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Sample records for intake alters gene

  1. Acute Heat Stress and Reduced Nutrient Intake Alter Intestinal Proteomic Profile and Gene Expression in Pigs

    PubMed Central

    Pearce, Sarah C.; Lonergan, Steven M.; Huff-Lonergan, Elisabeth; Baumgard, Lance H.; Gabler, Nicholas K.

    2015-01-01

    Heat stress and reduced feed intake negatively affect intestinal integrity and barrier function. Our objective was to compare ileum protein profiles of pigs subjected to 12 hours of HS, thermal neutral ad libitum feed intake, or pair-fed to heat stress feed intake under thermal neutral conditions (pair-fed thermal neutral). 2D-Differential In Gel Electrophoresis and gene expression were performed. Relative abundance of 281 and 138 spots differed due to heat stress, compared to thermal neutral and pair-fed thermal neutral pigs, respectively. However, only 20 proteins were different due to feed intake (thermal neutral versus pair-fed thermal neutral). Heat stress increased mRNA expression of heat shock proteins and protein abundance of heat shock proteins 27, 70, 90-α and β were also increased. Heat stress reduced ileum abundance of several metabolic enzymes, many of which are involved in the glycolytic or TCA pathways, indicating a change in metabolic priorities. Stress response enzymes peroxiredoxin-1 and peptidyl-prolyl cis-trans isomerase A were decreased in pair-fed thermal neutral and thermal neutral pigs compared to heat stress. Heat stress increased mRNA abundance markers of ileum hypoxia. Altogether, these data show that heat stress directly alters intestinal protein and mRNA profiles largely independent of reduced feed intake. These changes may be related to the reduced intestinal integrity associated with heat stress. PMID:26575181

  2. Raising gestational choline intake alters gene expression in DMBA-evoked mammary tumors and prolongs survival

    PubMed Central

    Kovacheva, Vesela P.; Davison, Jessica M.; Mellott, Tiffany J.; Rogers, Adrianne E.; Yang, Shi; O'Brien, Michael J.; Blusztajn, Jan Krzysztof

    2009-01-01

    . J., Blusztajn, J. K. Raising gestational choline intake alters gene expression in DMBA-evoked mammary tumors and prolongs survival. (2009) PMID:19047067

  3. GPR17 gene disruption does not alter food intake or glucose homeostasis in mice

    PubMed Central

    Mastaitis, Jason; Min, Soo; Elvert, Ralf; Kannt, Aimo; Xin, Yurong; Ochoa, Francisca; Gale, Nicholas W.; Valenzuela, David M.; Murphy, Andrew J.; Yancopoulos, George D.; Gromada, Jesper

    2015-01-01

    G protein-coupled receptor 17 (GPR17) was recently reported to be a Foxo1 target in agouti-related peptide (AGRP) neurons. Intracerebroventricular injection of GPR17 agonists induced food intake, whereas administration of an antagonist to the receptor reduced feeding. These data lead to the conclusion that pharmacological modulation of GPR17 has therapeutic potential to treat obesity. Here we report that mice deficient in Gpr17 (Gpr17−/−) have similar food intake and body weight compared with their wild-type littermates. Gpr17−/− mice have normal hypothalamic Agrp mRNA expression, AGRP plasma levels, and metabolic rate. GPR17 deficiency in mice did not affect glucose homeostasis or prevent fat-induced insulin resistance. These data do not support a role for GPR17 in the control of food intake, body weight, or glycemic control. PMID:25624481

  4. Dietary intake alters behavioral recovery and gene expression profiles in the brain of juvenile rats that have experienced a concussion

    PubMed Central

    Mychasiuk, Richelle; Hehar, Harleen; Ma, Irene; Esser, Michael J.

    2015-01-01

    Concussion and mild traumatic brain injury (mTBI) research has made minimal progress diagnosing who will suffer from lingering symptomology or generating effective treatment strategies. Research demonstrates that dietary intake affects many biological systems including brain and neurological health. This study determined if exposure to a high fat diet (HFD) or caloric restriction (CR) altered post-concussion susceptibility or resiliency using a rodent model of pediatric concussion. Rats were maintained on HFD, CR, or standard diet (STD) throughout life (including the prenatal period and weaning). At postnatal day 30, male and female rats experienced a concussion or a sham injury which was followed by 17 days of testing. Prefrontal cortex and hippocampus tissue was collected for molecular profiling. Gene expression changes in BDNF, CREB, DNMT1, FGF-2, IGF1, LEP, PGC-1α, SIRT1, Tau, and TERT were analyzed with respect to injury and diet. Analysis of telomere length (TL) using peripheral skin cells and brain tissue found that TL in skin significantly correlated with TL in brain tissue and TL was affected by dietary intake and injury status. With respect to mTBI outcomes, diet was correlated with recovery as animals on the HFD often displayed poorer performance than animals on the CR diet. Molecular analysis demonstrated that diet induced epigenetic changes that can be associated with differences in individual predisposition and resiliency to post-concussion syndrome. PMID:25698949

  5. Dietary intake alters gene expression in colon tissue: possible underlying mechanism for the influence of diet on disease

    PubMed Central

    Pellatt, Andrew J.; Mullany, Lila E.; Wolff, Roger K.; Pellatt, Daniel F.

    2016-01-01

    Background Although the association between diet and disease is well documented, the biologic mechanisms involved have not been entirely elucidated. In this study, we evaluate how dietary intake influences gene expression to better understand the underlying mechanisms through which diet operates. Methods We used data from 144 individuals who had comprehensive dietary intake and gene expression data from RNAseq using normal colonic mucosa. Using the DESeq2 statistical package, we identified genes that showed statistically significant differences in expression between individuals in high-intake and low-intake categories for several dietary variables of interest adjusting for age and sex. We examined total calories, total fats, vegetable protein, animal protein, carbohydrates, trans-fatty acids, mutagen index, red meat, processed meat, whole grains, vegetables, fruits, fiber, folate, dairy products, calcium, and prudent and western dietary patterns. Results Using a false discovery rate of less than 0.1, meat-related foods were statistically associated with 68 dysregulated genes, calcium with three dysregulated genes, folate with four dysregulated genes, and nonmeat-related foods with 65 dysregulated genes. With a more stringent false discovery rate of less than 0.05, there were nine meat-related dysregulated genes and 23 nonmeat-related genes. Ingenuity pathway analysis identified three major networks among genes identified as dysregulated with respect to meat-related dietary variables and three networks among genes identified as dysregulated with respect to nonmeat-related variables. The top networks (Ingenuity Pathway Analysis network score >30) associated with meat-related genes were (i) cancer, organismal injury, and abnormalities, tumor morphology, and (ii) cellular function and maintenance, cellular movement, cell death, and survival. Among genes related to nonmeat consumption variables, the top networks were (i) hematological system development and function

  6. The Orphan G Protein-Coupled Receptor Gene GPR178 Is Evolutionary Conserved and Altered in Response to Acute Changes in Food Intake

    PubMed Central

    Shirazi Fard, Shahrzad; Haitina, Tatjana; Olszewski, Pawel K.; Alsiö, Johan; Schiöth, Helgi B.; Fredriksson, Robert

    2015-01-01

    G protein-coupled receptors (GPCRs) are a class of integral membrane proteins mediating physiological functions fundamental for survival, including energy homeostasis. A few years ago, an amino acid sequence of a novel GPCR gene was identified and named GPR178. In this study, we provide new insights regarding the biological significance of Gpr178 protein, investigating its evolutionary history and tissue distribution as well as examining the relationship between its expression level and feeding status. Our phylogenetic analysis indicated that GPR178 is highly conserved among all animal species investigated, and that GPR178 is not a member of a protein family. Real-time PCR and in situ hybridization revealed wide expression of Gpr178 mRNA in both the brain and periphery, with high expression density in the hypothalamus and brainstem, areas involved in the regulation of food intake. Hence, changes in receptor expression were assessed following several feeding paradigms including starvation and overfeeding. Short-term starvation (12–48h) or food restriction resulted in upregulation of Gpr178 mRNA expression in the brainstem, hypothalamus and prefrontal cortex. Conversely, short-term (48h) exposure to sucrose or Intralipid solutions downregulated Gpr178 mRNA in the brainstem; long-term exposure (10 days) to a palatable high-fat and high-sugar diet resulted in a downregulation of Gpr178 in the amygdala but not in the hypothalamus. Our results indicate that hypothalamic Gpr178 gene expression is altered during acute exposure to starvation or acute exposure to palatable food. Changes in gene expression following palatable diet consumption suggest a possible involvement of Gpr178 in the complex mechanisms of feeding reward. PMID:26047506

  7. Altered energy intake and the amplitude of the body temperature rhythm are associated with changes in phase, but not amplitude, of clock gene expression in the rat suprachiasmatic nucleus in vivo.

    PubMed

    Goh, Grace H; Mark, Peter J; Maloney, Shane K

    2016-01-01

    Circadian rhythms in mammals are driven by a central clock in the suprachiasmatic nucleus (SCN). In vitro, temperature cycles within the physiological range can act as potent entraining cues for biological clocks. We altered the body temperature (Tc) rhythm in rats by manipulating energy intake (EI) to determine whether EI-induced changes in Tc oscillations are associated with changes in SCN clock gene rhythms in vivo. Male Wistar rats (n = 16 per diet) were maintained on either an ad libitum diet (CON), a high energy cafeteria diet (CAF), or a calorie restricted diet (CR), and Tc was recorded every 30 min for 6-7 weeks. SCN tissue was harvested from rats at zeitgeber time (ZT) 0, ZT6, ZT12, or ZT18. Expression of the clock genes Bmal1, Per2, Cry1, and Rev-erbα, the heat shock transcription factor Hsf1, and the heat shock protein Hsp90aa1, were determined using qPCR. The circadian profile of gene expression for each gene was characterized using cosinor analysis. Compared to the CON rats, the amplitude of Tc was decreased in CAF rats by 0.1 °C (p < 0.001), and increased in CR rats by 0.3 °C (p < 0.001). The amplitude of Hsp90aa1 expression was lowest in CAF rats and highest in CR rats (p = 0.045), but the amplitude of all of the clock genes and Hsf1 were unaffected by diet (p > 0.25). Compared to CON, phase advances of the Tc, Bmal1, and Per2 rhythms were observed with CR feeding (p < 0.05), but CAF feeding elicited no significant changes in phase. The present results indicate that in vivo, the SCN is largely resistant to entrainment by EI-induced changes in the Tc rhythm, although some phase entrainment may occur. PMID:26745660

  8. Common genes regulate food and ethanol intake in Drosophila.

    PubMed

    Sekhon, Morgan L; Lamina, Omoteniola; Hogan, Kerry E; Kliethermes, Christopher L

    2016-06-01

    The abuse liability of alcohol (ethanol) is believed to result in part from its actions on neurobiological substrates that underlie the motivation toward food and other natural reinforcers, and a growing body of evidence indicates that these substrates are broadly conserved among animal phyla. Understanding the extent to which the substrates regulating ethanol and food intake overlap is an important step toward developing therapeutics that selectively reduce ethanol intake. In the current experiments, we measured food and ethanol intake in Recombinant Inbred (RI) lines of Drosophila melanogaster using several assays, and then calculated genetic correlations to estimate the degree to which common genes might underlie behavior in these assays. We found that food intake and ethanol intake as measured in the capillary assay are genetically correlated traits in D. melanogaster, as well as in a panel of 11 Drosophila species that we tested subsequently. RI line differences in food intake in a dyed food assay were genetically unrelated to ethanol intake in the capillary assay or to ethanol preference measured using an olfactory trap apparatus. Using publicly available gene expression data, we found that expression profiles across the RI lines of a number of genes (including the D2-like dopamine receptor, DOPA decarboxylase, and fruitless) correlated with the RI line differences in food and ethanol intake we measured, while the expression profiles of other genes, including NPF, and the NPF and 5-HT2 receptors, correlated only with ethanol intake or preference. Our results suggest that food and ethanol intake are regulated by some common genes in Drosophila, but that other genes regulate ethanol intake independently of food intake. These results have implications toward the development of therapeutics that preferentially reduce ethanol intake. PMID:27286934

  9. Gonadal Transcriptome Alterations in Response to Dietary Energy Intake: Sensing the Reproductive Environment

    PubMed Central

    Martin, Bronwen; Pearson, Michele; Brenneman, Randall; Golden, Erin; Wood, William; Prabhu, Vinayakumar; Becker, Kevin G.; Mattson, Mark P.; Maudsley, Stuart

    2009-01-01

    Reproductive capacity and nutritional input are tightly linked and animals' specific responses to alterations in their physical environment and food availability are crucial to ensuring sustainability of that species. We have assessed how alterations in dietary energy intake (both reductions and excess), as well as in food availability, via intermittent fasting (IF), affect the gonadal transcriptome of both male and female rats. Starting at four months of age, male and female rats were subjected to a 20% or 40% caloric restriction (CR) dietary regime, every other day feeding (IF) or a high fat-high glucose (HFG) diet for six months. The transcriptional activity of the gonadal response to these variations in dietary energy intake was assessed at the individual gene level as well as at the parametric functional level. At the individual gene level, the females showed a higher degree of coherency in gonadal gene alterations to CR than the males. The gonadal transcriptional and hormonal response to IF was also significantly different between the male and female rats. The number of genes significantly regulated by IF in male animals was almost 5 times greater than in the females. These IF males also showed the highest testosterone to estrogen ratio in their plasma. Our data show that at the level of gonadal gene responses, the male rats on the IF regime adapt to their environment in a manner that is expected to increase the probability of eventual fertilization of females that the males predict are likely to be sub-fertile due to their perception of a food deficient environment. PMID:19127293

  10. Chronic liquid nutrition intake induces obesity and considerable but reversible metabolic alterations in Wistar rats.

    PubMed

    Mikuska, Livia; Vrabcova, Michaela; Tillinger, Andrej; Balaz, Miroslav; Ukropec, Jozef; Mravec, Boris

    2016-06-01

    We have previously described the development of substantial, but reversible obesity in Wistar rats fed with palatable liquid nutrition (Fresubin). In this study, we investigated changes in serum hormone levels, glycemia, fat mass, adipocyte size, and gene expression of adipokines and inflammatory markers in adipose tissue of Wistar rats fed by Fresubin (i) for 5 months, (ii) up to 90 days of age, or (iii) after 90 days of age to characterize metabolic alterations and their reversibility in rats fed with Fresubin. An intra-peritoneal glucose tolerance test was also performed to determine levels of serum leptin, adiponectin, insulin, and C-peptide in 2- and 4-month-old animals. In addition, mesenteric and epididymal adipose tissue weight, adipocyte diameter, and gene expression of pro- and anti-inflammatory adipokines and other markers were determined at the end of the study. Chronic Fresubin intake significantly increased adipocyte diameter, reduced glucose tolerance, and increased serum leptin, adiponectin, insulin, and C-peptide levels. Moreover, gene expression of leptin, adiponectin, CD68, and nuclear factor kappa B was significantly increased in mesenteric adipose tissue of Fresubin fed rats. Monocyte chemotactic protein 1 messenger RNA (mRNA) levels increased in mesenteric adipose tissue only in the group fed Fresubin during the entire experiment. In epididymal adipose tissue, fatty acid binding protein 4 mRNA levels were significantly increased in rats fed by Fresubin during adulthood. In conclusion, chronic Fresubin intake induced complex metabolic alterations in Wistar rats characteristic of metabolic syndrome. However, transition of rats from Fresubin to standard diet reversed these alterations. PMID:26939586

  11. Altered salience network connectivity predicts macronutrient intake after sleep deprivation

    PubMed Central

    Fang, Zhuo; Spaeth, Andrea M.; Ma, Ning; Zhu, Senhua; Hu, Siyuan; Goel, Namni; Detre, John A.; Dinges, David F.; Rao, Hengyi

    2015-01-01

    Although insufficient sleep is a well-recognized risk factor for overeating and weight gain, the neural mechanisms underlying increased caloric (particularly fat) intake after sleep deprivation remain unclear. Here we used resting-state functional magnetic resonance imaging and examined brain connectivity changes associated with macronutrient intake after one night of total sleep deprivation (TSD). Compared to the day following baseline sleep, healthy adults consumed a greater percentage of calories from fat and a lower percentage of calories from carbohydrates during the day following TSD. Subjects also exhibited increased brain connectivity in the salience network from the dorsal anterior cingulate cortex (dACC) to bilateral putamen and bilateral anterior insula (aINS) after TSD. Moreover, dACC-putamen and dACC-aINS connectivity correlated with increased fat and decreased carbohydrate intake during the day following TSD, but not during the day following baseline sleep. These findings provide a potential neural mechanism by which sleep loss leads to increased fat intake. PMID:25645575

  12. Maternal separation alters drug intake patterns in adulthood in rats.

    PubMed

    Moffett, M C; Vicentic, A; Kozel, Marie; Plotsky, Paul; Francis, D D; Kuhar, M J

    2007-02-01

    Maternal separation/handling (MS/H) is an animal model of early life stress that causes profound neurochemical and behavioral alterations in pups that persist into adulthood. Many recent studies have used the MS/H model to study changes in drug effects in adulthood that are linked to behavioral treatments and stressors in the perinatal period. The drug effects focused on in this review are the reinforcing properties of the abused drugs, cocaine and alcohol. A striking finding is that variations in maternal separation and handling cause changes in ethanol and cocaine self-administration. Further, these changes indicate that various manipulations in the perinatal period can have long lasting effects of interest to biochemical pharmacologists. This article will review recent studies on ethanol and cocaine self-administration using the MS/H model and the neurochemical alterations that may play a role in the effects of MS/H on ethanol and cocaine self-administration. Studying the MS/H model can provide important clues into the vulnerability to drug abuse and perhaps identify a crucial window of opportunity for therapeutic intervention. PMID:16962564

  13. Chronic Ethanol Intake Alters Circadian Phase Shifting and Free-Running Period in Mice

    PubMed Central

    Seggio, Joseph A.; Fixaris, Michael C.; Reed, Jeffrey D.; Logan, Ryan W.; Rosenwasser, Alan M.

