Browsing by Subject "alcohol consumption"
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Item Alcohol consumption promotes breast cancer development in female mice(2008) Fan, Betty; Nomeli NunezBackgrounds: Epidemiological studies show that alcohol consumption increases breast cancer risk. However, the mechanism by which alcohol causes this effect is not known. Therefore, our objective is to generate an animal model to find the mechanism by which alcohol increases breast cancer risk. Methods: To determine the effects of alcohol consumption on breast cancer development, 65 female FVB/N mice were randomized (30-water, 35-alcohol) to have free access to water or 20% alcohol. All mice were given the same diet and placed in similar living conditions. Eleven weeks into the study, mice were injected with Met-1 mammary cancer cells subcutaneously in their backs. We measured body weight, food, liquid consumption, and tumor growth rate throughout the study. To determine body composition, mice were scanned using a GE Lunar Piximus Densitometer, which measures percent body fat, percent lean body mass, and bone mineral density. Results: Results showed that tumor development is exacerbated in the alcohol consuming mice. Alcohol consuming mice developed tumors earlier than water consuming mice. Furthermore, tumors in the alcohol consuming mice were larger in volume. Body weights, caloric consumption, and body composition showed no significant difference between the alcohol and water consuming mice. Conclusion: We present a suitable animal model where we can elucidate the mechanism by which alcohol consumption promotes mammary tumor development.Item Effects of body weight and alcohol consumption on insulin sensitivity(Nutrition Journal, 2010-03-22) Paulson, Qiwei X.; Hong, Jina; Holcomb, Valerie B.; Nunez, Nomeli P.Background: Obesity is a risk factor for the development of insulin resistance, which can eventually lead to type-2 diabetes. Alcohol consumption is a protective factor against insulin resistance, and thus protects against the development of type-2 diabetes. The mechanism by which alcohol protects against the development of type-2 diabetes is not well known. To determine the mechanism by which alcohol improves insulin sensitivity, we fed water or alcohol to lean, control, and obese mice. The aim of this study was to determine whether alcohol consumption and body weights affect overlapping metabolic pathways and to identify specific target genes that are regulated in these pathways. Method: Adipose tissue dysfunction has been associated with the development of type-2 diabetes. We assessed possible gene expression alterations in epididymal white adipose tissue (WAT). We obtained WAT from mice fed a calorie restricted (CR), low fat (LF Control) or high fat (HF) diets and either water or 20% ethanol in the drinking water. We screened the expression of genes related to the regulation of energy homeostasis and insulin regulation using a gene array composed of 384 genes. Results: Obesity induced insulin resistance and calorie restriction and alcohol improved insulin sensitivity. The insulin resistance in obese mice was associated with the increased expression of inflammatory markers Cd68, Il-6 and Il-1α; in contrast, most of these genes were down-regulated in CR mice. Anti-inflammatory factors such as Il-10 and adrenergic beta receptor kinase 1 (Adrbk1) were decreased in obese mice and increased by CR and alcohol. Also, we report a direct correlation between body weight and the expression of the following genes: Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Lpin2 (lipin2), and Dusp9 (dual-specificity MAP kinase phosphatase 9). Conclusion: We show that alcohol consumption increased insulin sensitivity. Additionally, alterations in insulin sensitivity related with obesity were coupled with alterations in inflammatory genes. We provide evidence that alcohol may improve insulin sensitivity by up-regulating anti-inflammatory genes. Moreover, we have indentified potential gene targets in energy metabolic pathways and signal transducers that may contribute to obesity-related insulin resistance as well as calorie restriction and alcohol-induced insulin sensitivity.Item IL-6 levels after exposure to lipopolysaccharide through injection or alcohol consumption(2008) Chan, Kara; Harris, R. AdronAlcohol interacts with the immune system in multiple ways that are not fully understood but which likely contribute to alcoholic pathologies and may be relevant to the study and treatment of alcohol dependence. Alcohol consumption permeabilizes the gut, allowing the release of lipopolysaccharide (LPS), an endotoxin that elicits the production of pro-inflammatory cytokines (protein signaling molecules produced by immune cells) including interleukin-6 (IL- 6). As excessive inflammation may lead to shock, there exists a protective mechanism, endotoxin tolerance, that suppresses the inflammatory response to LPS after an initial exposure. Because of the phenomenon of endotoxin tolerance, we hypothesized that chronic alcohol exposure would result in the suppression of the IL-6 response to LPS. In this study, mice were treated with a single injection of LPS, repeated injections of