Unknown,Transcriptomics,Genomics,Proteomics

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Dietary zinc modulation of cancer-related inflammation genes and esophageal tumor development and prevention in rats

ABSTRACT: Weaning male Sprague-Dawley rats were divided into 2 dietary groups to form the Zn-deficient (ZD) and Zn-sufficient (ZS) groups. After 5 weeks, the animals received intragastrically, their 1st N-nitrosomethylbenzylamine dose (NMBA, an esophagus carcinogen) at 2 mg/kg body weight. Immediately after NMBA treatment, half of the ZD rats were switched to a ZS diet to form the Zn-replenished (ZR) group, the other half of ZD rats and ZS rats continued on their respective diets. Five weeks after the 1st NMBA dose, 8 ZD, 8 ZR, and 8 ZS rats were sacrificed gene expression profiling and related studies. The remaining rats received their 2nd and 3rd NMBA dose at 6 weeks and 12 weeks after the 1st NMBA dose. At 15 weeks (endpoint) after the 1st NMBA dose, all animals were sacrificed for tumor incidence analysis and gene expression profiling studies. In this study, ZD rats documented a significantly higher tumorigenic outcome than control ZS rats (tumor incidence, ZD vs ZS: 100% vs 16.6%; tumor multiplicity, 11 ± 3.8 vs 0.5 ± 0.3, P<0.001). Replenishing zinc after the first NMBA dose led to a significantly reduced tumor incidence and multiplicity in ZR vs ZD rats (incidence, 28.9% vs 100%; multiplicity, 0.6 ± 0.4 vs 11 ± 3.8, P<0.001). Expression profiling of esophageal epithelia from NMBA-treated ZD, ZR, and control ZS rats (n=4/group) was performed at 5 weeks and at 15 weeks after the 1st carcinogen dose, using Rat Genome 230 2.0 GeneChip (Affymetrix, Santa Clara, CA)

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Cristian Taccioli

PROVIDER: E-MTAB-428 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:To date, there is little information on early molecular events in the development of N-nitrosomethylbenzylamine (NMBA) induced esophageal tumorigenesis and of the effects of chemopreventive agents on these events. In this study, we identified genes in rat esophagus that were differentially expressed in response to shortâ??term NMBA-treatment and modulated by co-treatment with phenethylisothiocyanate (PEITC). Rats were fed AIN-76A diet or AIN-76A diet containing PEITC for three weeks. During the third week of dietary treatment, they were administered three s.c. doses of NMBA (0.5 mg/kg b.w.). Rats were sacrificed 24 h after the last treatment, esophagi excised and processed for histological grading, microarray and real-time PCR analysis. Our histopathological data showed that treatment of rats with PEITC had protective effect on NMBA-induced preneoplastic lesions in the rat esophagus. We identified 2261 genes that were differentially expressed in the NMBA-treated vs. control esophagi and 1936 genes in the NMBA+PEITC- vs. NMBA-treated esophagi. The intersection of these two sets resulted in the identification of 1323 genes in NMBA-treated esophagus that were modulated by PEITC to near-normal levels of expression. The measured changes in the expression levels of 10 selected genes were validated using real-time PCR. Principle components analysis (PCA) was applied to all twelve microarrays in the study, which suggested that in terms of global gene expression, PEITC treatment had a genome-wide modulating effect on NMBA-induced gene expression. Samples obtained from animals treated with PEITC alone or co-treated with NMBA were more similar to controls than they were to NMBA treatment alone. Experiment Overall Design: For each treatment we used a pooling strategy to enable the inclusion of samples from numerous animals. Three replicate microarrays were completed for each of the four treatments (control, PEITC, NMBA and NMBA+PEITC) for a total of twelve microarrays. Each microarray was hybridized using a pooled RNA sample, and each pool was created from equal amounts of total RNA from two or three independent RNA samples, representing individual animals. Each of these samples was obtained from a different animal, and no sample was included in more than one pool. In total, samples from nine animals per group were pooled for control, NMBA, PEITC and NMBA+PEITC microarrays. To facilitate comparisons of gene expression across all treatments, we utilized a reference design in which each microarray was co-hybridized with a common reference sample labeled with Cy3, and RNA from the treatment pool was labeled with Cy5. Stratageneâ??s Universal Rat reference RNA (Stratagene, La Jolla, CA) was used as the common reference in all microarrays.