    2011-01-01

    Chronic alcohol intake is associated with widespread disruptions in sleep and circadian rhythms in both human alcoholics and in experimental animals. Recent studies have demonstrated that chronic and acute ethanol treatments alter fundamental properties of the circadian pacemaker—including free-running period and responsiveness to photic and nonphotic phase-shifting stimuli—in rats and hamsters. In the present work, the authors extend these observations to the C57BL/6J mouse, an inbred strain characterized by very high levels of voluntary ethanol intake and by reliable and stable free-running circadian activity rhythms. Mice were housed individually in running-wheel cages under conditions of either voluntary or forced ethanol intake, whereas controls were maintained on plain water. Forced ethanol intake significantly attenuated photic phase delays (but not phase advances) and shortened free-running period in constant darkness, but voluntary ethanol intake failed to affect either of these parameters. Thus, high levels of chronic ethanol intake, beyond those normally achieved under voluntary drinking conditions, are required to alter fundamental circadian pacemaker properties in C57BL/6J mice. These observations may be related to the relative ethanol insensitivity displayed by this strain in several other phenotypic domains, including ethanol-induced sedation, ataxia, and withdrawal. Additional experiments will investigate chronobiological sensitivity to ethanol in a range of inbred strains showing diverse ethanol-related phenotypes. PMID:19625732

  14. Chronic ethanol intake alters circadian phase shifting and free-running period in mice.

    PubMed

    Seggio, Joseph A; Fixaris, Michael C; Reed, Jeffrey D; Logan, Ryan W; Rosenwasser, Alan M

    2009-08-01

    Chronic alcohol intake is associated with widespread disruptions in sleep and circadian rhythms in both human alcoholics and in experimental animals. Recent studies have demonstrated that chronic and acute ethanol treatments alter fundamental properties of the circadian pacemaker--including free-running period and responsiveness to photic and nonphotic phase-shifting stimuli--in rats and hamsters. In the present work, the authors extend these observations to the C57BL/6J mouse, an inbred strain characterized by very high levels of voluntary ethanol intake and by reliable and stable free-running circadian activity rhythms. Mice were housed individually in running-wheel cages under conditions of either voluntary or forced ethanol intake, whereas controls were maintained on plain water. Forced ethanol intake significantly attenuated photic phase delays (but not phase advances) and shortened free-running period in constant darkness, but voluntary ethanol intake failed to affect either of these parameters. Thus, high levels of chronic ethanol intake, beyond those normally achieved under voluntary drinking conditions, are required to alter fundamental circadian pacemaker properties in C57BL/6J mice. These observations may be related to the relative ethanol insensitivity displayed by this strain in several other phenotypic domains, including ethanol-induced sedation, ataxia, and withdrawal. Additional experiments will investigate chronobiological sensitivity to ethanol in a range of inbred strains showing diverse ethanol-related phenotypes. PMID:19625732

  15. Methylation Alterations at Imprinted Genes Detected Among Long Term Shiftworkers

    PubMed Central

    Jacobs, Daniel I.; Hansen, Johnni; Fu, Alan; Stevens, Richard G.; Tjonneland, Anne; Vogel, Ulla B.; Zheng, Tongzhang; Zhu, Yong

    2016-01-01

    Exposure to light at night through shiftwork has been linked to alterations in DNA methylation and increased risk of cancer development. Using an Illumina Infinium Methylation Assay, we analyzed methylation levels of 397 CpG sites in the promoter regions of 56 normally imprinted genes to investigate whether shiftwork is associated with alteration of methylation patterns. Methylation was significantly higher at 20 CpG sites and significantly lower at 30 CpG sites (P < 0.05) in 10 female long-term shiftworkers as compared to 10 female age- and folate intake-matched day workers. The strongest evidence for altered methylation patterns in shiftworkers was observed for DLX5, IGF2AS, and TP73 based on the magnitude of methylation change and consistency in the direction of change across multiple CpG sites, and consistent results were observed using quantitative DNA methylation analysis. We conclude that long-term shiftwork may alter methylation patterns at imprinted genes, which may be an important mechanism by which shiftwork has carcinogenic potential and warrants further investigation. PMID:23193016

  16. Excess dietary salt intake alters the excitability of central sympathetic networks.

    PubMed

    Stocker, Sean D; Madden, Christopher J; Sved, Alan F

    2010-07-14

    The ingestion of excess dietary salt (defined as NaCl) is strongly correlated with cardiovascular disease, morbidity, mortality, and is regarded as a major contributing factor to the pathogenesis of hypertension. Although several mechanisms contribute to the adverse consequences of dietary salt intake, accumulating evidence suggests that dietary salt loading produces neurogenically-mediated increases in total peripheral resistance to raise arterial blood pressure (ABP). Evidence from clinical studies and experimental models clearly establishes a hypertensive effect of dietary salt loading in a subset of individuals who are deemed "salt-sensitive". However, we will discuss and present evidence to develop a novel hypothesis to suggest that while chronic increases in dietary salt intake do not elevate mean ABP in "non-salt-sensitive" animals, dietary salt intake does enhance several sympathetic reflexes thereby predisposing these animals and/or individuals to the development of salt-sensitive hypertension. Additional evidence raises an intriguing hypothesis that these enhanced sympathetic reflexes are largely attributed to the ability of excess dietary salt intake to selectively enhance the excitability of sympathetic-regulatory neurons in the rostral ventrolateral medulla. Insight into the cellular mechanisms by which dietary salt intake alters the responsiveness of RVLM circuits will likely provide a foundation for developing new therapeutic approaches to treat salt-sensitive hypertension. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009. PMID:20434471

  17. Gray matter alterations and correlation of nutritional intake with the gray matter volume in prediabetes

    PubMed Central

    Hou, Yi-Cheng; Lai, Chien-Han; Wu, Yu-Te; Yang, Shwu-Huey

    2016-01-01

    Abstract The neurophysiology of prediabetes plays an important role in preventive medicine. The dysregulation of glucose metabolism is likely linked to changes in neuron-related gray matter. Therefore, we designed this study to investigate gray matter alterations in medication-naive prediabetic patients. We expected to find alterations in the gray matter of prediabetic patients. A total of 64 prediabetic patients and 54 controls were enrolled. All subjects received T1 scans using a 3-T magnetic resonance imaging machine. Subjects also completed nutritional intake records at the 24-hour and 3-day time points to determine their carbohydrate, protein, fat, and total calorie intake. We utilized optimized voxel-based morphometry to estimate the gray matter differences between the patients and controls. In addition, the preprandial serum glucose level and the carbohydrate, protein, fat, and total calorie intake levels were tested to determine whether these parameters were correlated with the gray matter volume. Prediabetic patients had lower gray matter volumes than controls in the right anterior cingulate gyrus, right posterior cingulate gyrus, left insula, left super temporal gyrus, and left middle temporal gyrus (corrected P < 0.05; voxel threshold: 33). Gray matter volume in the right anterior cingulate was also negatively correlated with the preprandial serum glucose level gyrus in a voxel-dependent manner (r = –0.501; 2-tailed P = 0.001). The cingulo-temporal and insula gray matter alterations may be associated with the glucose dysregulation in prediabetic patients. PMID:27336893

  18. Gray matter alterations and correlation of nutritional intake with the gray matter volume in prediabetes.

    PubMed

    Hou, Yi-Cheng; Lai, Chien-Han; Wu, Yu-Te; Yang, Shwu-Huey

    2016-06-01

    The neurophysiology of prediabetes plays an important role in preventive medicine. The dysregulation of glucose metabolism is likely linked to changes in neuron-related gray matter. Therefore, we designed this study to investigate gray matter alterations in medication-naive prediabetic patients. We expected to find alterations in the gray matter of prediabetic patients.A total of 64 prediabetic patients and 54 controls were enrolled. All subjects received T1 scans using a 3-T magnetic resonance imaging machine. Subjects also completed nutritional intake records at the 24-hour and 3-day time points to determine their carbohydrate, protein, fat, and total calorie intake. We utilized optimized voxel-based morphometry to estimate the gray matter differences between the patients and controls. In addition, the preprandial serum glucose level and the carbohydrate, protein, fat, and total calorie intake levels were tested to determine whether these parameters were correlated with the gray matter volume.Prediabetic patients had lower gray matter volumes than controls in the right anterior cingulate gyrus, right posterior cingulate gyrus, left insula, left super temporal gyrus, and left middle temporal gyrus (corrected P < 0.05; voxel threshold: 33). Gray matter volume in the right anterior cingulate was also negatively correlated with the preprandial serum glucose level gyrus in a voxel-dependent manner (r = -0.501; 2-tailed P = 0.001).The cingulo-temporal and insula gray matter alterations may be associated with the glucose dysregulation in prediabetic patients. PMID:27336893

  19. High sodium intake increases blood pressure and alters renal function in intrauterine growth-retarded rats.

    PubMed

    Sanders, Marijke W; Fazzi, Gregorio E; Janssen, Ger M J; Blanco, Carlos E; De Mey, Jo G R

    2005-07-01

    A suboptimal fetal environment increases the risk to develop cardiovascular disease in the adult. We reported previously that intrauterine stress in response to reduced uteroplacental blood flow in the pregnant rat limits fetal growth and compromises renal development, leading to an altered renal function in the adult offspring. Here we tested the hypothesis that high dietary sodium intake in rats with impaired renal development attributable to intrauterine stress, results in increased blood pressure, altered renal function, and organ damage. In rats, intrauterine stress was induced by bilateral ligation of the uterine arteries at day 17 of pregnancy. At the age of 12 weeks, the offspring was given high-sodium drinking water (2% sodium chloride). At the age of 16 weeks, rats were instrumented for monitoring of blood pressure and renal function. After intrauterine stress, litter size and birth weight were reduced, whereas hematocrit at birth was increased. Renal blood flow, glomerular filtration rate, and the glomerular filtration fraction were increased significantly after intrauterine stress. High sodium intake did not change renal function and blood pressure in control animals. However, during high sodium intake in intrauterine stress offspring, renal blood flow, glomerular filtration rate, and the filtration fraction were decreased, and blood pressure was increased. In addition, these animals developed severe albuminuria, an important sign of renal dysfunction. Thus, a suboptimal fetal microenvironment, which impairs renal development, results in sodium-dependent hypertension and albuminuria. PMID:15956110

  20. Prominent pancreatic endocrinopathy and altered control of food intake disrupt energy homeostasis in prion diseases

    USGS Publications Warehouse

    Bailey, J.D.; Berardinelli, J.G.; Rocke, T.E.; Bessen, R.A.

    2008-01-01

    Prion diseases are fatal neurodegenerative diseases that can induce endocrinopathies. The basis of altered endocrine function in prion diseases is not well understood, and the purpose of this study was to investigate the spatiotemporal relationship between energy homeostasis and prion infection in hamsters inoculated with either the 139H strain of scrapie agent, which induces preclinical weight gain, or the HY strain of transmissible mink encephalopathy (TME), which induces clinical weight loss. Temporal changes in body weight, feed, and water intake were measured as well as both non-fasted and fasted concentrations of serum glucose, insulin, glucagon, ??-ketones, and leptin. In 139H scrapie-infected hamsters, polydipsia, hyperphagia, non-fasted hyperinsulinemia with hyperglycemia, and fasted hyperleptinemia were found at preclinical stages and are consistent with an anabolic syndrome that has similarities to type II diabetes mellitus and/or metabolic syndrome X. In HY TME-infected hamsters, hypodipsia, hypersecretion of glucagon (in both non-fasted and fasted states), increased fasted ??-ketones, fasted hypoglycemia, and suppressed non-fasted leptin concentrations were found while feed intake was normal. These findings suggest a severe catabolic syndrome in HY TME infection mediated by chronic increases in glucagon secretion. In both models, alterations of pancreatic endocrine function were not associated with PrPSc deposition in the pancreas. The results indicate that prominent endocrinopathy underlies alterations in body weight, pancreatic endocrine function, and intake of food. The prion-induced alterations of energy homeostasis in 139H scrapie- or HY TME-infected hamsters could occur within areas of the hypothalamus that control food satiety and/or within autonomic centers that provide neural outflow to the pancreas. ?? 2008 Society for Endocrinology.

  1. Adolescent vitamin A intake alters susceptibility to mammary carcinogenesis in the Sprague-Dawley rat.

    PubMed

    Metz, Richard P; Kaeck, Mark; Stacewicz-Sapuntzakis, Maria; Mitrenga, Terry; McCarty, Heidi; Schedin, Pepper

    2002-01-01

    We tested the hypothesis that adolescent dietary vitamin A intake impacts mammary gland development and subsequent sensitivity to carcinogenesis. Sprague-Dawley rats were fed a purified diet that was vitamin A deficient, adequate (2.2 mg retinyl palmitate/kg diet), or supranutritional (16 mg retinyl palmitate/kg diet) from 21 to 63 days of age, the period of adolescent mammary gland development. At 73 days of age, rats were given 1-methyl-1-nitrosourea (25 mg/kg body wt i.p.) and monitored for mammary tumors. Tumors appeared earlier and more frequently in rats fed vitamin A-deficient or -supplemented diets. Vitamin A deficiency during adolescence was associated with alveolar mammary gland development and precocious milk protein expression, while supplementation was associated with ductal gland development and suppression of milk protein expression. Differences in circulating estradiol and mammary gland estrogen receptor-alpha, and estrogen-responsive progesterone receptor mRNA were not observed, suggesting that the effects of vitamin A on mammary gland development and carcinogenesis are estrogen independent. Mammary expression of another hormone receptor that regulates milk protein expression, the glucocorticoid receptor, was also unaffected. These results demonstrate that vitamin A intake during adolescence alters mammary gland differentiation and indicate that a narrow range of vitamin A intake during adolescence protects against carcinogenesis. PMID:12235654

  2. Chronic ethanol intake leads to structural and molecular alterations in the rat endometrium.

    PubMed

    Martinez, Marcelo; Milton, Flora A; Pinheiro, Patricia Fernanda F; Almeida-Francia, Camila C D; Cagnon-Quitete, Valeria H A; Tirapelli, Luiz F; Padovani, Carlos Roberto; Chuffa, Luiz Gustavo A; Martinez, Francisco Eduardo

    2016-05-01

    We described the effects of low- and high-dose ethanol intake on the structure and apoptosis signaling of the uterine endometrium of UChA and UChB rats (animals with voluntary ethanol consumption). Thirty adult female rats, 90 days old, were divided into three groups (n = 10/group): UChA rats fed with 10% (v/v) ethanol ad libitum (free choice for water or ethanol) drinking < 1.9 g/kg/day; UChB rats fed with 10% (v/v) ethanol ad libitum (free choice for water or ethanol) drinking from 2 to 5 g/kg/day; control rats without ethanol (only water). After 120 days of treatment, rats displaying estrus were euthanized. Uterine epithelial cells of the UCh rats showed dilated cisterns of the rough endoplasmic reticulum, presence of lipid droplets, altered nuclear chromatin, and disrupted mitochondria. The UCh rats exhibited intense atrophied epithelial cells with smaller areas and perimeters of cytoplasm and nuclei. The endometrium of UChA rats showed higher levels of caspase-3 while Xiap and Bcl2 varied from moderate to weak. Both UChA and UChB rats exhibited a stronger immunoreaction to Ki-67 and IGFR-1 on epithelial and stromal cells. Chronic ethanol intake leads to structural and molecular alterations in the uterine endometrium of UCh rats, regardless of low- or high-dose consumption, promoting reproductive disorders. PMID:27139238

  3. Drospirenone intake alters plasmatic steroid levels and cyp17a1 expression in gonads of juvenile sea bass.

    PubMed

    Blanco, Maria; Fernandes, Denise; Medina, Paula; Blázquez, Mercedes; Porte, Cinta

    2016-06-01

    Drospirenone (DRO) is one of the most widely used progestins in contraceptive treatments and hormone replacement therapies. The pharmacokinetics and potential toxicological effects of DRO were investigated in juvenile sea bass (Dicentrarchus labrax) exposed through the diet (0.01-10 μg DRO/g) for up to 31 days. DRO was detected in the blood (4-27 ng/mL) of fish exposed to the highest concentration, with no significant bioaccumulation over time and no alteration of hepatic metabolizing enzymes, namely, CYP1A and CYP3A-catalysed activities and UDP-glucuronyltransferase (UGT). Pregnenolone (P5), progesterone (P4), 17α-hydroxyprogesterone (17P4), 17α-hydroxypregnenolone (17P5), androstenedione (AD) and testosterone (T) were determined in plasma and gene expression of cyp17a1, cyp19a1a and cyp11β analysed by qRT-PCR in gonads. The significant increase in plasmatic levels of 17P5, 17P4 and AD detected after 31 days exposure to 10 ng DRO/g together with the increased expression of cyp17a1 in females evidence the ability of DRO to alter steroid synthesis at low intake concentrations (7 ng DRO/day). However, the potential consequences of this steroid shift for female reproduction remain to be investigated. PMID:26995450

  4. Differential expression of genes in the liver associated with gain and intake in beef steers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of this study was to identify genes associated with gain and intake in the liver in beef cattle. The liver uses 25% of the body’s energy, while constituting less than 2% of total body weight. It is likely that the liver plays a key role in gain and intake due to its high energy utilizati...

  5. Withdrawal of dietary phytoestrogens in adult male rats affects hypothalamic regulation of food intake, induces obesity and alters glucose metabolism.