LPS, or one injection of LPS after a period of chronic alcohol dinking, and then the levels of IL- 6 were measured in order to assess the immune response. It was found that while mice given a single injection of LPS showed a significant increase in IL-6, those given repeated injections of LPS did not show any increase; they had developed tolerance to the multiple exposures of LPS. After 18 days of chronic voluntary intake of alcohol, the IL-6 response to LPS was also suppressed. This shows that chronic alcohol consumption produces an alteration in the immune system that could play a possible role in the development of alcohol dependence. Further research is necessary to determine if this area of study could lead to the better understanding and treatment of alcohol dependence.Item Integration of miRNA and Protein Profiling Reveals Coordinated Neuroadaptations in the Alcohol-Dependent Mouse Brain(PLOS One, 2013-12-16) Gorini, Giorgio; Nunez. Yuury O.; Mayfield, R. DayneThe molecular mechanisms underlying alcohol dependence involve different neurochemical systems and are brain region-dependent. Chronic Intermittent Ethanol (CIE) procedure, combined with a Two-Bottle Choice voluntary drinking paradigm, represents one of the best available animal models for alcohol dependence and relapse drinking. MicroRNAs, master regulators of the cellular transcriptome and proteome, can regulate their targets in a cooperative, combinatorial fashion, ensuring fine tuning and control over a large number of cellular functions. We analyzed cortex and midbrain microRNA expression levels using an integrative approach to combine and relate data to previous protein profiling from the same CIE-subjected samples, and examined the significance of the data in terms of relative contribution to alcohol consumption and dependence. MicroRNA levels were significantly altered in CIE-exposed dependent mice compared with their non-dependent controls. More importantly, our integrative analysis identified modules of coexpressed microRNAs that were highly correlated with CIE effects and predicted target genes encoding differentially expressed proteins. Coexpressed CIE-relevant proteins, in turn, were often negatively correlated with specific microRNA modules. Our results provide evidence that microRNA-orchestrated translational imbalances are driving the behavioral transition from alcohol consumption to dependence. This study represents the first attempt to combine ex vivo microRNA and protein expression on a global scale from the same mammalian brain samples. The integrative systems approach used here will improve our understanding of brain adaptive changes in response to drug abuse and suggests the potential therapeutic use of microRNAs as tools to prevent or compensate multiple neuroadaptations underlying addictive behavior.Item Neurobiological Signatures of Alcohol Dependence Revealed by Protein Profiling(PLOS One, 2013-12-16) Gorini, Giorgio; Roberts, Amanda J.; Mayfield, Dayne R.Alcohol abuse causes dramatic neuroadaptations in the brain, which contribute to tolerance, dependence, and behavioral modifications. Previous proteomic studies in human alcoholics and animal models have identified candidate alcoholism-related proteins. However, recent evidences suggest that alcohol dependence is caused by changes in co-regulation that are invisible to single protein-based analysis. Here, we analyze global proteomics data to integrate differential expression, co-expression networks, and gene annotations to unveil key neurobiological rearrangements associated with the transition to alcohol dependence modeled by a Chronic Intermittent Ethanol (CIE), two-bottle choice (2BC) paradigm. We analyzed cerebral cortices (CTX) and midbrains (MB) from male C57BL/6J mice subjected to a CIE, 2BC paradigm, which induces heavy drinking and represents one of the best available animal models for alcohol dependence and relapse drinking. CIE induced significant changes in protein levels in dependent mice compared with their non-dependent controls. Multiple protein isoforms showed region-specific differential regulation as a result of post-translational modifications. Our integrative analysis identified modules of co-expressed proteins that were highly correlated with CIE treatment. We found that modules most related to the effects of CIE treatment coordinate molecular imbalances in endocytic- and energy-related pathways, with specific proteins involved, such as dynamin-1. The qRT-PCR experiments validated both differential and co-expression analyses, and the correspondence among our data and previous genomic and proteomic studies in humans and rodents substantiates our findings. The changes identified above may play a key role in the escalation of ethanol consumption associated with dependence. Our approach to alcohol addiction will advance knowledge of brain remodeling mechanisms and adaptive changes in response to drug abuse, contribute to understanding of organizational principles of CTX and MB proteomes, and define potential new molecular targets for treating alcohol addiction. The integrative analysis employed here highlight the advantages of systems approaches in studying the neurobiology of alcohol addiction.