Yi-Chang Huang, Chun-Fa Journal Article Research Support, Non-U.S. Gov't Switzerland Int J Mol Sci. 2012 Sep 26;13(10):12349-66. doi: 10.3390/ijms131012349. 1422-0067 Pmc3497276+International journal of molecular sciences23202902Department of Urology, China Medical University Hospital, and School of Medicine, China Medical University, No.2 Yuh-Der Rd., Taichung 404, Taiwan. cfh|<5Z7Mitsumori, K. Hirano, M. Ueda, H. Maita, K. Shirasu, Y.1990MChronic toxicity and carcinogenicity of methylmercury chloride in B6C3F1 mice179-90Fundam Appl Toxicol141 1990/01/01Animals Cerebellum/drug effects/pathology Female Kidney/drug effects/pathology Kidney Neoplasms/*chemically induced Male Methylmercury Compounds/*toxicity Mice Mice, Inbred ICR Mice, Inbred Strains Neurons, Afferent/drug effects/pathology Species SpecificityJanA 2-year feeding study of methylmercury chloride (MMC: 0, 0.4, 2, or 10 ppm) was conducted in B6C3F1 mice (60 mice of each sex/group) to compare chronic toxicity and carcinogenicity results with those for ICR mice from our previous study in which males of the 10-ppm group showed an increased incidence of renal tumors without any abnormal in-life parameters. In B6C3F1 mice of the 10-ppm group, neurotoxic signs characterized by posterior paralysis were observed in 33 males after 59 weeks and in 3 females after 80 weeks. In males, a marked increase in mortality and a remarkable decrease in body weight gain were observed after 60 weeks. Toxic encephalopathy consisting of neuronal necrosis of the brain and toxic peripheral sensory neuropathy were induced in both sexes in this group. Chronic nephropathy, testicular atrophy, and glandular stomach ulcer increased in incidence in the males; chronic nephropathy also increased in incidence in females. In proliferative lesions, there were significant increases in the incidence of renal adenoma and/or carcinoma (16/60) and tubular cell hyperplasia (14/60) in males of the 10-ppm group, as compared to the control group. The incidence of chronic nephropathy also increased in males of the 2-ppm group. The results of this study indicate that the susceptibility of B6C3F1 mice to renal toxicity and renal carcinogenicity is comparable to that of ICR mice, and B6C3F1 mice are more sensitive to the chronic neurotoxic effects of MMC than are ICR mice.|Mitsumori, K Hirano, M Ueda, H Maita, K Shirasu, Y Journal Article United states Fundam Appl Toxicol. 1990 Jan;14(1):179-90.0272-0590 (Print) 0272-0590RFundamental and applied toxicology : official journal of the Society of Toxicology23073164Institute of Environmental Toxicology, Tokyo, Japan.NLMengw|<5[7Hirano, M. Ueda, H. Mitsumori, K. Maita, K. Shirasu, Y.1988>Hormonal influence on carcinogenicity of methylmercury in mice886-93Nihon Juigaku Zasshi504 1988/08/01Animals Female Male Methylmercury Compounds/*toxicity Mice Mice, Inbred ICR Neoplasms, Experimental/*chemically induced Orchiectomy Ovariectomy Testosterone/*pharmacologyAugHirano, M Ueda, H Mitsumori, K Maita, K Shirasu, Y Comparative Study Journal Article Japan Nihon Juigaku Zasshi. 1988 Aug;50(4):886-93.0021-5295 (Print) 0021-5295@Nihon juigaku zasshi. The Japanese journal of veterinary science3172597NLMeng?6|<5\.Hirano, M. Mitsumori, K. Maita, K. Shirasu, Y.1986CFurther carcinogenicity study on methylmercury chloride in ICR mice127-35Nihon Juigaku Zasshi481 1986/02/01Animals Female Kidney Neoplasms/*chemically induced Male Methylmercury Compounds/administration & dosage/*toxicity Mice Mice, Inbred ICRFebHirano, M Mitsumori, K Maita, K Shirasu, Y Comparative Study Journal Article Japan Nihon Juigaku Zasshi. 