    PubMed

    Andreoli, María Florencia; Stoker, Cora; Rossetti, María Florencia; Alzamendi, Ana; Castrogiovanni, Daniel; Luque, Enrique H; Ramos, Jorge Guillermo

    2015-02-01

    The absence of phytoestrogens in the diet during pregnancy has been reported to result in obesity later in adulthood. We investigated whether phytoestrogen withdrawal in adult life could alter the hypothalamic signals that regulate food intake and affect body weight and glucose homeostasis. Male Wistar rats fed from conception to adulthood with a high phytoestrogen diet were submitted to phytoestrogen withdrawal by feeding a low phytoestrogen diet, or a high phytoestrogen-high fat diet. Withdrawal of dietary phytoestrogens increased body weight, adiposity and energy intake through an orexigenic hypothalamic response characterized by upregulation of AGRP and downregulation of POMC. This was associated with elevated leptin and T4, reduced TSH, testosterone and estradiol, and diminished hypothalamic ERα expression, concomitant with alterations in glucose tolerance. Removing dietary phytoestrogens caused manifestations of obesity and diabetes that were more pronounced than those induced by the high phytoestrogen-high fat diet intake. PMID:25486512

  6. Ruminal and adipose gene expression in beef steers selected for diverse feed intake and gain phenotypes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Limited information exists regarding the genes responsible for phenotypic variation in feed efficiency. To determine whether cattle feed intake or growth phenotypes are related to transcript abundance of genes expressed in the rumen and adipose, the variation in five candidate genes from two groups ...

  7. The effects of sleep restriction and altered sleep timing on energy intake and energy expenditure.

    PubMed

    McNeil, Jessica; Doucet, Éric; Brunet, Jean-François; Hintze, Luzia Jaeger; Chaumont, Isabelle; Langlois, Émilie; Maitland, Riley; Riopel, Alexandre; Forest, Geneviève

    2016-10-01

    Experimental evidence suggests that sleep restriction increases energy intake (EI) and may alter energy expenditure (EE). However, it is unknown whether the timing of a sleep restriction period impacts EI and EE the following day. Hence, we examined the effects of sleep restriction with an advanced wake-time or delayed bedtime on next day EI and EE. Twelve men and 6 women (age: 23±4years, body fat: 18.8±10.1%) participated in 3 randomized crossover sessions: control (habitual bed- and wake-times), 50% sleep restriction with an advanced wake-time and 50% sleep restriction with a delayed bedtime. Outcome variables included sleep architecture (polysomnography), EI (food menu), total EE and activity times (accelerometry). Carbohydrate intake was greater on day 2 in the delayed bedtime vs. control session (1386±513 vs. 1579±571kcal; P=0.03). Relative moderate-intensity physical activity (PA) time was greater in the delayed bedtime session vs. control and advanced wake-time sessions on day 1 (26.6±19.9 vs. 16.1±10.6 and 17.5±11.8%; P=0.01), whereas vigorous-intensity PA time was greater following advanced wake-time vs. delayed bedtime on day 1 (2.7±3.0 vs. 1.3±2.4%; P=0.004). Greater stage 1 sleep (β=110kcal, 95% CI for β=42 to 177kcal; P=0.004), and a trend for lower REM sleep (β=-20kcal, 95% CI for β=-41 to 2kcal; P=0.07), durations were associated with greater EI between sleep restriction sessions. These findings suggest that the timing of a sleep restriction period impacts energy balance parameters. Additional studies are needed to corroborate these findings, given the increasing prevalence of shift workers and incidences of sleep disorders and voluntary sleep restriction. PMID:27260515

  8. Genetic Deletion of Rheb1 in the Brain Reduces Food Intake and Causes Hypoglycemia with Altered Peripheral Metabolism

    PubMed Central

    Yang, Wanchun; Jiang, Wanxiang; Luo, Liping; Bu, Jicheng; Pang, Dejiang; Wei, Jing; Du, Chongyangzi; Xia, Xiaoqiang; Cui, Yiyuan; Liu, Shuang; Mao, Qing; Chen, Mina

    2014-01-01

    Excessive food/energy intake is linked to obesity and metabolic disorders, such as diabetes. The hypothalamus in the brain plays a critical role in the control of food intake and peripheral metabolism. The signaling pathways in hypothalamic neurons that regulate food intake and peripheral metabolism need to be better understood for developing pharmacological interventions to manage eating behavior and obesity. Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a master regulator of cellular metabolism in different cell types. Pharmacological manipulations of mTOR complex 1 (mTORC1) activity in hypothalamic neurons alter food intake and body weight. Our previous study identified Rheb1 (Ras homolog enriched in brain 1) as an essential activator of mTORC1 activity in the brain. Here we examine whether central Rheb1 regulates food intake and peripheral metabolism through mTORC1 signaling. We find that genetic deletion of Rheb1 in the brain causes a reduction in mTORC1 activity and impairs normal food intake. As a result, Rheb1 knockout mice exhibit hypoglycemia and increased lipid mobilization in adipose tissue and ketogenesis in the liver. Our work highlights the importance of central Rheb1 signaling in euglycemia and energy homeostasis in animals. PMID:24451134

  9. Hematologic and immunological indicators are altered by chronic intake of flaxseed in Wistar rats.

    PubMed

    Ferreira Medeiros de França Cardozo, L; Leal Soares, L; Cardozo Brant, L H; Alves Chagas, M; Alves Pereira, V; Coca Velarde, L G; Teles Boaventura, G

    2011-01-01

    This work sought to evaluate the effects of chronic intake of flaxseed upon hematologic parameters and immunological findings on body development of Wistar rats. Female Wistar rats were used after gestation. They were randomly assigned into two groups during lactation period: Control group (CG), fed with casein based diet, made up of 17% protein and flaxseed group (FG), fed with casein based diet with the addition of 25% flaxseed. At weaning, 12 male pups of each group continued to receive the experimental diets of their mothers (with only 10% of protein) until adult age, when they were killed at 250 days of life aiming at blood collection. At 250 days old FG presented significant reduction in body mass (p<0.000) and higher levels of hemoglobin (p=0.019) and albumin (p=0.030) than CG. It was observed smaller percentage of segmented lymphocytes (p=0.016) in rats from FG and bigger percentage of segmented leucocytes (p=0.023) when compared to CG. The chronic consumption of flaxseed altered hematologic and immunological indicators in adult Wistar rats. Supplementation with flaxseed seems to be beneficial to maintenance or reduction of body mass. PMID:22072357

  10. Gene expression profiling of hormonal regulation related to the residual feed intake of Holstein cattle.

    PubMed

    Xi, Y M; Yang, Z; Wu, F; Han, Z Y; Wang, G L

    2015-09-11

    An accumulation of over a decade of research in cattle has shown that genetic selection for decreased residual feed intake (RFI), defined as the difference between an animal's actual feed intake and its expected feed intake, is a viable option for improving feed efficiency and reducing the feed requirements of herds, thereby improving the profitability of cattle producers. Hormonal regulation is one of the most important factors in feed intake. To determine the relationship between hormones and feed efficiency, we performed gene expression profiling of jugular vein serum on hormonal regulation of Chinese Holstein cattle with low and high RFI coefficients. 857 differential expression genes (from 24683 genes) were found. Among these, 415 genes were up-regulated and 442 genes were down-regulated in the low RFI group. The gene ontology (GO) search revealed 6 significant terms and 64 genes associated with hormonal regulation, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) selected the adipocytokine signaling pathway, insulin signaling pathway. In conclusion, the study indicated that the molecular expression of genes associated with hormonal regulation differs in dairy cows, depending on their RFI coefficients, and that these differences may be related to the molecular regulation of the leptin-NPY and insulin signaling pathways. PMID:26231801

  11. An acute intake of plant stanol esters alters immune-related pathways in the jejunum of healthy volunteers.

    PubMed

    De Smet, Els; Mensink, Ronald P; Boekschoten, Mark V; de Ridder, Rogier; Germeraad, Wilfred T V; Wolfs, Tim G A M; Plat, Jogchum

    2015-03-14

    Plant sterols and stanols inhibit intestinal cholesterol absorption and consequently lower serum LDL-cholesterol (LDL-C) concentrations. The underlying mechanisms are not yet known. In vitro and animal studies have suggested that changes in intestinal sterol metabolism are attributed to the LDL-C-lowering effects of plant stanol esters. However, similar studies in human subjects are lacking. Therefore, we examined the effects of an acute intake of plant stanol esters on gene expression profiles of the upper small intestine in healthy volunteers. In a double-blind cross-over design, fourteen healthy subjects (eight female and six male; age 21-55 years), with a BMI ranging from 21 to 29 kg/m², received in random order a shake with or without plant stanol esters (4 g). At 5 h after consumption of the shake, biopsies were taken from the duodenum (around the papilla of Vater) and from the jejunum (20 cm distal from the papilla of Vater). Microarray analysis showed that the expression profiles of genes involved in sterol metabolism were not altered. Surprisingly, the pathways involved in T-cell functions were down-regulated in the jejunum. Furthermore, immunohistochemical analysis showed that the number of CD3 (cluster of differentiation number 3), CD4 (cluster of differentiation number 4) and Foxp3⁺ (forkhead box P3-positive) cells was reduced in the plant stanol ester condition compared with the control condition, which is in line with the microarray data. The physiological and functional consequences of the plant stanol ester-induced reduction of intestinal T-cell-based immune activity in healthy subjects deserve further investigation. PMID:25683704

  12. The intake of high-fat diets induces an obesogenic-like gene expression profile in peripheral blood mononuclear cells, which is reverted by dieting.

    PubMed

    Reynés, Bàrbara; García-Ruiz, Estefanía; Palou, Andreu; Oliver, Paula

    2016-06-01

    Peripheral blood mononuclear cells (PBMC) are increasingly used for nutrigenomic studies. In this study, we aimed to identify whether these cells could reflect the development of an obesogenic profile associated with the intake of high-fat (HF) diets. We analysed, by real-time RT-PCR, the dietary response of key genes related to lipid metabolism, obesity and inflammation in PBMC of control rats, rats fed a cafeteria or a commercial HF diet and rats fed a control diet after the intake of a cafeteria diet (post-cafeteria model). Cafeteria diet intake, which resulted in important overweight and related complications, altered the expressions of most of the studied genes in PBMC, evidencing the development of an obesogenic profile. Commercial HF diet, which produced metabolic alterations but in the absence of noticeably increased body weight, also altered PBMC gene expression, inducing a similar regulatory pattern as that observed for the cafeteria diet. Regulation of carnitine palmitoyltransferase I (Cpt1a) mRNA expression was of special interest; its expression reflected metabolic alterations related to the intake of both obesogenic diets (independently of increased body weight) even at an early stage as well as metabolic recovery in post-cafeteria animals. Thus, PBMC constitute an important source of biomarkers that reflect the increased adiposity and metabolic deregulation associated with the intake of HF diets. In particular, we propose an analysis of Cpt1a expression as a good biomarker to detect the early metabolic alterations caused by the consumption of hyperlipidic diets, and also as a marker of metabolic recovery associated to weight loss. PMID:27080153

  13. Efflux Pump Control Alters Synthetic Gene Circuit Function.

    PubMed

    Diao, Junchen; Charlebois, Daniel A; Nevozhay, Dmitry; Bódi, Zoltán; Pál, Csaba; Balázsi, Gábor

    2016-07-15

    Synthetic biology aims to design new biological systems for predefined purposes, such as the controlled secretion of biofuels, pharmaceuticals, or other chemicals. Synthetic gene circuits regulating an efflux pump from the ATP-binding cassette (ABC) protein family could achieve this. However, ABC efflux pumps can also drive out intracellular inducer molecules that control the gene circuits. This will introduce an implicit feedback that could alter gene circuit function in ways that are poorly understood. Here, we used two synthetic gene circuits inducible by tetracycline family molecules to regulate the expression of a yeast ABC pump (Pdr5p) that pumps out the inducer. Pdr5p altered the dose-responses of the original gene circuits substantially in Saccharomyces cerevisiae. While one aspect of the change could be attributed to the efflux pumping function of Pdr5p, another aspect remained unexplained. Quantitative modeling indicated that reduced regulator gene expression in addition to efflux pump function could fully explain the altered dose-responses. These predictions were validated experimentally. Overall, we highlight how efflux pumps can alter gene circuit dynamics and demonstrate the utility of mathematical modeling in understanding synthetic gene circuit function in new circumstances. PMID:27111147

  14. Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes

    PubMed Central

    Fang, Xiefan; Mei, Wenbin; Barbazuk, William B.; Rivkees, Scott A.

    2014-01-01

    Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20–60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3–65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes. PMID:25354728

  15. Carbon Nanomaterials Alter Global Gene Expression Profiles.

    PubMed

    Woodman, Sara; Short, John C W; McDermott, Hyoeun; Linan, Alexander; Bartlett, Katelyn; Gadila, Shiva Kumar Goud; Schmelzle, Katie; Wanekaya, Adam; Kim, Kyoungtae

    2016-05-01

    Carbon nanomaterials (CNMs), which include carbon nanotubes (CNTs) and their derivatives, have diverse technological and biomedical applications. The potential toxicity of CNMs to cells and tissues has become an important emerging question in nanotechnology. To assess the toxicity of CNTs and fullerenol C60(OH)24, we in the present work used the budding yeast Saccharomyces cerevisiae, one of the simplest eukaryotic organisms that share fundamental aspects of eukaryotic cell biology. We found that treatment with CNMs, regardless of their physical shape, negatively affected the growth rates, end-point cell densities and doubling times of CNM-exposed yeast cells when compared to unexposed cells. To investigate potential mechanisms behind the CNMs-induced growth defects, we performed RNA-Seq dependent transcriptional analysis and constructed global gene expression profiles of fullerenol C60(OH)24- and CNT-treated cells. When compared to non-treated control cells, CNM-treated cells displayed differential expression of genes whose functions are implicated in membrane transporters and stress response, although differentially expressed genes were not consistent between CNT- and fullerenol C60(OH)24-treated groups, leading to our conclusion that CNMs could serve as environmental toxic factors to eukaryotic cells. PMID:27483901

  16. Calorie Anticipation Alters Food Intake After Low-Caloric but Not High-Caloric Preloads

    PubMed Central

    Hogenkamp, PS; Cedernaes, J; Chapman, CD; Vogel, H; Hjorth, OC; Zarei, S; Lundberg, LS; Brooks, SJ; Dickson, SL; Benedict, C; Schiöth, HB

    2013-01-01

    Objective Cognitive factors and anticipation are known to influence food intake. The current study examined the effect of anticipation and actual consumption of food on hormone (ghrelin, cortisol, and insulin) and glucose levels, appetite and ad libitum intake, to assess whether changes in hormone levels might explain the predicted differences in subsequent food intake. Design and Methods During four breakfast sessions, participants consumed a yogurt preload that was either low caloric (LC: 180 kcal/300 g) or high caloric (HC: 530 kcal/300 g) and was provided with either consistent or inconsistent calorie information (i.e., stating the caloric content of the preload was low or high). Appetite ratings and hormone and glucose levels were measured at baseline (t = 0), after providing the calorie information about the preload (t = 20), after consumption of the preload (t = 40), and just before ad libitum intake (t = 60). Results Ad libitum intake was lower after HC preloads (as compared to LC preloads; P < 0.01). Intake after LC preloads was higher when provided with (consistent) LC information (467±254 kcal) as compared to (inconsistent) HC information (346±210 kcal), but intake after the HC preloads did not depend on the information provided (LC information: 290±178 kcal, HC information: 333±179 kcal; caloric load*information P = 0.03). Hormone levels did not respond in an anticipatory manner, and the post-prandial responses depended on actual calories consumed. Conclusions These results suggest that both cognitive and physiological information determine food intake. When actual caloric intake was sufficient to produce physiological satiety, cognitive factors played no role; however, when physiological satiety was limited, cognitively induced satiety reduced intake to comparable levels. PMID:23585292

  17. Altered Preconception Fatty Acid Intake Is Associated with Improved Pregnancy Rates in Overweight and Obese Women Undertaking in Vitro Fertilisation.

    PubMed

    Moran, Lisa J; Tsagareli, Victoria; Noakes, Manny; Norman, Robert

    2016-01-01

    Maternal preconception diet is proposed to affect fertility. Prior research assessing the effect of altering the fatty acid profile on female fertility is conflicting. The aim of this study was to assess the effect of preconception maternal diet, specifically fatty acid profile, on pregnancies and live births following in vitro fertilisation (IVF). Forty-six overweight and obese women undergoing IVF were randomised to a diet and physical activity intervention (intervention) or standard care (control). Outcome measures included pregnancy, live birth and pre-study dietary intake from food frequency questionnaire. Twenty pregnancies (n = 12/18 vs. n = 8/20, p = 0.12) and 12 live births (n = 7/18 vs. n = 5/20, p = 0.48) occurred following the intervention with no differences between the treatment groups. On analysis adjusted for BMI and smoking status, women who became pregnant had higher levels of polyunsaturated fatty acid (PUFA) intake (p = 0.03), specifically omega-6 PUFA and linoleic acid (LA) (p = 0.045) with a trend for an elevated intake of omega-3 PUFA (p = 0.06). There were no dietary differences for women who did or did not have a live birth. Maternal preconception PUFA, and specifically omega-6 and LA intake, are associated with improved pregnancy rates in overweight and obese women undergoing IVF. This has implications for optimising fertility through preconception nutrition. PMID:26742065

  18. Alterations of prefrontal cortical microRNAs in methamphetamine self-administering rats: From controlled drug intake to escalated drug intake.