Project description:Zinc (Zn) is a major elemental component of respirable ambient particulate matter (PM) detected often at alarming levels in urban air. Exposure to PM has been widely associated with increased cardiovascular morbidity and mortality, however, it is not known what components or sources of PM are causative. We recently demonstrated that long-term episodic inhalation of combustion PM, having similar amount of Zn found in urban PM, caused myocardial lesions in rats. We further demonstrated that a single pulmonary exposure to Zn at high concentration is associated with disturbances in cardiac mitochondrial function, ion channel regulation, calcium homeostasis, and cell signaling. Therefore, in this study we investigated the role of PM-associated Zn in cardiac injury using multiple exposure scenarios. Male Wistar-Kyoto (WKY) rats of 12-14 wks age were intratracheally exposed (once per wk x 8 or16 wks) to either (1) saline (control); (2) PM having no soluble Zn; (3) combustion PM suspension containing 14.5 ug/mg water-soluble Zn at high and (4) low dose levels, (5) the aqueous fraction of this suspension devoid of solid insoluble particulate fraction (14.5 ug/mg soluble Zn), or (6) Zn sulfate. Zn concentrations were identical in groups 3, 5 and 6. Pulmonary toxicity was apparent in all exposure groups when compared to saline as determined by recovery of cells in bronchoalveolar lavage fluid. Long-term exposure to PM with or without soluble Zn, or Zn sulfate caused distinct myocardial lesions characterized by subepicardial and randomly distributed myocardial inflammation, degeneration, and fibrosis. The lesion severity was higher in those groups receiving Zn PM. Because cardiac mitochondria are likely the primary target of inhaled metal or other absorbed PM components, we analyzed mitochondrial DNA damage using QPCR and found that all exposure groups except those exposed to PM without Zn caused variable degree of damage. Aconitase activity, sensitive to inhibition by oxidative stress was inhibited slightly but significantly in rats receiving zinc sulfate. Although modest, microarray (Affymetrix) analysis revealed expression changes in the heart reflective of effects on cell signaling, inflammation/oxidative stress, mitochondrial fatty acid metabolisms and cell cycle regulation in rats exposed to zinc sulfate. However, these changes were minimal following exposure to PM devoid of soluble metals. We demonstrate that episodic subchronic pulmonary exposure to zinc sulfate causes cardiac injury and mitochondrial DNA damage. Thus, water-soluble PM-associated zinc may be one of the PM components responsible for cardiovascular morbidity. Keywords: Pulmonary exposure, Cardiac gene expression

Project description:Objective: To determine the oxidative stress during cycles of chemotherapy in patients after surgery for colorectal cancer, with or without oral zinc supplementation. Subjects: Twenty four adults from both genders participated in this study. All patients underwent stage II, III or IV colorectal cancer surgical resection and were starting chemotherapy in HCFMRP- USP. Patients were randomized into two groups. The first one (QTx-Zn Group, n=10) received 70 mg/d of zinc orally and the second one received placebo (QTx-Placebo Group, n=14) for 16 weeks. The study also included 30 healthy volunteers matched for age, gender and socioeconomic status, who received 70 mg/d of zinc supplement (Control-Zn Group, n=21) or placebo (Control-Placebo Group, n=9) for 16 weeks. Methods: The questionnaires about dietary intake (semiquantitative food frequency and food record), fatigue and quality of life (FACIT-F) and questionnaires that assess the side effects of chemotherapy (CTCAE) were evaluated. Anthropometry and bioelectrical impedance measurements were made. Blood collection was performed before the 1st, 2nd, 3rd and 4th cycles of chemotherapy (median duration of 21 days among cicles). Routine laboratory tests, vitamin E and markers anti and pro-oxidants (MDA, SOD, GPx and isoprostane) ere determined. The control group underwent the same procedures, except for chemotherapy. A longitudinal linear mixed effects model was adjusted for each of the variables of interest. The models were fitted using PROC MIXED of SAS version 9 (SAS, CARY, NC, USA). To analyze the association of categorical variables in the different items of the CTCAE, the investigators used the Fisher exact test. Results: The oral zinc supplementation was sufficient to increase plasma levels of zinc and did not alter food intake, body composition and routine laboratory evaluation of patients undergoing chemotherapy for colorectal cancer. Compared with QTx-Placebo Group, QTx-Zn Group showed lower prevalence of complaint on the salivary gland (17 vs. 75%). Fatigue (43 ± 6 vs. 36 ± 13) and quality of life (126 ± 160 vs. 116 ± 27) has become worst in the period between the 1st and 4th cycles of QTx in QTx-Placebo Group. When compared with QTx-Placebo Group, QTx-Zn Group had higher values of SOD before the 1st (2297 ± 503 vs. 1604 ± 352 USOD/g Hb), 2nd (2037 ± 515 vs. 1712 ± 417 USOD/g Hb) and 4th (2202 ± 323 vs. 1821 ± 360 USOD/g Hb) cycles of QTx. GPx values decreased in QTx-Zn Group before the 3rd cycle of QTx (48.5 ± 7.0 vs. 54.3 ± 2.3 mol NADPH/min/gHb). Conclusions: These data suggest that zinc supplementation reduces complaints related to the change in salivary gland, preserving the quality of life and preventing the worsening of fatigue. The increase in SOD can be attributed to zinc supplementation per se, whereas this mineral is a cofactor that endogenous antioxidant enzyme. The highest activity of SOD increases the production of H2O2, whose detoxification involves the participation of GPx, justifying its reduction. There were no changes in plasma levels of vitamin E, MDA and isoprostane during the study period. Considering the values of MDA and isoprostane, the data indicate that regardless of zinc supplementation, the lipid peroxidation of the cell membrane was unchanged during chemotherapy.

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Dietary zinc modulation of cancer-related inflammation genes and esophageal tumor development and prevention in rats

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