1986 Feb;48(1):127-35.0021-5295 (Print) 0021-5295@Nihon juigaku zasshi. The Japanese journal of veterinary science3959366L /6\|<5]2Ginsberg, G. Sonawane, B. Nath, R. Lewandowski, P.2014]Methylmercury-induced inhibition of paraoxonase-1 (PON1)-implications for cardiovascular risk1004-23J Toxicol Environ Health A7717 2014/07/30Animals Antioxidants/metabolism Aryldialkylphosphatase/antagonists & inhibitors/*metabolism Carboxylic Ester Hydrolases/antagonists & inhibitors/metabolism Cardiovascular Diseases/*chemically induced/pathology Disease Models, Animal Dose-Response Relationship, Drug Fatty Acids, Omega-3/administration & dosage Fishes Food Contamination/analysis Humans Lipid Metabolism/physiology Meat/analysis Methylmercury Compounds/*toxicity Mice Reactive Oxygen Species/metabolism Risk Assessment Risk FactorsMethylmercury (MeHg) has been associated with increased risk for cardiovascular disease in some but not all epidemiology studies. These inconsistent results may stem from the fact that exposure typically occurs in the context of fish consumption, which is also associated with cardioprotective factors such as omega-3 fatty acids. Mechanistic information may help to understand whether MeHg represents a risk to cardiovascular health. MeHg is a pro-oxidant that inactivates protein sulfhydryls. These biochemical effects may diminish critical antioxidant defense mechanism(s) involved in protecting against atherosclerosis. One such defense mechanism is paraoxonase-1 (PON1), an enzyme present on high-density lipoproteins and that prevents the oxidation of blood lipids and their deposition in vascular endothelium. PON1 is potentially useful as a clinical biomarker of cardiovascular risk, as well as a critical enzyme in the detoxification of certain organophosphate oxons. MeHg and other metals are known to inhibit PON1 activity in vitro. MeHg is associated with lowered serum PON1 activity in a fish-eating population. The implications of lowering PON1 are evaluated by predicting the shift in PON1 population distribution induced by various doses of MeHg. An MeHg dose of 0.3 mug/kg/d is estimated to decrease the population average PON1 level by 6.1% and to increase population risk of acute cardiovascular events by 9.7%. This evaluation provides a plausible mechanism for MeHg-induced cardiovascular risk and suggests means to quantify the risk. This case study exemplifies the use of upstream disease biomarkers to evaluate the additive effect of chemical toxicity with background disease processes in assessing human risk.?http://www.tandfonline.com/doi/abs/10.1080/15287394.2014.919837Ginsberg, G Sonawane, B Nath, R Lewandowski, P Journal Article Research Support, Non-U.S. Gov't England J Toxicol Environ Health A. 2014;77(17):1004-23. doi: 10.1080/15287394.2014.919837.1528-7394 (Print) 0098-41086Journal of toxicology and environmental health. Part A25072822Ia Connecticut Department of Public Healt uang@mail.cmu.edu.tw.10.3390/ijms131012349Linternal-pdf://0329238581/Chen-2012-Mercuric compounds induce pancreatic.pdfNLMeng U7(h , Hartford , Connecticut , USA.10.1080/15287394.2014.919837Linternal-pdf://082 Yinternal-pdf://2127029550/Hirano-1986-Further carcinogenicity study on m.pdfNLMeng F3730519/Ginsberg-2014-Methylmercury-induced inhibitio1.pdfNLMeng S8|<5_,Liang, J. Inskip, M. Newhook, D. Messier, C.2009wNeurobehavioral effect of chronic and bolus doses of methylmercury following prenatal exposure in C57BL/6 weanling mice372-81Neurotoxicol Teratol316 2009/08/27~Animals Behavior, Animal/*drug effects Conditioning, Operant Drug Administration Schedule Emoti ETons/drug effects Exploratory Behavior/drug effects Female Learning/drug effects Male Maternal Exposure Methylmercury Compounds/*administration & dosage/*toxicity Mice Mice, Inbred C57BL Motor Activity/drug effects Pregnancy Prenatal Exposure Delayed Effects/*psychology Random AllocationNov-Dec Several studies with animals have shown that even low and