    PubMed

    Du, Hao-Yue; Cao, Dan-Ni; Chen, Ying; Wang, Lv; Wu, Ning; Li, Jin

    2016-01-12

    Drug addiction is a process that transits from recreative and regular drug use into compulsive drug use. The two patterns of drug use, controlled drug intake and escalated drug intake, represent different stages in the development of drug addiction; and escalation of drug use is a hallmark of addiction. Accumulating studies indicate that microRNAs (miRNAs) play key regulatory roles in drug addiction. However, the molecular adaptations in escalation of drug use, as well as the difference in the adaptations between escalated and controlled drug use, remain unclear. In the present study, 28 altered miRNAs in the prefrontal cortex (PFC) were found in the groups of controlled methamphetamine self-administration (1h/session) and escalated self-administration (6h/session), and some of them were validated. Compared with saline control group, miR-186 was verified to be up-regulated while miR-195 and miR-329 were down-regulated in the rats with controlled methamphetamine use. In the rats with escalated drug use, miR-127, miR-186, miR-222 and miR-24 were verified to be up-regulated while miR-329 was down-regulated compared with controls. Furthermore, bioinformatic analysis indicated that the predicted targets of these verified miRNAs involved in the processes of neuronal apoptosis and synaptic plasticity. However, the putative regulated molecules may be different between controlled and escalated drug use groups. Taken together, we detected the altered miRNAs in rat PFC under the conditions of controlled methamphetamine use and escalated use respectively, which may extend our understanding of the molecular adaptations underlying the transition from controlled drug use to addiction. PMID:26592480

  19. Alcohol Consumption Modulates Host Defense in Rhesus Macaques by Altering Gene Expression in Circulating Leukocytes.

    PubMed

    Barr, Tasha; Girke, Thomas; Sureshchandra, Suhas; Nguyen, Christina; Grant, Kathleen; Messaoudi, Ilhem

    2016-01-01

    Several lines of evidence indicate that chronic alcohol use disorder leads to increased susceptibility to several viral and bacterial infections, whereas moderate alcohol consumption decreases the incidence of colds and improves immune responses to some pathogens. In line with these observations, we recently showed that heavy ethanol intake (average blood ethanol concentrations > 80 mg/dl) suppressed, whereas moderate alcohol consumption (blood ethanol concentrations < 50 mg/dl) enhanced, T and B cell responses to modified vaccinia Ankara vaccination in a nonhuman primate model of voluntary ethanol consumption. To uncover the molecular basis for impaired immunity with heavy alcohol consumption and enhanced immune response with moderate alcohol consumption, we performed a transcriptome analysis using PBMCs isolated on day 7 post-modified vaccinia Ankara vaccination, the earliest time point at which we detected differences in T cell and Ab responses. Overall, chronic heavy alcohol consumption reduced the expression of immune genes involved in response to infection and wound healing and increased the expression of genes associated with the development of lung inflammatory disease and cancer. In contrast, chronic moderate alcohol consumption upregulated the expression of genes involved in immune response and reduced the expression of genes involved in cancer. To uncover mechanisms underlying the alterations in PBMC transcriptomes, we profiled the expression of microRNAs within the same samples. Chronic heavy ethanol consumption altered the levels of several microRNAs involved in cancer and immunity and known to regulate the expression of mRNAs differentially expressed in our data set. PMID:26621857

  20. Polymorphism of rs1836882 in NOX4 Gene Modifies Associations between Dietary Caloric Intake and ROS Levels in Peripheral Blood Mononuclear Cells

    PubMed Central

    Liu, Qiang; Li, Hong; Wang, Ningfu; Chen, Huaihong; Jin, Qihui; Zhang, Ruoyu; Wang, Jing; Chen, Ying

    2013-01-01

    Excessive caloric intake is a contributing risk factor for human metabolic disorders. Caloric restriction may prolong a person’s life by lowering the incidence of deadly diseases. Reactive oxygen species (ROS) in peripheral blood mononuclear cells (PBMC) have been associated with the biochemical basis of the relationship between caloric intake and pathophysiologic processes. Polymorphisms associated with ROS generation genes are being increasingly implicated in inter-individual responses to daily caloric intake alterations. In the current study, a single nucleotide polymorphism, rs1836882, in the nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) gene’s promoter region was found to modulate associations between dietary caloric intake and ROS levels in PBMC. Based on rs1836882, 656 Chinese Han participants were classified into CC, CT and TT genotypes. ROS levels in PBMC were significantly higher in the CC or CT genotypes compared with the TT genotype with the same increases in daily caloric intake. Using an electrophoretic mobility shift assay, NOX4 promoter region with rs1836882 (T) was observed to have a higher affinity for hepatocyte nuclear factor gamma (HNF3γ) protein than rs1836882 (C). HNF3γ protein over-expression decreased NOX4 gene transcriptional activity in the TT genotype more than in the CC genotype (5.68% vs. 2.12%, P<0.05) in a dual luciferase reporter assay. By silencing the NOX4 gene using small interfering RNA or over-expressing HNF3γ using an expression plasmid, serum from high dietary caloric intake participants decreased ROS levels in PBMC of the TT genotype more than in the CC or CT genotype via HNF3γ down-regulating the NOX4 gene expression signaling pathway. This is the first study to report on the functions of phenotypes of rs1836882 in the NOX4 gene, and it suggests rs1836882 as a candidate gene for interpreting inter-individual ROS levels differences in PBMC induced by alterations in daily caloric intake. PMID:24392026

  1. Identification of reference genes in human myelomonocytic cells for gene expression studies in altered gravity.

    PubMed

    Thiel, Cora S; Hauschild, Swantje; Tauber, Svantje; Paulsen, Katrin; Raig, Christiane; Raem, Arnold; Biskup, Josefine; Gutewort, Annett; Hürlimann, Eva; Unverdorben, Felix; Buttron, Isabell; Lauber, Beatrice; Philpot, Claudia; Lier, Hartwin; Engelmann, Frank; Layer, Liliana E; Ullrich, Oliver

    2015-01-01

    Gene expression studies are indispensable for investigation and elucidation of molecular mechanisms. For the process of normalization, reference genes ("housekeeping genes") are essential to verify gene expression analysis. Thus, it is assumed that these reference genes demonstrate similar expression levels over all experimental conditions. However, common recommendations about reference genes were established during 1 g conditions and therefore their applicability in studies with altered gravity has not been demonstrated yet. The microarray technology is frequently used to generate expression profiles under defined conditions and to determine the relative difference in expression levels between two or more different states. In our study, we searched for potential reference genes with stable expression during different gravitational conditions (microgravity, normogravity, and hypergravity) which are additionally not altered in different hardware systems. We were able to identify eight genes (ALB, B4GALT6, GAPDH, HMBS, YWHAZ, ABCA5, ABCA9, and ABCC1) which demonstrated no altered gene expression levels in all tested conditions and therefore represent good candidates for the standardization of gene expression studies in altered gravity. PMID:25654098

  2. Restricted nutrient intake does not alter serum-mediated measures of implant response in cell culture

    PubMed Central

    2013-01-01

    Background During nutritional stress, reduced intake may reduce the efficacy of anabolic implants. This study was conducted to evaluate basic cellular responses to a growth promotant implant at two intake levels. Methods Sixteen crossbred steers (293 ± 19.3 kg) were used to evaluate the impact of anabolic implants in either an adequate or a restricted nutritional state. Steers were trained to individual Calan gates, and then randomly assigned to 1 of 4 treatments in a 2 × 2 factorial arrangement. Treatments consisted of: presence or absence of an anabolic growth implant (Revalor-XS, 200 mg TBA and 40 mg estradiol; IMPLANT or CONTROL) and a moderate energy, pelleted, starting cattle diet fed at either 2.0 × or 1.0 × maintenance energy (NEM) requirements (HIGH or LOW). Serum (d 0, 14, and 28) was used for application to bovine muscle satellite cells. After treatment with the serum (20% of total media) from the trial cattle, the satellite cells were incubated for 72 h. Protein abundance of myosin heavy chain (MHC), phosphorylated extracellular signal-related kinase (phospho-ERK), and phosphorylated mammalian target of rapamycin (phospho-mTOR) were analyzed to determine the effects of implant, intake, and their interaction (applied via the serum). Results Intake had no effect on MHC (P = 0.85) but IMPLANT increased (P < 0.01) MHC abundance vs. CONTROL. Implant status, intake status, and the interaction had no effect on the abundance of phospho-ERK (P ≥ 0.23). Implanting increased phospho-mTOR (P < 0.01) but there was no effect (P ≥ 0.51) of intake or intake × implant. Conclusions The nearly complete lack of interaction between implant and nutritional status indicates that the signaling molecules measured herein respond to implants and nutritional status independently. Furthermore, results suggest that the muscle hypertrophic effects of anabolic implants may not be mediated by circulating IGF-1. PMID:24245980

  3. Adult Onset Global Loss of the Fto Gene Alters Body Composition and Metabolism in the Mouse

    PubMed Central

    Wells, Sara; Teboul, Lydia; Tung, Y. C. Loraine; Rimmington, Debra; Bosch, Fatima; Jimenez, Veronica; Yeo, Giles S. H.; O'Rahilly, Stephen; Ashcroft, Frances M.; Coll, Anthony P.; Cox, Roger D.

    2013-01-01

    The strongest BMI–associated GWAS locus in humans is the FTO gene. Rodent studies demonstrate a role for FTO in energy homeostasis and body composition. The phenotypes observed in loss of expression studies are complex with perinatal lethality, stunted growth from weaning, and significant alterations in body composition. Thus understanding how and where Fto regulates food intake, energy expenditure, and body composition is a challenge. To address this we generated a series of mice with distinct temporal and spatial loss of Fto expression. Global germline loss of Fto resulted in high perinatal lethality and a reduction in body length, fat mass, and lean mass. When ratio corrected for lean mass, mice had a significant increase in energy expenditure, but more appropriate multiple linear regression normalisation showed no difference in energy expenditure. Global deletion of Fto after the in utero and perinatal period, at 6 weeks of age, removed the high lethality of germline loss. However, there was a reduction in weight by 9 weeks, primarily as loss of lean mass. Over the subsequent 10 weeks, weight converged, driven by an increase in fat mass. There was a switch to a lower RER with no overall change in food intake or energy expenditure. To test if the phenotype can be explained by loss of Fto in the mediobasal hypothalamus, we sterotactically injected adeno-associated viral vectors encoding Cre recombinase to cause regional deletion. We observed a small reduction in food intake and weight gain with no effect on energy expenditure or body composition. Thus, although hypothalamic Fto can impact feeding, the effect of loss of Fto on body composition is brought about by its actions at sites elsewhere. Our data suggest that Fto may have a critical role in the control of lean mass, independent of its effect on food intake. PMID:23300482

  4. Body mass, composition, and food intake in rabbits during altered acceleration fields

    NASA Technical Reports Server (NTRS)

    Katovich, M. J.; Smith, A. H.

    1978-01-01

    Mature male Polish rabbits were subjected to varying gravitational fields in an animal centrifuge in order to evaluate the effects of acceleration and deacceleration on body mass, body composition, and food intake. The acceleration field intensity was increased by 0.25-G increments to a maximum of 2.5 G at intervals which permitted physiological adaptation at each field. Control animals of the same age were maintained at earth gravity under identical conditions of constant-light environment at a room temperature of 23 + or - 5 C. It is shown that increasing the acceleration-field intensity leads to a decrease in body mass. The regulated nature of this decreased body mass is tested by the response to an additional three-day fasting of animals adapted physiologically to 2.5 G. Ad libitum food intake per kg body mass per day tends to increase in chronically accelerated animals above 1.75 G. Increase in water content in centrifuged animals after physiological adaptation to 2.5 G is the result of decreasing body fat. Body mass and food intake returned to the precentrifuged levels of control animals within six weeks after cessation of centrifugation.

  5. Identification of Reference Genes in Human Myelomonocytic Cells for Gene Expression Studies in Altered Gravity

    PubMed Central

    Thiel, Cora S.; Hauschild, Swantje; Tauber, Svantje; Paulsen, Katrin; Raig, Christiane; Raem, Arnold; Biskup, Josefine; Gutewort, Annett; Hürlimann, Eva; Philpot, Claudia; Lier, Hartwin; Engelmann, Frank; Layer, Liliana E.

    2015-01-01

    Gene expression studies are indispensable for investigation and elucidation of molecular mechanisms. For the process of normalization, reference genes (“housekeeping genes”) are essential to verify gene expression analysis. Thus, it is assumed that these reference genes demonstrate similar expression levels over all experimental conditions. However, common recommendations about reference genes were established during 1 g conditions and therefore their applicability in studies with altered gravity has not been demonstrated yet. The microarray technology is frequently used to generate expression profiles under defined conditions and to determine the relative difference in expression levels between two or more different states. In our study, we searched for potential reference genes with stable expression during different gravitational conditions (microgravity, normogravity, and hypergravity) which are additionally not altered in different hardware systems. We were able to identify eight genes (ALB, B4GALT6, GAPDH, HMBS, YWHAZ, ABCA5, ABCA9, and ABCC1) which demonstrated no altered gene expression levels in all tested conditions and therefore represent good candidates for the standardization of gene expression studies in altered gravity. PMID:25654098

  6. Long-time alcohol intake modifies resistin secretion and expression of resistin gene in adipose tissue.

    PubMed

    Pravdová, E; Macho, L; Hlavácová, N; Ficková, M

    2007-09-01

    Elevated serum resistin is implicated in insulin resistance associated with obesity and type 2 diabetes mellitus. Alcohol consumption interferes with the nutritional status, metabolic and hormonal activity of the drinker. Impact of ethanol intake on resistin level and resistin metabolic effects is unknown. Effect of long-time (28 days) ad libitum moderate alcohol (6% ethanol solution) intake on serum resistin and resistin mRNA level in adipose tissue of rats (A) was compared to control (C) and pair-fed (PF) animals. PF rats were fed the same caloric amount as A rats on previous day. Alcohol consumption resulted in reduction of food and energy intake, decreased body mass gain, epididymal fat pads mass and smaller adipocytes (vs. C rats). Alcohol intake significantly increased serum resistin and glucose, insulinemia remained unchanged. Systemic insulin resistance was not proved by HOMA, QUICKI and McAuley indexes, but impaired insulin effect on glucose transport in isolated adipocytes was present. Elevated serum resistin was positively correlated with glycemia (r = 0.88, p < 0.01) and negatively with fat cell size (r = -0.73, p < 0.05). High resistin level as the consequence of long-time alcohol intake could contribute to smaller adipocytes, higher glycemia, attenuation of insulin-stimulated glucose transport in adipocytes. Diminished resistin gene expression in adipose tissue of A and PF rats was present. PMID:18063850

  7. In vitro maturation alters gene expression in bovine oocytes.

    PubMed

    Adona, Paulo R; Leal, Cláudia L V; Biase, Fernando H; De Bem, Tiago H; Mesquita, Lígia G; Meirelles, Flávio V; Ferraz, André L; Furlan, Luiz R; Monzani, Paulo S; Guemra, Samuel

    2016-08-01

    Gene expression profiling of in vivo- and in vitro-matured bovine oocytes can identify transcripts related to the developmental potential of oocytes. Nonetheless, the effects of in vitro culturing oocytes are yet to be fully understood. We tested the effects of in vitro maturation on the transcript profile of oocytes collected from Bos taurus indicus cows. We quantified the expression of 1488 genes in in vivo- and in vitro-matured oocytes. Of these, 51 genes were up-regulated, whereas 56 were down-regulated (≥2-fold) in in vivo-matured oocytes in comparison with in vitro-matured oocytes. Quantitative real-time polymerase chain reaction (PCR) of nine genes confirmed the microarray results of differential expression between in vivo- and in vitro-matured oocytes (EZR, EPN1, PSEN2, FST, IGFBP3, RBBP4, STAT3, FDPS and IRS1). We interrogated the results for enrichment of Gene Ontology categories and overlap with protein-protein interactions. The results revealed that the genes altered by in vitro maturation are mostly related to the regulation of oocyte metabolism. Additionally, analysis of protein-protein interactions uncovered two regulatory networks affected by the in vitro culture system. We propose that the differentially expressed genes are candidates for biomarkers of oocyte competence. In vitro oocyte maturation can affect the abundance of specific transcripts and are likely to deplete the developmental competence. PMID:26885679

  8. Heme-related gene expression signatures of meat intakes in lung cancer tissues.

    PubMed

    Lam, Tram Kim; Rotunno, Melissa; Ryan, Brid M; Pesatori, Angela C; Bertazzi, Pier Alberto; Spitz, Margaret; Caporaso, Neil E; Landi, Maria Teresa

    2014-07-01

    Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the environment and genetics in lung cancer etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a false discovery rate (FDR) ≤ 0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR = 0.12). Sixty-three (∼ 28%) of the 232 identified genes (12 expected by chance, P-value < 0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, and WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, and UCP3) and oxidative stress (e.g., TPO, SGK2, and MTHFR) that may be indirectly related to heme-toxicity. The study's results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer. PMID:23681825

  9. Heme-related gene expression signatures of meat intakes in lung cancer tissues

    PubMed Central

    Lam, Tram Kim; Rotunno, Melissa; Ryan, Brid M.; Pesatori, Angela C.; Bertazzi, Pier Alberto; Spitz, Margaret; Caporaso, Neil E.; Landi, Maria Teresa

    2014-01-01

    Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the Environment and Genetics in Lung cancer Etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a False Discovery Rate (FDR) ≤0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR=0.12). Sixty-three (~28%) of the 232 identified genes (12 expected by chance, p-value<0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, UCP3) and oxidative stress (e.g., TPO, SGK2, MTHFR) that may be indirectly related to heme-toxicity. The study’s results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer. PMID:23681825

  10. Differential gene expression in the duodenum, jejunum and ileum among crossbred beef steers with divergent gain and feed intake phenotypes.

    PubMed

    Lindholm-Perry, A K; Butler, A R; Kern, R J; Hill, R; Kuehn, L A; Wells, J E; Oliver, W T; Hales, K E; Foote, A P; Freetly, H C

    2016-08-01

    Small intestine mass and cellularity were previously associated with cattle feed efficiency. The small intestine is responsible for the digestion of nutrients and absorption of fatty acids, amino acids and carbohydrates, and it contributes to the overall feed efficiency of cattle. The objective of this study was to evaluate transcriptome differences among the small intestine from cattle with divergent gain and feed intake. Animals most divergent from the bivariate mean in each of the four phenotypic Cartesian quadrants for gain × intake were selected, and the transcriptomes of duodenum, jejunum and ileum were evaluated. Gene expression analyses were performed comparing high gain vs. low gain animals, high intake vs. low intake animals and each of the phenotypic quadrants to all other groups. Genes differentially expressed within the high gain-low intake and low gain-high intake groups of animals included those involved in immune function and inflammation in all small intestine sections. The high gain-high intake group differed from the high gain-low intake group by immune response genes in all sections of the small intestine. In all sections of small intestine, animals with low gain-low intake displayed greater abundance of heat-shock genes compared to other groups. Several over-represented pathways were identified. These include the antigen-processing/presentation pathway in high gain animals and PPAR signaling, starch/sucrose metabolism, retinol metabolism and melatonin degradation pathways in the high intake animals. Genes with functions in immune response, inflammation, stress response, influenza pathogenesis and melatonin degradation pathways may have a relationship with gain and intake in beef steers. PMID:27226174

  11. FHIT gene alterations in head and neck squamous cell carcinomas.

    PubMed Central

    Virgilio, L; Shuster, M; Gollin, S M; Veronese, M L; Ohta, M; Huebner, K; Croce, C M

    1996-01-01

    To determine whether the FHIT gene at 3p14.2 is altered in head and neck squamous cell carcinomas (HNSCC), we examined 26 HNSCC cell lines for deletions within the FHIT locus by Southern analysis, for allelic losses of specific exons FHIT by fluorescence in situ hybridization (FISH) and for integrity of FHIT transcripts. Three cell lines exhibited homozygous deletions within the FHIT gene, 55% (15/25) showed the presence of aberrant transcripts, and 65% (13/20) showed the presence of multiple cell populations with losses of different portions of FHIT alleles by FISH of FHIT genomic clones to interphase nuclei. When the data obtained by FISH and by reverse transcriptase-PCR analyses are combined, 22 of 26 cell lines showed alterations of at least one allele of the FHIT gene. Our data indicate that the FHIT gene is disrupted in HNSCCs and hence, loss of FHIT function may be important in the development and/or progression of head and neck cancers. Images Fig. 1 Fig. 2 PMID:8790406

  12. Risperidone alters food intake, core body temperature, and locomotor activity in mice

    PubMed Central

    Cope, Mark B.; Li, Xingsheng; Jumbo-Lucioni, Patricia; DiCostanzo, Catherine A.; Jamison, Wendi G.; Kesterson, Robert A.; Allison, David B.; Nagy, Tim R.

    2009-01-01

    Risperidone induces significant weight gain in female mice; however, the underlying mechanisms related to this effect are unknown. We investigated the effects of risperidone on locomotor activity, core body temperature, and uncoupling protein (UCP) and hypothalamic orexin mRNA expression. Female C57BL/6J mice were acclimated to individual housing and randomly assigned to either risperidone (4 mg/kg BW*day) or placebo (PLA). Activity and body temperature were measured over 48-hour periods twice a week for 3 weeks. Food intake and body weights were measured weekly. UCP1 (BAT), UCP3 (gastrocnemius), and orexin (hypothalamus) mRNA expressions were measured using RT-PCR. Risperidone-treated mice consumed more food (p=0.050) and gained more weight (p=0.0001) than PLA-treated mice after 3 weeks. During the initial 2-days of treatment, there was an acute effect of treatment on activity (p=0.046), but not body temperature (p=0.290). During 3 weeks of treatment, average core body temperatures were higher in risperidone-treated mice compared to controls during the light phase (p=0.0001), and tended to be higher during the dark phase (p=0.057). Risperidone-treated mice exhibited lower activity levels than controls during the dark phase (p=0.006); there were no differences in activity during the light phase (p=0.47). UCP1 (p<0.01) and UCP3 (p<0.05) mRNA expressions were greater in risperidone-treated mice compared to controls, whereas, orexin mRNA expression was lower in risperidone-treated mice (p<0.01). These results suggest that risperidone-induced weight gain in mice is a consequence of increased energy intake and reduced activity, while the elevation in body temperature may be a result of thermogenic effect of food intake and elevated UCP1, UCP3, and a reduced hypothalamic orexin expression. PMID:19084548

  13. Gene Expression Profiling of Biological Pathway Alterations by Radiation Exposure

    PubMed Central

    Lee, Kuei-Fang; Weng, Julia Tzu-Ya; Hsu, Paul Wei-Che; Chi, Yu-Hsiang; Chen, Ching-Kai; Liu, Ingrid Y.; Chen, Yi-Cheng; Wu, Lawrence Shih-Hsin

    2014-01-01

    Though damage caused by radiation has been the focus of rigorous research, the mechanisms through which radiation exerts harmful effects on cells are complex and not well-understood. In particular, the influence of low dose radiation exposure on the regulation of genes and pathways remains unclear. In an attempt to investigate the molecular alterations induced by varying doses of radiation, a genome-wide expression analysis was conducted. Peripheral blood mononuclear cells were collected from five participants and each sample was subjected to 0.5 Gy, 1 Gy, 2.5 Gy, and 5 Gy of cobalt 60 radiation, followed by array-based expression profiling. Gene set enrichment analysis indicated that the immune system and cancer development pathways appeared to be the major affected targets by radiation exposure. Therefore, 1 Gy radioactive exposure seemed to be a critical threshold dosage. In fact, after 1 Gy radiation exposure, expression levels of several genes including FADD, TNFRSF10B, TNFRSF8, TNFRSF10A, TNFSF10, TNFSF8, CASP1, and CASP4 that are associated with carcinogenesis and metabolic disorders showed significant alterations. Our results suggest that exposure to low-dose radiation may elicit changes in metabolic and immune pathways, potentially increasing the risk of immune dysfunctions and metabolic disorders. PMID:25276823

  14. Evaluation of FHIT gene alterations in ovarian cancer.

    PubMed Central

    Buttitta, F.; Marchetti, A.; Radi, O.; Bertacca, G.; Pellegrini, S.; Gadducci, A.; Genazzani, A. R.; Bevilacqua, G.

    1998-01-01

    The FHIT gene, recently cloned and mapped on chromosome 3p14.2, has frequently been found to be abnormal in several established cancer cell lines and primary tumours. As alterations of chromosome 3p are common events in ovarian cancers with breakpoint sites at 3p14.2, we decided to investigate the role of FHIT in human ovarian tumorigenesis. Fifty-four primary ovarian carcinomas were studied by reverse transcription of FHIT mRNA followed by polymerase chain reaction (PCR) amplification and sequencing of products. The same tumours and matched normal tissues were also investigated for loss of heterozygosity using three microsatellite markers located inside the gene. We found an abnormal transcript of the FHIT gene in two cases (4%) and allelic losses in eight cases (15%). Twelve (22%) of the 54 tumours investigated belonged to young patients with a family history of breast/ovarian cancer. In none of these cases was the FHITgene found to be altered. Our results indicate that FHITplays a role in a small proportion of ovarian carcinomas. Images Figure 1 Figure 2 PMID:9569038

  15. The Oral Intake of Organic Germanium, Ge-132, Elevates α-Tocopherol Levels in the Plas-ma and Modulates Hepatic Gene Expression Profiles to Promote Immune Activation in Mice.

    PubMed

    Nakamura, Takashi; Takeda, Tomoya; Tokuji, Yoshihiko

    2014-01-01

    The common water-soluble organic germanium compound poly-trans-[(2-carboxyethyl) germasesquioxane] (Ge-132) exhibits activities related to immune responses and antioxidant induction. In this study, we evaluated the antioxidative effect of dietary Ge-132 in the plasma of mice. Male ICR mice (seven mice per group) received an AIN-76 diet with 0.05% Ge-132; three groups received the Ge-132-containing diet for 0, 1 or 4 days. The plasma alpha-tocopherol (α-tocopherol) concentration increased from 6.85 to 9.60 μg/ml after 4 days of Ge-132 intake (p<0.05). We evaluated the changes in hepatic gene expression related to antioxidative activity as well as in the entire expression profile after one day of Ge-132 intake, using DNA microarray technology. We identified 1,220 genes with altered expression levels greater than 1.5-fold (increased or decreased) as a result of Ge-132 intake, and α-tocopherol transfer protein (Ttpa) gene expression was increased 1.62-fold. Immune activation was identified as the category with the most changes (containing 60 Gene Ontology (GO) term biological processes (BPs), 41 genes) via functional clustering analysis of altered gene expression. Ge-132 affected genes in clusters related to ATP production (22 GO term BPs, 21 genes), lipid metabolism (4 GO term BPs, 38 genes) and apoptosis (5 GO term BPs). Many GO term BPs containing these categories were significantly affected by the Ge-132 intake. Oral Ge-132 intake may therefore have increased plasma α-tocopherol levels by up-regulating α-tocopherol transfer protein (Ttpa) gene expression. PMID:26098482

  16. Altered patterns of gene duplication and differential gene gain and loss in fungal pathogens

    PubMed Central

    Powell, Amy J; Conant, Gavin C; Brown, Douglas E; Carbone, Ignazio; Dean, Ralph A

    2008-01-01

    Background Duplication, followed by fixation or random loss of novel genes, contributes to genome evolution. Particular outcomes of duplication events are possibly associated with pathogenic life histories in fungi. To date, differential gene gain and loss have not been studied at genomic scales in fungal pathogens, despite this phenomenon's known importance in virulence in bacteria and viruses. Results To determine if patterns of gene duplication differed between pathogens and non-pathogens, we identified gene families across nine euascomycete and two basidiomycete species. Gene family size distributions were fit to power laws to compare gene duplication trends in pathogens versus non-pathogens. Fungal phytopathogens showed globally altered patterns of gene duplication, as indicated by differences in gene family size distribution. We also identified sixteen examples of gene family expansion and five instances of gene family contraction in pathogenic lineages. Expanded gene families included those predicted to be important in melanin biosynthesis, host cell wall degradation and transport functions. Contracted families included those encoding genes involved in toxin production, genes with oxidoreductase activity, as well as subunits of the vacuolar ATPase complex. Surveys of the functional distribution of gene duplicates indicated that pathogens show enrichment for gene duplicates associated with receptor and hydrolase activities, while euascomycete pathogens appeared to have not only these differences, but also significantly more duplicates associated with regulatory and carbohydrate binding functions. Conclusion Differences in the overall levels of gene duplication in phytopathogenic species versus non-pathogenic relatives implicate gene inventory flux as an important virulence-associated process in fungi. We hypothesize that the observed patterns of gene duplicate enrichment, gene family expansion and contraction reflect adaptation within pathogenic life

  17. Radiation Exposure Alters Expression of Metabolic Enzyme Genes In Mice

    NASA Technical Reports Server (NTRS)

    Wotring, Virginia E.; Mangala, L. S.; Zhang, Y.; Wu, H.

    2010-01-01

    Most pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Because of the importance of the liver in drug metabolism it is important to understand the effects of spaceflight on the enzymes of the liver. Exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. This study is an effort to examine the effects of adaptive mechanisms that may be triggered by early exposure to low radiation doses. Using procedures approved by the JSC Animal Care & Use Committee, C57 male mice were exposed to Cs-137 in groups: controls, low dose (50 mGy), high dose (6Gy) and a fourth group that received both radiation doses separated by 24 hours. Animals were anesthetized and sacrificed 4 hours after their last radiation exposure. Livers were removed immediately and flash-frozen in liquid nitrogen. Tissue was homogenized, RNA extracted and purified (Absolutely RNA, Agilent). Quality of RNA samples was evaluated (Agilent Bioanalyzer 2100). Complementary DNA was prepared from high-quality RNA samples, and used to run RT-qPCR screening arrays for DNA Repair and Drug Metabolism (SuperArray, SABiosciences/Qiagen; BioRad Cfx96 qPCR System). Of 91 drug metabolism genes examined, expression of 7 was altered by at least one treatment condition. Genes that had elevated expression include those that metabolize promethazine and steroids (4-8-fold), many that reduce oxidation products, and one that reduces heavy metal exposure (greater than 200-fold). Of the 91 DNA repair and general metabolism genes examined, expression of 14 was altered by at least one treatment condition. These gene expression changes are likely homeostatic and could lead to development of new radioprotective countermeasures.

  18. Thyrotropin receptor gene alterations in thyroid hyperfunctioning adenomas

    SciTech Connect

    Russo, D.; Arturi, F.; Filetti, S.

    1996-04-01

    Forty-four thyroid autonomously hyperfunctioning adenomas were analyzed to assess the frequency of mutations occurring in the TSH receptor (TSHR). PCR-amplified fragments encompassing the entire exon 10 of the TSHR gene were obtained from the genomic DNA extracted from the tumors and their adjacent normal tissues and were examined by direct nucleotide sequencing. Point mutations were found in 9 of 44 adenomas examined (20%). One mutation occurred in codon 619 (Asp to Gly), four in codon 623 (three were Ala to Ser, one Ala to substitution), two in codon 632 (both Thr to Ile), and two in codon 633 (Asp to Tyr or His). All the alterations were located in a part of the gene coding for an area including the third intracellular loop and the sixth transmembrane domain of the TSH receptor. All mutations were somatic and heterozygotic, and none was simultaneous with alterations of ras or gsp oncogenes. Thus, our data show that in our series of 44 hyperfunctioning thyroid adenomas, a somatic mutation of the TSHR, responsible for the constitutive activation of the cAMP pathway, occurs in 20% of the tumors. 28 refs., 2 tabs.

  19. Prolonged Intake of Dietary Lipids Alters Membrane Structure and T Cell Responses in LDLr-/- Mice.

    PubMed

    Pollock, Abigail H; Tedla, Nicodemus; Hancock, Sarah E; Cornely, Rhea; Mitchell, Todd W; Yang, Zhengmin; Kockx, Maaike; Parton, Robert G; Rossy, Jérémie; Gaus, Katharina

    2016-05-15

    Although it is recognized that lipids and membrane organization in T cells affect signaling and T cell activation, to what extent dietary lipids alter T cell responsiveness in the absence of obesity and inflammation is not known. In this study, we fed low-density lipoprotein receptor knockout mice a Western high-fat diet for 1 or 9 wk and examined T cell responses in vivo along with T cell lipid composition, membrane order, and activation ex vivo. Our data showed that high levels of circulating lipids for a prolonged period elevated CD4(+) and CD8(+) T cell proliferation and resulted in an increased proportion of CD4(+) central-memory T cells within the draining lymph nodes following induction of contact hypersensitivity. In addition, the 9-wk Western high-fat diet elevated the total phospholipid content and monounsaturated fatty acid level, but decreased saturated phosphatidylcholine and sphingomyelin within the T cells. The altered lipid composition in the circulation, and of T cells, was also reflected by enhanced membrane order at the activation site of ex vivo activated T cells that corresponded to increased IL-2 mRNA levels. In conclusion, dietary lipids can modulate T cell lipid composition and responses in lipoprotein receptor knockout mice even in the absence of excess weight gain and a proinflammatory environment. PMID:27183636

  20. Alcohol intake alters immune responses and promotes CNS viral persistence in mice.

    PubMed

    Loftis, Jennifer M; Taylor, Jonathan; Raué, Hans-Peter; Slifka, Mark K; Huang, Elaine

    2016-10-01

    Chronic hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic effects, including central nervous system (CNS) damage and neuropsychiatric impairments. Alcohol abuse can exacerbate these adverse effects on brain and behavior, but the molecular mechanisms are not well understood. This study investigated the role of alcohol in regulating viral persistence and CNS immunopathology in mice infected with lymphocytic choriomeningitis virus (LCMV), a model for HCV infections in humans. Female and male BALB/c mice (n=94) were exposed to alcohol (ethanol; EtOH) and water (or water only) using a two-bottle choice paradigm, followed one week later by infection with either LCMV clone 13 (causes chronic infection similar to chronic HCV), LCMV Armstrong (causes acute infection), or vehicle. Mice were monitored for 60days post-infection and continued to receive 24-h access to EtOH and water. Animals infected with LCMV clone 13 drank more EtOH, as compared to those with an acute or no viral infection. Six weeks after infection with LCMV clone 13, mice with EtOH exposure evidenced higher serum viral titers, as compared to mice without EtOH exposure. EtOH intake was also associated with reductions in virus-specific CD8(+) T cell frequencies (particularly CD11a(hi) subsets) and evidence of persistent CNS viremia in chronically infected mice. These findings support the hypothesis that EtOH use and chronic viral infection can result in combined toxic effects accelerating CNS damage and neuropsychiatric dysfunction and suggest that examining the role of EtOH in regulating viral persistence and CNS immunopathology in mice infected with LCMV can lead to a more comprehensive understanding of comorbid alcohol use disorder and chronic viral infection. PMID:27269869

  1. Renal cortex taurine content regulates renal adaptive response to altered dietary intake of sulfur amino acids.

    PubMed Central

    Chesney, R W; Gusowski, N; Dabbagh, S

    1985-01-01

    Rats fed a reduced sulfur amino acid diet (LTD) or a high-taurine diet (HTD) demonstrate a renal adaptive response. The LTD results in hypotaurinuria and enhanced brush border membrane vesicle (BBMV) accumulation of taurine. The HTD causes hypertaurinuria and reduced BBMV uptake. This adaptation may relate to changes in plasma or renal cortex taurine concentration. Rats were fed a normal-taurine diet (NTD), LTD, or HTD for 14 d or they underwent: (a) 3% beta-alanine for the last 8 d of each diet; (b) 3 d of fasting; or (c) a combination of 3% beta-alanine added for 8 d and 3 d of fasting. Each maneuver lowered the cortex taurine concentration, but did not significantly lower plasma taurine values compared with controls. Increased BBMV taurine uptake occurred after each manipulation. Feeding 3% glycine did not alter the plasma, renal cortex, or urinary taurine concentrations, or BBMV uptake of taurine. Feeding 3% methionine raised plasma and urinary taurine excretion but renal tissue taurine was unchanged, as was initial BBMV uptake. Hence, nonsulfur-containing alpha-amino acids did not change beta-amino acid transport. The increase in BBMV uptake correlates with the decline in renal cortex and plasma taurine content. However, since 3% methionine changed plasma taurine without altering BBMV uptake, it is more likely that the change in BBMV uptake and the adaptive response expressed at the brush border surface relate to changes in renal cortex taurine concentrations. Finally, despite changes in urine and renal cortex taurine content, brain taurine values were unchanged, which suggests that this renal adaptive response maintains stable taurine concentrations where taurine serves as a neuromodulator. PMID:3935668