medium prenatal and postnatal exposure to methylmercury (MeHg) can result in locomotor, motor coordination and learning deficits. However, some behavioural effects of MeHg remain controversial and the methods to model human MeHg exposure in animal still remain to be optimized. We investigated the neurobehavioral effects of two different patterns of MeHg exposure. MeHg was given mixed in palatable food that mice readily ate. For the first pattern (chronic group), C57BL/6 mice dams were given 1.4 microg/g body weight (BW)/day (n=20) throughout gestation mixed in palatable food. For the second pattern (bolus) dams were given 6.0 microg/g BW/day mixed in palatable food on gestation day 12 and 16 together with a lower chronic dose of 0.85 microg/g BW/day mixed in palatable food on all remaining gestation days (n=20). Day 12 and 16 were chosen because neuron proliferation and the start of migration for many brain regions occur during that period. Behavioural testing on weanling animals started at 8 weeks. Both the chronic and bolus groups showed an impairment of working memory and visual spatial ability in the radial arm maze task. Other tests did not provide clear evidence that methylmercury exposure had significant adverse effects on locomotor activity, motor coordination or emotional reactivity. However, the chronic groups had a tendency for lower performance in most tests including activity in Skinner box and open field trials, as well as a higher number of anxiety-like behaviors. Chronic exposure to lower levels of MeHg combined to acute exposure with high levels of a few days during gestation appears to be less damaging than chronic exposure to slightly higher levels without acute MeHg exposure even though, equal amounts were administered during gestation. Possibly, as indicated by preliminary data, the relatively larger impact of chronic administration of a higher daily dose could be the consequence of a higher brain MeHg burden in pups compared to brain MeHg levels in the pups from dams receiving a smaller daily dose with 2 large doses on gestation day 12 and 16. Alternatively, bolus MeHg could have had a larger impact if administered on different gestation days when some neural development processes are more sensitive to MeHg.1872-9738 Liang, Jacky Inskip, Mike Newhook, Deborah Messier, Claude Comparative Study Journal Article Research Support, Non-U.S. Gov't United States Neurotoxicol Teratol. 2009 Nov-Dec;31(6):372-81. doi: 10.1016/j.ntt.2009.08.007. Epub 2009 Aug 23. 0892-0362Neurotoxicology and teratology19706324tSchool of Psychology, University of Ottawa, 200 Lees, Building E, 2nd floor, Room 260 J, Ottawa, ON, Canada K1N 6N5.10.1016/j.ntt.2009.08.007Li Vnternal-pdf://3758169680/Kirkpatrick-2015-The effects of methylmercury.pdfNLMEng Wnternal-pdf://3297624437/Liang-2009-Neurobehavioral effect of chronic a.pdfNLMeng |<5`7Branco, V. Canario, J. Lu, J. Holmgren, A. Carvalho, C.2012eMercury and selenium interaction in vivo: effects on thioredoxin reductase and glutathione peroxidase781-93Free Radic Biol Med524 2011/12/27.Animals Antioxidants/pharmacokinetics/*pharmacology Brain/drug effects/enzymology Drug Interactions Fish Proteins/*metabolism Glutathione Peroxidase/antagonists & inhibitors/*metabolism Glutathione Reductase/metabolism Kidney/drug effects/enzymology Liver/drug effects/enzymology Mercury/pharmacokinetics/*toxicity Methylmercury Compounds/pharmacokinetics/*toxicity Muscle, Skeletal/drug effects Sea Bream Selenium/pharmacokinetics/*pharmacology Thioredoxin-Disulfide Reductase/antagonists & inhibitors/*metabolism Thioredoxins/metabolism Tissue DistributionFeb 15CMercury compounds exert toxic effects via interaction with many vital enzymes involved in antioxidant regulation, such as selenoenzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx). Selenium supplementation can reactivate the mercury-inhibited TrxR and recover the cell viability in vitro. To gain an insight on how selenium supplementation affects mercury toxicity in vertebrates, we investigated the effects of selenium on the mercury accumulation and TrxR and GPx activities in a fish model. Juvenile zebra-seabreams were exposed either to methylmercury (MeHg) or inorganic mercury (Hg(2+)) in the presence or absence of sodium selenite (Se) for 28 days followed by 14 days of depuration. Mercury accumulation was found to be 10-fold higher under MeHg exposure than under Hg(2+) exposure. Selenium supplementation caused a half decrease of the accumulation of MeHg but did not influence Hg(2+) accumulation. Exposure to both mercurials led to a decrease of the activity of TrxR (<50% of control) in all organs. Se supplementation coincident with Hg(2+) exposure protected the thioredoxin system in fish liver. However, supplementation of Se during the depuration phase had no effects. The activity of GPx was only affected in the brain of fishes upon the exposure to MeHg and coexposure to MeHg and Se. Selenium supplementation has a limited capacity to prevent mercury effects in brain and kidney. These results demonstrate that Se supplementation plays a protective role in a tissue-specific manner and also highlight the importance of TrxR as a main target for mercurials in vivo.1873-4596 Branco, Vasco Canario, Joao Lu, Jun Holmgren, Arne Carvalho, Cristina Journal Article Research Support, Non-U.S. Gov't United States Free Radic Biol Med. 2012 Feb 15;52(4):781-93. doi: 10.1016/j.freeradbiomed.2011.12.002. Epub 2011 Dec 13. 0891-5849Free radical biology & medicine22198265Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto 1649-003 Lisbon, Portugal. vbranco@ipimar.pt#10.1016/j.freeradbiomed.2011.12.002Linternal-pdf://2194637162/Branco-2012-Mercury and selenium interaction i.pdfNLMeng ary Medical University, Shanghai, China.10.1111/cns.12440Linternal-pdf://3538488138/Song-2015-Exposure to Methylmercury Does Not C.pdfNLMeng T@?a-Faix, S Faixova, Z Boldizarova, K Javorsky, P2005iThe effect of long-term high heavy metal intake on lipid peroxidation of gastrointestinal tissue in sheep401-405 Vet Med-Czec7T?bCosta, Max Zhitkovich, Anatoly Gargas, Michael Paustenbach, Dennis Finley, Brent Kuykendall, Jim Billings, Ruth Carlson, Timothy J Wetterhahn, Karen Xu, Jian1996DInterlaboratory validation of a new assay for DNA-protein crosslinks13-21$Mutation Research/Genetic Toxicology3691 01Yh509Linternal-pdf://3008646255/Faix-2005-The effect of long-term high heavy m.pdf V65-1218Linternal-pdf://1540965396/Costa-1996-Interlaboratory validation of a new.pdfs?cPinheiro, MCN Macchi, BM Vieira, JLF Oikawa, T Amoras, WW Guimarães, GA Costa, CA Crespo-López, ME Herculano, AM Silveira, LCL2008UMercury exposure and antioxidant defenses in women: a comparative study in the Amazon53-59Environmental Research1071 0013-9351Linternal-pdf://2496852180/Pinheiro-2008-Mercury exposure and antioxidant.pdfPKFI/**refs.frm 0B< !// !HPRIMARYyearIndex 6ByP/) idreference_type text_stylesauthoryear title pages secondary_title volume numbernumber_of_volumessecondary_authorplace_published publishersubsidiary_authoredition keywords type_of_workdate2)  abstractlabelurltertiary_titletertiary_author notes isbn custom_1 custom_2 custom_3 custom_4alternate_titleaccession_number call_number short_title custom_5 custom_6sectionoriginal_publicationH) reprint_editionreviewed_itemauthor_addressimagecaption custom_7 electronic_resource_number link_to_pdf translated_author translated_titlename_of_databasedatabase_providerresearch_notes language access_datelast_modified_date !! 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