  2. Chronic Intake of Japanese Sake Mediates Radiation-Induced Metabolic Alterations in Mouse Liver

    PubMed Central

    Nakajima, Tetsuo; Vares, Guillaume; Wang, Bing; Nenoi, Mitsuru

    2016-01-01

    Sake is a traditional Japanese alcoholic beverage that is gaining popularity worldwide. Although sake is reported to have beneficial health effects, it is not known whether chronic sake consumption modulates health risks due to radiation exposure or other factors. Here, the effects of chronic administration of sake on radiation-induced metabolic alterations in the livers of mice were evaluated. Sake (junmai-shu) was administered daily to female mice (C3H/He) for one month, and the mice were exposed to fractionated doses of X-rays (0.75 Gy/day) for the last four days of the sake administration period. For comparative analysis, a group of mice were administered 15% (v/v) ethanol in water instead of sake. Metabolites in the liver were analyzed by capillary electrophoresis-time-of-flight mass spectrometry one day following the last exposure to radiation. The metabolite profiles of mice chronically administered sake in combination with radiation showed marked changes in purine, pyrimidine, and glutathione (GSH) metabolism, which were only partially altered by radiation or sake administration alone. Notably, the changes in GSH metabolism were not observed in mice treated with radiation following chronic administration of 15% ethanol in water. Changes in several metabolites, including methionine and valine, were induced by radiation alone, but were not detected in the livers of mice who received chronic administration of sake. In addition, the chronic administration of sake increased the level of serum triglycerides, although radiation exposure suppressed this increase. Taken together, the present findings suggest that chronic sake consumption promotes GSH metabolism and anti-oxidative activities in the liver, and thereby may contribute to minimizing the adverse effects associated with radiation. PMID:26752639

  3. Alterations in energy balance from an exercise intervention with ad libitum food intake.

    PubMed

    Melzer, Katarina; Renaud, Anne; Zurbuchen, Stefanie; Tschopp, Céline; Lehmann, Jan; Malatesta, Davide; Ruch, Nicole; Schutz, Yves; Kayser, Bengt; Mäder, Urs

    2016-01-01

    Better understanding is needed regarding the effects of exercise alone, without any imposed dietary regimens, as a single tool for body-weight regulation. Thus, we evaluated the effects of an 8-week increase in activity energy expenditure (AEE) on ad libitum energy intake (EI), body mass and composition in healthy participants with baseline physical activity levels (PAL) in line with international recommendations. Forty-six male adults (BMI = 19·7-29·3 kg/m(2)) participated in an intervention group, and ten (BMI = 21·0-28·4 kg/m(2)) in a control group. Anthropometric measures, cardiorespiratory fitness, EI, AEE and exercise intensity were recorded at baseline and during the 1st, 5th and 8th intervention weeks, and movement was recorded throughout. Body composition was measured at the beginning and at the end of the study, and resting energy expenditure was measured after the study. The intervention group increased PAL from 1·74 (se 0·03) to 1·93 (se 0·03) (P < 0·0001) and cardiorespiratory fitness from 41·4 (se 0·9) to 45·7 (se 1·1) ml O2/kg per min (P = 0·001) while decreasing body mass (-1·36 (se 0·2) kg; P = 0·001) through adipose tissue mass loss (ATM) (-1·61 (se 0·2) kg; P = 0·0001) compared with baseline. The control group did not show any significant changes in activity, body mass or ATM. EI was unchanged in both groups. The results indicate that in normal-weight and overweight men, increasing PAL from 1·7 to 1·9 while keeping EI ad libitum over an 8-week period produces a prolonged negative energy balance. Replication using a longer period (and/or more intense increase in PAL) is needed to investigate if and at what body composition the increase in AEE is met by an equivalent increase in EI. PMID:27066256

  4. Daily energy intake of broiler chickens is altered by proximate nutrient content and form of the diet.

    PubMed

    Latshaw, J D

    2008-01-01

    An experiment was designed to test the ability of broiler chickens to equalize daily energy intake when proximate components of the diet were changed. A factorial arrangement was used to test effects of protein, fat, and fiber content in the diet. The simplest diet contained only corn and soybean meal to provide energy and protein. Protein contents were calculated to be 16.4, 18.2, and 20.0%, with added protein from a combination of corn gluten meal, fish meal, and peanut meal. Hydrolyzed fat was added at 0, 2.5, 5.0, and 7.5% of the diets. A combination of alfalfa meal, oats, and wheat middlings was used to increase the fiber of the corn soy diet by approximately 2 and 4%. The 36 combinations were fed as mash. In addition, 8 of the diets were fed as pellets. All diets were fed for 12 d from the time broilers reached approximately 1.2 kg. A total excreta collection was used to determine ME, and carcass analysis provided fat and energy content. When fed mash, only sex had a significant effect on grams of feed eaten per day. Sex and dietary fat content affected gain per day. Sex, fat, and fiber altered the kcal of ME eaten per day. Broilers fed 5% added fat ate approximately 10% more energy per day than those fed no added fat, and broilers fed 4% added fiber ate approximately 20% less ME than those fed no added fiber. A comparison of results from mash and pellets showed that only sex and form affected gain per day, feed per day, and kilocalories of ME eaten per day. For the mash and pellets, protein, fat, fiber, and several interactions affected the ME per gram; however, the ME per gram was similar for pellets and mash. The results suggest that the diet composition and form have a significant effect on the energy intake of broiler chickens. PMID:18079455

  5. Adenosinergic regulation of striatal clock gene expression and ethanol intake during constant light.

    PubMed

    Ruby, Christina L; Vadnie, Chelsea A; Hinton, David J; Abulseoud, Osama A; Walker, Denise L; O'Connor, Katheryn M; Noterman, Maria F; Choi, Doo-Sup

    2014-09-01

    Circadian rhythm and sleep disruptions occur frequently in individuals with alcohol use disorders (AUD) and present significant barriers to treatment. Recently, a variant of adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), was associated with the co-occurrence of sleep problems and AUD. We have previously shown that mice lacking ENT1 (ENT1 KO) have reduced adenosine levels in the striatum and drink more alcohol compared with wild types (WT). However, it is unknown whether ENT1 deletion disrupts circadian rhythms, which may contribute to alcohol preference in ENT1 KO mice. Here we used these mice to determine whether endogenous adenosine regulates circadian genetic and behavioral rhythms and influences alcohol intake during chronodisruption. We examined circadian locomotor activity in ENT1 KO vs WT littermates and found that ENT1 KO mice were both active earlier and hyperactive compared with WT mice at night. We used real-time PCR and immunohistochemistry to estimate striatal clock gene levels and found that PER2 expression in the striatum was blunted by ENT1 deletion or A2A receptor (A2AR) antagonism. Next, we exposed ENT1 KO and WT mice to constant light (LL) and found further elevation in ethanol intake in ENT1 KO, but not in WT mice, supporting the notion that circadian dysfunction may contribute to increased alcohol intake in ENT1 KO mice. Finally, we showed that A2AR agonist administration normalized PER1 and PER2 expression and circadian locomotor activity in ENT1 KO mice. Together, our results demonstrate that adenosine signaling regulates cellular and behavioral circadian timing and influences alcohol intake during chronodisruption. PMID:24755889

  6. Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

    PubMed Central

    Ruby, Christina L; Vadnie, Chelsea A; Hinton, David J; Abulseoud, Osama A; Walker, Denise L; O'Connor, Katheryn M; Noterman, Maria F; Choi, Doo-Sup

    2014-01-01

    Circadian rhythm and sleep disruptions occur frequently in individuals with alcohol use disorders (AUD) and present significant barriers to treatment. Recently, a variant of adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), was associated with the co-occurrence of sleep problems and AUD. We have previously shown that mice lacking ENT1 (ENT1 KO) have reduced adenosine levels in the striatum and drink more alcohol compared with wild types (WT). However, it is unknown whether ENT1 deletion disrupts circadian rhythms, which may contribute to alcohol preference in ENT1 KO mice. Here we used these mice to determine whether endogenous adenosine regulates circadian genetic and behavioral rhythms and influences alcohol intake during chronodisruption. We examined circadian locomotor activity in ENT1 KO vs WT littermates and found that ENT1 KO mice were both active earlier and hyperactive compared with WT mice at night. We used real-time PCR and immunohistochemistry to estimate striatal clock gene levels and found that PER2 expression in the striatum was blunted by ENT1 deletion or A2A receptor (A2AR) antagonism. Next, we exposed ENT1 KO and WT mice to constant light (LL) and found further elevation in ethanol intake in ENT1 KO, but not in WT mice, supporting the notion that circadian dysfunction may contribute to increased alcohol intake in ENT1 KO mice. Finally, we showed that A2AR agonist administration normalized PER1 and PER2 expression and circadian locomotor activity in ENT1 KO mice. Together, our results demonstrate that adenosine signaling regulates cellular and behavioral circadian timing and influences alcohol intake during chronodisruption. PMID:24755889

  7. Altered sleep-wake cycles and food intake: the Ramadan model.

    PubMed

    Reilly, Thomas; Waterhouse, Jim

    2007-02-28

    In this review the effects of diurnal fasting on normal physiological processes are considered. Ramadan is placed in a circadian context, food and fluid ingestion being displaced to the pre-sunrise and post-sunset hours. Over the holy month, negative energy balance is often experienced, though this deficit is not a universal finding. Responses to exercise during the day show influences consistent with hypohydration and an increased reliance on fat as a source of fuel for exercise. Muscle performance and psychomotor performance are impaired as the month of fasting progresses but it is not clear how circadian rhythms in responses to activity are altered. For some measures at rest there is a reduction in amplitude and a delay in acrophase. Health-related benefits are reflected in a rise in high-density lipoprotein cholesterol and individuals with predispositions for coronary heart disease are not at increased risk of cardiovascular disorders due to fasting. The physiological adjustments during the month have some similarities to the disturbances in circadian rhythms experienced in different circumstances. The Ramadan model provides an alternative to those for ageing, nocturnal shift-work and time-zone transitions in understanding the links between behaviour and endogenous circadian rhythms. PMID:17081572

  8. Genomic aberrations frequently alter chromatin regulatory genes in chordoma.

    PubMed

    Wang, Lu; Zehir, Ahmet; Nafa, Khedoudja; Zhou, Nengyi; Berger, Michael F; Casanova, Jacklyn; Sadowska, Justyna; Lu, Chao; Allis, C David; Gounder, Mrinal; Chandhanayingyong, Chandhanarat; Ladanyi, Marc; Boland, Patrick J; Hameed, Meera

    2016-07-01

    Chordoma is a rare primary bone neoplasm that is resistant to standard chemotherapies. Despite aggressive surgical management, local recurrence and metastasis is not uncommon. To identify the specific genetic aberrations that play key roles in chordoma pathogenesis, we utilized a genome-wide high-resolution SNP-array and next generation sequencing (NGS)-based molecular profiling platform to study 24 patient samples with typical histopathologic features of chordoma. Matching normal tissues were available for 16 samples. SNP-array analysis revealed nonrandom copy number losses across the genome, frequently involving 3, 9p, 1p, 14, 10, and 13. In contrast, copy number gain is uncommon in chordomas. Two minimum deleted regions were observed on 3p within a ∼8 Mb segment at 3p21.1-p21.31, which overlaps SETD2, BAP1 and PBRM1. The minimum deleted region on 9p was mapped to CDKN2A locus at 9p21.3, and homozygous deletion of CDKN2A was detected in 5/22 chordomas (∼23%). NGS-based molecular profiling demonstrated an extremely low level of mutation rate in chordomas, with an average of 0.5 mutations per sample for the 16 cases with matched normal. When the mutated genes were grouped based on molecular functions, many of the mutation events (∼40%) were found in chromatin regulatory genes. The combined copy number and mutation profiling revealed that SETD2 is the single gene affected most frequently in chordomas, either by deletion or by mutations. Our study demonstrated that chordoma belongs to the C-class (copy number changes) tumors whose oncogenic signature is non-random multiple copy number losses across the genome and genomic aberrations frequently alter chromatin regulatory genes. © 2016 Wiley Periodicals, Inc. PMID:27072194

  9. Feed intake alters immune cell functions and ovarian infiltration in broiler hens: implications for reproductive performance.

    PubMed

    Liu, Zu-Chen; Xie, Yi-Lun; Chang, Chai-Ju; Su, Chia-Ming; Chen, Yu-Hui; Huang, San-Yuan; Walzem, Rosemary L; Chen, Shuen-Ei

    2014-06-01

    Leukocytes are known to participate in ovarian activities in several species, but there is a surprising lack of information for the common chicken. Broiler hens consuming feed ad libitum (AL) exhibit a number of ovarian irregularities, but leukocyte functions are unstudied. In contrast to feed-restricted (R) hens, AL feeding for 7 wk significantly reduced egg production and clutch length while increasing pause length and atretic follicle numbers (P < 0.05). Granulosa cells from F1 follicles of AL hens contained less progesterone, and follicle walls were thicker with loose fibrous morphology and had less collagenase-3-like gelatinolytic activity but more IL-1beta (P < 0.05) production, suggestive of slower maturation in ovulatory process and inflamed necrosis. Interestingly, while highly infiltrated with immune cells, particularly heterophils, IL-1beta, MMP-22-like, and gelatinase A activities were reduced in AL hen peripheral heterophils and monocytes (P < 0.05); however, AL monocytes showed an increase in phagocytosis rate (P < 0.05). Generation of reactive oxygen intermediates was also suppressed in AL heterophils but increased in AL monocytes (P < 0.05). In contrast to leukocyte-free control, both AL and R heterophils and monocytes suppressed progesterone production and increased cell death in a dose-dependent manner when coincubated with granulosa cells at different ratios (P < 0.05). AL monocytes suppressed progesterone production more, but AL heterophils were less proapoptotic when compared to their R counterparts (P < 0.05). Alterations of cellular ceramide content (P < 0.05) corresponded to the discrepancy between heterophil and monocyte functionality. In conclusion, leukocyte dysfunction contributes to impaired ovarian activities of overfed broiler hens. PMID:24829031

  10. Fluconazole alters CYP26 gene expression in mouse embryos.

    PubMed

    Tiboni, Gian Mario; Marotta, Francesca; Carletti, Erminia

    2009-04-01

    Disruption of embryonal retinoic acid homeostasis has been postulated to represent an etiological factor involved in the onset of fluconazole-induced teratogenesis. In the present study the impact of a teratogenic pulse of fluconazole on the gene expression of cytochrome P450 (CYP) 26 isoforms, which plays a central role in maintaining proper retinoic acid levels by mediating its degradation, was investigated. ICR pregnant mice were orally administered with 0 (vehicle) or 700mg/kg of fluconazole on gestation day 8. Embryos were collected 12, 24 and 48h after treatment. Quantitative real-time reverse-transcription polymerase chain reaction (quantitative real-time RT-PCR) assay was used to quantify the mRNA expression of CYP26a1, CYP26b1 and CYP26c1 in embryos. As result, fluconazole exposure was associated to an up-regulation of CYP26a1, CYP26b1, whereas no significant change was identified for the CYP26c1 isoform. This study demonstrates the capacity of fluconazole to alter CYP26 gene expression in mouse embryos. PMID:19429397

  11. Serum Metabolite Profiles and Target Tissue Gene Expression Define the Effect of Cholecalciferol Intake on Calcium Metabolism in Rats and Mice1,2

    PubMed Central

    Fleet, James C.; Gliniak, Christy; Zhang, Zhentao; Xue, Yingben; Smith, Kathleen B.; McCreedy, Rebecca; Adedokun, Sunday A.

    2008-01-01

    We studied the effect of cholecalciferol (VD3) intake on VD3 status and markers of calcium (Ca) homeostasis in mice and rats. Serum 25 hydroxycholecalciferol (25OH-VD3) concentrations were increased in animals fed diets containing 400–20,000 international units (IU) VD3/kg (37 nmol·L−1·1000 IU VD3−1), but body weight, serum Ca, and duodenal gene expression were not altered. High-VD3 intake decreased serum 1, 25-dihydroxycholecalciferol [1,25(OH)2-VD3] and renal 25 hydroxycholecalciferol-1ahydroxylase (CYP27B1) mRNA, suggesting that rodents tolerate high-VD3 intake by suppressing the activity of the VD3 endocrine system. Serum 25OH-VD3 declined when animals were fed diets containing 1000 to 25 IU VD3/kg (9–11 wk, inflection at 200 IU/kg, 4-fold steeper slope below this). Neither body weight nor serum Ca were influenced by low-VD3 intake. However, mice fed the 25-IU/kg diet had lower serum 1,25(OH)2-VD3, duodenal calbindin D9k mRNA, bone mineral density, and renal 25 hydroxycholecalciferol-24 hydroxylase mRNA, whereas renal CYP27B1 mRNA was elevated when rodents were fed ,200 IU VD3/kg. These data reveal a stress on VD3 and Ca metabolism at low dietary VD3 intake. Dietary Ca restriction (0.25 vs. 0.5%, 9 wk) increased serum 1,25(OH)2-VD3 and was 30% greater in rats fed a 10,000-IU VD3/kg diet. High-VD3 intake did not prevent Ca restriction-induced bone loss. Our data show that modeling human VD3 status requires lower intake than the current NRC rodent requirement (1000-IU/kg diet). Also, although rodents are very tolerant of high-VD3 intake, it cannot compensate for moderate Ca restriction. PMID:18492843

  12. Blocking opioid receptors alters short-term feed intake and oro-sensorial preferences in weaned calves.

    PubMed

    Montoro, C; Ipharraguerre, I R; Bach, A

    2012-05-01

    during the first 4 h after feeding and tended to prefer SF only after 6 h from feeding. Plasma glucose, insulin, and cholecystokinin concentrations were greater in FED than in FAS calves. Injection of naloxone decreased plasma glucagon-like peptide-1 (GLP-1) in NAL calves. Blocking opioid receptors reduced intake the first 2 h after naloxone injection in FED calves, altered oro-sensorial preferences, and reduced plasma GLP-1 concentration. In conclusion, the opioid peptide system may control short-term feed intake by modulating the oro-sensorial response triggered by feed consumption, especially when calves are fed ad libitum. PMID:22541480

  13. Alterations in hypothalamic gene expression following Roux-en-Y gastric bypass

    PubMed Central

    Barkholt, Pernille; Pedersen, Philip J.; Hay-Schmidt, Anders; Jelsing, Jacob; Hansen, Henrik H.; Vrang, Niels

    2016-01-01

    Objective The role of the central nervous system in mediating metabolic effects of Roux-en-Y gastric bypass (RYGB) surgery is poorly understood. Using a rat model of RYGB, we aimed to identify changes in gene expression of key hypothalamic neuropeptides known to be involved in the regulation of energy balance. Methods Lean male Sprague-Dawley rats underwent either RYGB or sham surgery. Body weight and food intake were monitored bi-weekly for 60 days post-surgery. In situ hybridization mRNA analysis of hypothalamic AgRP, NPY, CART, POMC and MCH was applied to RYGB and sham animals and compared with ad libitum fed and food-restricted rats. Furthermore, in situ hybridization mRNA analysis of dopaminergic transmission markers (TH and DAT) was applied in the midbrain. Results RYGB surgery significantly reduced body weight and intake of a highly palatable diet but increased chow consumption compared with sham operated controls. In the arcuate nucleus, RYGB surgery increased mRNA levels of orexigenic AgRP and NPY, whereas no change was observed in anorexigenic CART and POMC mRNA levels. A similar pattern was seen in food-restricted versus ad libitum fed rats. In contrast to a significant increase of orexigenic MCH mRNA levels in food-restricted animals, RYGB did not change MCH expression in the lateral hypothalamus. In the VTA, RYGB surgery induced a reduction in mRNA levels of TH and DAT, whereas no changes were observed in the substantia nigra relative to sham surgery. Conclusion RYGB surgery increases the mRNA levels of hunger-associated signaling markers in the rat arcuate nucleus without concomitantly increasing downstream MCH expression in the lateral hypothalamus, suggesting that RYGB surgery puts a brake on orexigenic hypothalamic output signals. In addition, down-regulation of midbrain TH and DAT expression suggests that altered dopaminergic activity also contributes to the reduced intake of palatable food in RYGB rats. PMID:27069869

  14. Bitter Receptor Gene (TAS2R38), 6-n-Propylthiouracil (PROP) Bitterness and Alcohol Intake

    PubMed Central

    Duffy, Valerie B.; Davidson, Andrew C.; Kidd, Judith R.; Kidd, Kenneth K.; Speed, William C.; Pakstis, Andrew J.; Reed, Danielle R.; Snyder, Derek J.; Bartoshuk, Linda M.

    2006-01-01

    Background Phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), chemically related compounds, are probes for genetic variation in bitter taste, although PROP is safer with less sulfurous odor. Threshold for PROP distinguishes nontasters (increased threshold) from tasters (lower threshold); perceived intensity subdivides tasters into medium tasters (PROP is bitter) and supertasters (PROP is very bitter). Compared with supertasters, nontasters have fewer taste papillae on the anterior tongue (fungiform papillae) and experience less negative (e.g., bitterness) and more positive (eg, sweetness) sensations from alcohol. We determined whether the TAS2R38 gene at 7q36 predicted PROP bitterness, alcohol sensation and use. Methods Healthy adults (53 women, 31 men; mean age 36 years)—primarily light and moderate drinkers—reported the bitterness of five PROP concentrations (0.032–3.2 mM) and intensity of 50% ethanol on the general Labeled Magnitude Scale. PROP threshold and density of fungiform papillae were also measured. Subjects had common TAS2R38 gene haplotypes [alanine-valine-isoleucine (AVI) and proline-alanine-valine (PAV)]. Results PROP bitterness varied significantly across genotypes with repeated measures ANOVA: 26 AVI/AVI homozygotes tasted less bitterness than either 37 PAV/AVI heterozygotes or 21 PAV/PAV homozygotes. The PAV/PAV group exceeded the PAV/AVI group for bitterness only for the top PROP concentrations. The elevated bitterness was musch less than if we defined the groups using psychophysical criteria. With multiple regression analyses, greater bitterness from 3.2 mM PROP was a significant predictor of greater ethanol intensity and less alcohol intake—effects separate from age and sex. Genotype was a significant predictor of alcohol intake, but not ethanol intensity. With ANOVA, AVI/AVI homozygotes reported higher alcohol use than either PAV/AVI heterozygotes or PAV/PAV homozygotes. When age effects were minimized, PROP bitterness

  15. Does Increased Exercise or Physical Activity Alter Ad-Libitum Daily Energy Intake or Macronutrient Composition in Healthy Adults? A Systematic Review

    PubMed Central

    Donnelly, Joseph E.; Herrmann, Stephen D.; Lambourne, Kate; Szabo, Amanda N.; Honas, Jeffery J.; Washburn, Richard A.

    2014-01-01

    Background The magnitude of the negative energy balance induced by exercise may be reduced due to compensatory increases in energy intake. Objective To address the question: Does increased exercise or physical activity alter ad-libitum daily energy intake or macronutrient composition in healthy adults? Data Sources PubMed and Embase were searched (January 1990–January 2013) for studies that presented data on energy and/or macronutrient intake by level of exercise, physical activity or change in response to exercise. Ninety-nine articles (103 studies) were included. Study Eligibility Criteria Primary source articles published in English in peer-reviewed journals. Articles that presented data on energy and/or macronutrient intake by level of exercise or physical activity or changes in energy or macronutrient intake in response to acute exercise or exercise training in healthy (non-athlete) adults (mean age 18–64 years). Study Appraisal and Synthesis Methods Articles were grouped by study design: cross-sectional, acute/short term, non-randomized, and randomized trials. Considerable heterogeneity existed within study groups for several important study parameters, therefore a meta-analysis was considered inappropriate. Results were synthesized and presented by study design. Results No effect of physical activity, exercise or exercise training on energy intake was shown in 59% of cross-sectional studies (n = 17), 69% of acute (n = 40), 50% of short-term (n = 10), 92% of non-randomized (n = 12) and 75% of randomized trials (n = 24). Ninety-four percent of acute, 57% of short-term, 100% of non-randomized and 74% of randomized trials found no effect of exercise on macronutrient intake. Forty-six percent of cross-sectional trials found lower fat intake with increased physical activity. Limitations The literature is limited by the lack of adequately powered trials of sufficient duration, which have prescribed and measured exercise energy expenditure

  16. Shift Work or Food Intake during the Rest Phase Promotes Metabolic Disruption and Desynchrony of Liver Genes in Male Rats

    PubMed Central

    Salgado-Delgado, Roberto C.; Saderi, Nadia; Basualdo, María del Carmen; Guerrero-Vargas, Natali N.; Escobar, Carolina; Buijs, Ruud M.

    2013-01-01

    In the liver, clock genes are proposed to drive metabolic rhythms. These gene rhythms are driven by the suprachiasmatic nucleus (SCN) mainly by food intake and via autonomic and hormonal pathways. Forced activity during the normal rest phase, induces also food intake, thus neglecting the signals of the SCN, leading to conflicting time signals to target tissues of the SCN. The present study explored in a rodent model of night-work the influence of food during the normal sleep period on the synchrony of gene expression between clock genes and metabolic genes in the liver. Male Wistar rats were exposed to forced activity for 8 h either during the rest phase (day) or during the active phase (night) by using a slow rotating wheel. In this shift work model food intake shifts spontaneously to the forced activity period, therefore the influence of food alone without induced activity was tested in other groups of animals that were fed ad libitum, or fed during their rest or active phase. Rats forced to be active and/or eating during their rest phase, inverted their daily peak of Per1, Bmal1 and Clock and lost the rhythm of Per2 in the liver, moreover NAMPT and metabolic genes such as Pparα lost their rhythm and thus their synchrony with clock genes. We conclude that shift work or food intake in the rest phase leads to desynchronization within the liver, characterized by misaligned temporal patterns of clock genes and metabolic genes. This may be the cause of the development of the metabolic syndrome and obesity in individuals engaged in shift work. PMID:23565183

  17. Early Life Exposure to Fructose Alters Maternal, Fetal and Neonatal Hepatic Gene Expression and Leads to Sex-Dependent Changes in Lipid Metabolism in Rat Offspring

    PubMed Central

    Clayton, Zoe E.; Vickers, Mark H.; Bernal, Angelica; Yap, Cassandra; Sloboda, Deborah M.

    2015-01-01

    Aim Fructose consumption is associated with altered hepatic function and metabolic compromise and not surprisingly has become a focus for perinatal studies. We have previously shown that maternal fructose intake results in sex specific changes in fetal, placental and neonatal outcomes. In this follow-up study we investigated effects on maternal, fetal and neonatal hepatic fatty acid metabolism and immune modulation. Methods Pregnant rats were randomised to either control (CON) or high-fructose (FR) diets. Fructose was given in solution and comprised 20% of total caloric intake. Blood and liver samples were collected at embryonic day 21 (E21) and postnatal day (P)10. Maternal liver samples were also collected at E21 and P10. Liver triglyceride and glycogen content was measured with standard assays. Hepatic gene expression was measured with qPCR. Results Maternal fructose intake during pregnancy resulted in maternal hepatic ER stress, hepatocellular injury and increased levels of genes that favour lipogenesis. These changes were associated with a reduction in the NLRP3 inflammasome. Fetuses of mothers fed a high fructose diet displayed increased hepatic fructose transporter and reduced fructokinase mRNA levels and by 10 days of postnatal age, also have hepatic ER stress, and elevated IL1β mRNA levels. At P10, FR neonates demonstrated increased hepatic triglyceride content and particularly in males, associated changes in the expression of genes regulating beta oxidation and the NLRP3 inflammasome. Further, prenatal fructose results in sex-dependant changes in levels of key clock genes. Conclusions Maternal fructose intake results in age and sex-specific alterations in maternal fetal and neonatal free fatty acid metabolism, which may be associated in disruptions in core clock gene machinery. How these changes are associated with hepatic inflammatory processes is still unclear, although suppression of the hepatic inflammasome, as least in mothers and male neonates may

  18. Sustained exposure to diets with an unbalanced macronutrient proportion alters key genes involved in energy homeostasis and obesity-related metabolic parameters in rats.

    PubMed

    Díaz-Rúa, Rubén; García-Ruiz, Estefanía; Caimari, Antoni; Palou, Andreu; Oliver, Paula

    2014-12-01

    We have investigated the effects of long term intake of two unbalanced diets (rich in fat -HF- or protein -HP-) administered under isocaloric conditions to a control balanced diet (pair-feeding) to adult rats. Isocaloric intake of a HF diet did not affect the body weight but increased adiposity, liver-fat deposition, and induced insulin resistance. Gene expression changes in the liver and adipose tissue (increased lipolytic and decreased lipogenic gene expression) could try to compensate for increased adiposity. The HP diet decreased caloric intake, the body weight, the size of subcutaneous adipocytes, and circulating cholesterol. Higher insulin levels apparently not related to insulin resistance were observed. Changes at the gene expression level reflected an adaptation to lower diet carbohydrate content and to the use of amino acids as the energy source. The kidney size increased in HP-fed animals but serum creatinine was not affected. Circulating TNF-alpha levels were higher in both dietary models. Thus, a long-term increase in dietary fat proportion produces alterations related to metabolic syndrome even in the absence of increased body weight, whereas an increase in diet protein content reduces the body weight but alters metabolic parameters and kidney size which could be linked to an increased risk of suffering from different pathologies. PMID:25266916

  19. Microarray expression profiling identifies genes with altered expression in HDL-deficient mice

    SciTech Connect

    Callow, Matthew J.; Dudoit, Sandrine; Gong, Elaine L.; Speed, Terence P.; Rubin, Edward M.

    2000-05-05

    Based on the assumption that severe alterations in the expression of genes known to be involved in HDL metabolism may affect the expression of other genes we screened an array of over 5000 mouse expressed sequence tags (ESTs) for altered gene expression in the livers of two lines of mice with dramatic decreases in HDL plasma concentrations. Labeled cDNA from livers of apolipoprotein AI (apo AI) knockout mice, Scavenger Receptor BI (SR-BI) transgenic mice and control mice were co-hybridized to microarrays. Two-sample t-statistics were used to identify genes with altered expression levels in the knockout or transgenic mice compared with the control mice. In the SR-BI group we found 9 array elements representing at least 5 genes to be significantly altered on the basis of an adjusted p value of less than 0.05. In the apo AI knockout group 8 array elements representing 4 genes were altered compared with the control group (p < 0.05). Several of the genes identified in the SR-BI transgenic suggest altered sterol metabolism and oxidative processes. These studies illustrate the use of multiple-testing methods for the identification of genes with altered expression in replicated microarray experiments of apo AI knockout and SR-BI transgenic mice.

  20. Effect of heat exposure on gene expression of feed intake regulatory peptides in laying hens.

    PubMed

    Song, Zhigang; Liu, Lei; Sheikhahmadi, Ardashir; Jiao, Hongchao; Lin, Hai

    2012-01-01

    The aim of this paper was to investigate the effect of heat stress on the regulation of appetite-associated genes in laying hens. Forty eight laying hens were randomly divided into two circumstances: high (31 ± 1.5°C; relative humidity, 82.0 ± 2.2%) or normal (20 ± 2°C, control; relative humidity, 60.1 ± 4.5%) ambient environment. Heat stress decreased body weight gain (P < 0.01), feed intake (P < 0.01), laying rate (P < 0.05), average egg mass (P < 0.01), egg production (P < 0.01), shell thickness (P < 0.01), and feed efficiency (P < 0.05). High ambient temperature decreased plasma uric acid (P < 0.05). Heat stress significantly increased mRNA levels of ghrelin and cocaine- and amphetamine-regulated transcript (P < 0.05) and decreased mRNA levels of cholecystokinin (P < 0.05) in the hypothalamus. Heat stress significantly increased (P < 0.05) mRNA levels of ghrelin in the glandular stomach and jejunum but significantly decreased (P < 0.05) mRNA levels of cholecystokinin in the duodenum and jejunum. In conclusion, heat stress plays a unique role in some special neuropeptides (e.g., ghrelin, cocaine- and amphetamine-regulated transcript, and cholecystokinin), which might participate in the regulation of feed intake in laying hens under high ambient temperature. PMID:22619495

  1. Lanosterol Synthase Gene Polymorphisms and Changes in Endogenous Ouabain in the Response to Low Sodium Intake.

    PubMed

    Lanzani, Chiara; Gatti, Guido; Citterio, Lorena; Messaggio, Elisabetta; Delli Carpini, Simona; Simonini, Marco; Casamassima, Nunzia; Zagato, Laura; Brioni, Elena; Hamlyn, John M; Manunta, Paolo

    2016-02-01

    Circulating levels of endogenous ouabain (EO), a vasopressor hormone of adrenocortical origin, are increased by sodium depletion. Furthermore, lanosterol synthase, an enzyme involved in cholesterol biosynthesis, has a missense polymorphism (rs2254524 V642L) that affects EO biosynthesis in adrenocortical cells. Here, we investigated the hypothesis that lanosterol synthase rs2254524 alleles in vivo impact the blood pressure (BP) and EO responses evoked by a low dietary Na intake (<100 mEq/d, 2 weeks) among patients with mild essential hypertension. During the low salt diet, the declines in both systolic BP (SBP: -8.7±1.7 versus -3.0±1.5; P=0.013) and diastolic BP (DBP: -5.1±0.98 versus -1.4±0.94 mm Hg; P<0.05), and the slope of the long-term pressure-natriuresis relationship affected significantly the presence of the lanosterol synthase rs2254524 A variant (AA: 0.71±0.22, AC 0.09±0.13, and CC 0.04±0.11 mEq/mm Hg/24 h; P=0.028). In addition, BP rose in ≈25% of the patients in response to the low salt diet and this was associated with increased circulating EO. Lanosterol synthase gene polymorphisms influence both the salt sensitivity of BP and changes in circulating EO in response to a low salt diet. The response of BP and EO to the low salt diet is markedly heterogeneous. Approximately 25% of patients experienced adverse effects, that is, increased BP and EO when salt intake was reduced and may be at increased long-term risk. The augmented response of EO to the low salt diet further supports the view that adrenocortical function is abnormal in some essential hypertensives. PMID:26667413

  2. Effect of Heat Exposure on Gene Expression of Feed Intake Regulatory Peptides in Laying Hens

    PubMed Central

    Song, Zhigang; Liu, Lei; Sheikhahmadi, Ardashir; Jiao, Hongchao; Lin, Hai

    2012-01-01

    The aim of this paper was to investigate the effect of heat stress on the regulation of appetite-associated genes in laying hens. Forty eight laying hens were randomly divided into two circumstances: high (31 ± 1.5°C; relative humidity, 82.0 ± 2.2%) or normal (20 ± 2°C, control; relative humidity, 60.1 ± 4.5%) ambient environment. Heat stress decreased body weight gain (P < 0.01), feed intake (P < 0.01), laying rate (P < 0.05), average egg mass (P < 0.01), egg production (P < 0.01), shell thickness (P < 0.01), and feed efficiency (P < 0.05). High ambient temperature decreased plasma uric acid (P < 0.05). Heat stress significantly increased mRNA levels of ghrelin and cocaine- and amphetamine-regulated transcript (P < 0.05) and decreased mRNA levels of cholecystokinin (P < 0.05) in the hypothalamus. Heat stress significantly increased (P < 0.05) mRNA levels of ghrelin in the glandular stomach and jejunum but significantly decreased (P < 0.05) mRNA levels of cholecystokinin in the duodenum and jejunum. In conclusion, heat stress plays a unique role in some special neuropeptides (e.g., ghrelin, cocaine- and amphetamine-regulated transcript, and cholecystokinin), which might participate in the regulation of feed intake in laying hens under high ambient temperature. PMID:22619495

  3. Consistent Prebiotic Effect on Gut Microbiota With Altered FODMAP Intake in Patients with Crohn's Disease: A Randomised, Controlled Cross-Over Trial of Well-Defined Diets

    PubMed Central

    Halmos, Emma P; Christophersen, Claus T; Bird, Anthony R; Shepherd, Susan J; Muir, Jane G; Gibson, Peter R

    2016-01-01

    Objectives: Altering FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) intake has substantial effects on gut microbiota. This study aimed to investigate effects of altering FODMAP intake on markers of colonic health in patients with Crohn's disease. Methods: After evaluation of their habitual diet, 9 patients with clinically quiescent Crohn's disease were randomised to 21 days of provided low or typical (“Australian”) FODMAP diets with ≥21-day washout in between. Five-day fecal samples were collected at the end of each diet and analyzed for calprotectin, pH, short-chain fatty acids (SCFA) and bacterial abundance. Gastrointestinal symptoms were recorded daily. Results: Eight participants collected feces and were adherent to the diets. FODMAP intake differed across the three dietary periods with lowaltering dietary FODMAP intake is associated with marked changes in fecal microbiota, most consistent with a prebiotic effect of increasing FODMAPs as shown in an irritable bowel/healthy cohort. This strategy might be favorable for gut health in Crohn's disease, but at the cost of inducing symptoms. PMID:27077959

  4. Constant light induces alterations in melatonin levels, food intake, feed efficiency, visceral adiposity, and circadian rhythms in rats.

    PubMed

    Wideman, Cyrilla H; Murphy, Helen M

    2009-10-01

    Melatonin levels, metabolic parameters, circadian rhythm activity patterns, and behavior were observed in rats subjected to a 12-h/12-h light/dark cycle (LD) compared to animals exposed to continuous dark (DD) or continuous light (LL). LD and DD animals were similar in melatonin levels, food intake, relative food intake, feed efficiency, water intake, circadian activity levels, and behavior. LL animals had lower melatonin levels in the subjective dark compared to LD and DD animals. Food intake, relative food intake, and water intake values were lower and feed efficiency was more positive in LL animals compared to LD and DD animals. In addition, LL animals exhibited greater visceral adiposity than the other two groups. The circadian rhythmicity of activity became free-running in LL animals and there was a decrease in overall activity. Notable behavioral changes in LL animals were an increase in irritability and excitability. Results indicate that a decrease in melatonin levels and concomitant changes in metabolism, circadian rhythms, and behavior are consequences of exposure to constant light. PMID:19761654

  5. Suppression of cytoplasmic male sterility by nuclear genes alters expression of a novel mitochondrial gene region.

    PubMed Central

    Singh, M; Brown, G G

    1991-01-01

    To identify regions of the mitochondrial genome that potentially could specify the "Polima" (pol) cytoplasmic male sterility (CMS) of Brassica napus, transcripts of 14 mitochondrial genes from nap (male fertile), pol (male sterile), and nuclear fertility-restored pol cytoplasm plants were analyzed. Transcriptional differences among these plants were detected only with the ATPase subunit 6 (atp6) gene. Structural analysis of the atp6 gene regions of pol and nap mitochondrial DNAs showed that rearrangements in the pol mitochondrial genome occurring upstream of atp6 have generated a chimeric 224-codon open reading frame, designated orf224, that is cotranscribed with atp6. In CMS plants, most transcripts of this region are dicistronic, comprising both orf224 and atp6 sequences. Nuclear restorer genes at either of two distinct loci appear to specifically alter this transcript pattern such that monocistronic atp6 transcripts predominate. The differences in expression of this region appear to result, in part, from differential processing of a tRNA-like element comprising a tRNA pseudogene present immediately upstream of atp6 in both the sterile and fertile mitochondrial DNAs. Possible mechanisms by which expression of the orf224/atp6 locus and the Polima CMS trait may be specifically related are considered. PMID:1840901

  6. Somatic gene copy number alterations in colorectal cancer: new quest for cancer drivers and biomarkers.

    PubMed

    Wang, H; Liang, L; Fang, J-Y; Xu, J

    2016-04-21

    Colorectal cancer (CRC) results from the accumulation of genetic alterations, and somatic copy number alterations (CNAs) are crucial for the development of CRC. Genome-wide survey of CNAs provides opportunities for identifying cancer driver genes in an unbiased manner. The detection of aberrant CNAs may provide novel markers for the early diagnosis and personalized treatment of CRC. A major challenge in array-based profiling of CNAs is to distinguish the alterations that play causative roles from the random alterations that accumulate during colorectal carcinogenesis. In this view, we systematically discuss the frequent CNAs in CRC, focusing on functional genes that have potential diagnostic, prognostic and therapeutic significance. PMID:26257062

  7. Arabidopsis gene expression patterns are altered during spaceflight

    NASA Astrophysics Data System (ADS)

    Paul, Anna-Lisa; Popp, Michael P.; Gurley, William B.; Guy, Charles; Norwood, Kelly L.; Ferl, Robert J.

    The exposure of Arabidopsis thaliana (Arabidopsis) plants to spaceflight environments results in differential gene expression. A 5-day mission on orbiter Columbia in 1999 (STS-93) carried transgenic Arabidopsis plants engineered with a transgene composed of the alcohol dehydrogenase (Adh) gene promoter linked to the β-Glucuronidase (GUS) reporter gene. The plants were used to evaluate the effects of spaceflight on gene expression patterns initially by using the Adh/GUS transgene to address specifically the possibility that spaceflight induces a hypoxic stress response (Paul, A.L., Daugherty, C.J., Bihn, E.A., Chapman, D.K., Norwood, K.L., Ferl, R.J., 2001. Transgene expression patterns indicate that spaceflight affects stress signal perception and transduction in arabidopsis, Plant Physiol. 126, 613-621). As a follow-on to the reporter gene analysis, we report here the evaluation of genome-wide patterns of native gene expression within Arabidopsis shoots utilizing the Agilent DNA array of 21,000 Arabidopsis genes. As a control for the veracity of the array analyses, a selection of genes was further characterized with quantitative Real-Time RT PCR (ABI - Taqman®). Comparison of the patterns of expression for arrays probed with RNA isolated from plants exposed to spaceflight compared to RNA isolated from ground control plants revealed 182 genes that were differentially expressed in response to the spaceflight mission by more than 4-fold, and of those only 50 genes were expressed at levels chosen to support a conservative change call. None of the genes that are hallmarks of hypoxic stress were induced to this level. However, genes related to heat shock were dramatically induced - but in a pattern and under growth conditions that are not easily explained by elevated temperatures. These gene expression data are discussed in light of current models for plant responses to the spaceflight environment and with regard to potential future spaceflight experiment

  8. Acute exercise increases feeding latency in healthy normal weight young males but does not alter energy intake.

    PubMed

    King, James A; Wasse, Lucy K; Stensel, David J

    2013-02-01

    This study investigated the acute influence of exercise on eating behaviour in an ecologically valid setting whereby healthy active males were permitted complete ad libitum access to food. Ten healthy males completed two, 8h trials (exercise and control) in a randomised-crossover design. In the exercise trials participants consumed a breakfast snack and then rested for 1h before undertaking a 60 min run (72% of VO(2)max) on a treadmill. Participants then rested in the laboratory for 6h during which time they were permitted complete ad libitum access to a buffet meal. The timing of meals, energy/macronutrient intake and eating frequency were assessed. Identical procedures were completed in the control trial except no exercise was performed. Exercise increased the length of time (35 min) before participants voluntarily requested to eat afterwards. Despite this, energy intake at the first meal consumed, or at subsequent eating episodes, was not influenced by exercise (total trial energy intake: control 7426 kJ, exercise 7418 kJ). Neither was there any difference in macronutrient intake or meal frequency between trials. These results confirm that food intake remains unaffected by exercise in the immediate hours after but suggest that exercise may invoke a delay before food is desired. PMID:23137828

  9. FABP4 is a leading candidate gene associated with residual feed intake in growing Holstein calves.

    PubMed

    Cohen-Zinder, Miri; Asher, Aviv; Lipkin, Ehud; Feingersch, Roi; Agmon, Rotem; Karasik, David; Brosh, Arieh; Shabtay, Ariel

    2016-05-01

    Ecological and economic concerns drive the need to improve feed utilization by domestic animals. Residual feed intake (RFI) is one of the most acceptable measures for feed efficiency (FE). However, phenotyping RFI-related traits is complex and expensive and requires special equipment. Advances in marker technology allow the development of various DNA-based selection tools. To assimilate these technologies for the benefit of RFI-based selection, reliable phenotypic measures are prerequisite. In the current study, we identified single nucleotide polymorphisms (SNPs) associated with RFI phenotypic consistency across different ages and diets (named RFI 1-3), using DNA samples of high or low RFI ranked Holstein calves. Using targeted sequencing of chromosomal regions associated with FE- and RFI-related traits, we identified 48 top SNPs significantly associated with at least one of three defined RFIs. Eleven of these SNPs were harbored by the fatty acid binding protein 4 (FABP4). While 10 significant SNPs found in FABP4 were common for RFI 1 and RFI 3, one SNP (FABP4_5; Agene, was significantly associated with all three RFIs. As the three RFI classes reflect changing diets and ages with concomitant RFI phenotypic consistency, the above polymorphisms and in particular FABP4_5, might be considered possible markers for RFI-based selection for FE in the Holstein breed, following a larger-scale validation. PMID:26993365

  10. Parasite-induced alteration of plastic response to predation threat: increased refuge use but lower food intake in Gammarus pulex infected with the acanothocephalan Pomphorhynchus laevis.

    PubMed

    Dianne, Lucile; Perrot-Minnot, Marie-Jeanne; Bauer, Alexandre; Guvenatam, Arnaud; Rigaud, Thierry

    2014-03-01

    Larvae of many trophically-transmitted parasites alter the behaviour of their intermediate host in ways that increase their probability of transmission to the next host in their life cycle. Before reaching a stage that is infective to the next host, parasite larvae may develop through several larval stages in the intermediate host that are not infective to the definitive host. Early predation at these stages results in parasite death, and it has recently been shown that non-infective larvae of some helminths decrease such risk by enhancing the anti-predator defences of the host, including decreased activity and increased sheltering. However, these behavioural changes may divert infected hosts from an optimal balance between survival and foraging (either seeking food or a mate). In this study, this hypothesis was tested using the intermediate host of the acanthocephalan parasite Pomphorhynchus laevis, the freshwater amphipod Gammarus pulex. We compared activity, refuge use, food foraging and food intake of hosts experimentally infected with the non-infective stage (acanthella), with that of uninfected gammarids. Behavioural assays were conducted in four situations varying in predation risk and in food accessibility. Acanthella-infected amphipods showed an increase in refuge use and a general reduction in activity and food intake. There was no effect of parasite intensity on these traits. Uninfected individuals showed plastic responses to water-borne cues from fish by adjusting refuge use, activity and food intake. They also foraged more when the food was placed outside the refuge. At the intra-individual level, refuge use and food intake were positively correlated in infected gammarids only. Overall, our findings suggest that uninfected gammarids exhibit risk-sensitive behaviour including increased food intake under predation risk, whereas gammarids infected with the non-infective larvae of P. laevis exhibit a lower motivation to feed, irrespective of predation risk

  11. Polyploidization altered gene functions in cotton (Gossypium spp.)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cotton fibers are seed trichomes derived from individual cells of the epidermal layer of the seed coat. It has been known for a long time that a large set of genes determine the development of cotton fiber, and more recently it has been determined that these genes are distributed across the At and ...

  12. Chromatin looping as a target for altering erythroid gene expression.

    PubMed

    Krivega, Ivan; Dean, Ann

    2016-03-01

    The β-hemoglobinopathies are the most common monogenic disorders in humans, with symptoms arising after birth when the fetal γ-globin genes are silenced and the adult β-globin gene is activated. There is a growing appreciation that genome organization and the folding of chromosomes are key determinants of gene transcription. Underlying this function is the activity of transcriptional enhancers that increase the transcription of target genes over long linear distances. To accomplish this, enhancers engage in close physical contact with target promoters through chromosome folding or looping that is orchestrated by protein complexes that bind to both sites and stabilize their interaction. We find that enhancer activity can be redirected with concomitant changes in gene transcription. Both targeting the β-globin locus control region (LCR) to the γ-globin gene in adult erythroid cells by tethering and epigenetic unmasking of a silenced γ-globin gene lead to increased frequency of LCR/γ-globin contacts and reduced LCR/β-globin contacts. The outcome of these manipulations is robust, pancellular γ-globin transcription activation with a concomitant reduction in β-globin transcription. These examples show that chromosome looping may be considered a therapeutic target for gene activation in β-thalassemia and sickle cell disease. PMID:26918894

  13. Sickness behavior induced by cisplatin chemotherapy and radiotherapy in a murine head and neck cancer model is associated with altered mitochondrial gene expression.

    PubMed

    Vichaya, Elisabeth G; Molkentine, Jessica M; Vermeer, Daniel W; Walker, Adam K; Feng, Rebekah; Holder, Gerard; Luu, Katherine; Mason, Ryan M; Saligan, Leo; Heijnen, Cobi J; Kavelaars, Annemieke; Mason, Kathy A; Lee, John H; Dantzer, Robert

    2016-01-15

    The present study was undertaken to explore the possible mechanisms of the behavioral alterations that develop in response to cancer and to cancer therapy. For this purpose we used a syngeneic heterotopic mouse model of human papilloma virus (HPV)-related head and neck cancer in which cancer therapy is curative. Mice implanted or not with HPV+ tumor cells were exposed to sham treatment or a regimen of cisplatin and radiotherapy (chemoradiation). Sickness was measured by body weight loss and reduced food intake. Motivation was measured by burrowing, a highly prevalent species specific behavior. Tumor-bearing mice showed a gradual decrease in burrowing over time and increased brain and liver inflammatory cytokine mRNA expression by 28 days post tumor implantation. Chemoradiation administered to healthy mice resulted in a mild decrease in burrowing, body weight, and food intake. Chemoradiation in tumor-bearing mice decreased tumor growth and abrogated liver and brain inflammation, but failed to attenuate burrowing deficits. PCR array analysis of selected hypoxia and mitochondrial genes revealed that both the tumor and chemoradiation altered the expression of genes involved in mitochondrial energy metabolism within the liver and brain and increased expression of genes related to HIF-1α signaling within the brain. The most prominent changes in brain mitochondrial genes were noted in tumor-bearing mice treated with chemoradiation. These findings indicate that targeting mitochondrial dysfunction following cancer and cancer therapy may be a strategy for prevention of cancer-related symptoms. PMID:26475509

  14. Assessment of usual dietary intake in population studies of gene-diet interaction

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dietary intake is a critical exposure when examining genetic factors on disease risk. Weighed diet records can provide the most accurate assessment of intake, but are usually not realistic in large population studies. Multiple 24 hour dietary recalls provide detail, allowing for diverse dietary prac...

  15. Land use change alters functional gene diversity, composition and abundance in Amazon forest soil microbial communities.

    PubMed

    Paula, Fabiana S; Rodrigues, Jorge L M; Zhou, Jizhong; Wu, Liyou; Mueller, Rebecca C; Mirza, Babur S; Bohannan, Brendan J M; Nüsslein, Klaus; Deng, Ye; Tiedje, James M; Pellizari, Vivian H

    2014-06-01

    Land use change in the Amazon rainforest alters the taxonomic structure of soil microbial communities, but whether it alters their functional gene composition is unknown. We used the highly parallel microarray technology GeoChip 4.0, which contains 83,992 probes specific for genes linked nutrient cycling and other processes, to evaluate how the diversity, abundance and similarity of the targeted genes responded to forest-to-pasture conversion. We also evaluated whether these parameters were reestablished with secondary forest growth. A spatially nested scheme was employed to sample a primary forest, two pastures (6 and 38 years old) and a secondary forest. Both pastures had significantly lower microbial functional genes richness and diversity when compared to the primary forest. Gene composition and turnover were also significantly modified with land use change. Edaphic traits associated with soil acidity, iron availability, soil texture and organic matter concentration were correlated with these gene changes. Although primary and secondary forests showed similar functional gene richness and diversity, there were differences in gene composition and turnover, suggesting that community recovery was not complete in the secondary forest. Gene association analysis revealed that response to ecosystem conversion varied significantly across functional gene groups, with genes linked to carbon and nitrogen cycling mostly altered. This study indicates that diversity and abundance of numerous environmentally important genes respond to forest-to-pasture conversion and hence have the potential to affect the related processes at an ecosystem scale. PMID:24806276

  16. Transposon-induced nuclear mutations that alter chloroplast gene expression

    SciTech Connect

    Barkan, A.

    1992-01-01

    The goal of this project is to use mutant phenotypes as a guide to nuclear genes that determine the timing and localization of chloroplast development The immediate goals are to identify nuclear mutants with defects in chloroplast gene expression from maize lines harboring active Mu transposons; characterize their phenotypes to determine the precise defect in gene expression; clone several of the most interesting mutations by exploiting the transposon tag; and use the clones to further define the roles of these genes in modulating chloroplast gene expression. Three mutants were described earlier that had global defects in chloroplast gene expression. We have found that two of these mutations are allelic. Both alleles have global defects in chloroplast translation initiation, as revealed by the failure to assemble chloroplast mRNAs into polysomes. We have isolated and characterized three new mutants from Mu lines that have novel defects in chloroplast RNA metabolism. We are now ready to begin the task of cloning several of these genes, by using the Mu transposon tag.

  17. Alteration of plant meristem function by manipulation of the Retinoblastoma-like plant RRB gene

    DOEpatents

    Durfee, Tim; Feiler, Heidi; Gruissem, Wilhelm; Jenkins, Susan; Roe, Judith; Zambryski, Patricia

    2007-01-16

    This invention provides methods and compositions for altering the growth, organization, and differentiation of plant tissues. The invention is based on the discovery that, in plants, genetically altering the levels of Retinoblastoma-related gene (RRB) activity produces dramatic effects on the growth, proliferation, organization, and differentiation of plant meristem.

  18. Alteration of Caenorhabditis elegans gene expression by targeted transformation.

    PubMed Central

    Broverman, S; MacMorris, M; Blumenthal, T

    1993-01-01

    We have produced strains carrying a synthetic fusion of parts of two vitellogenin genes, vit-2 and vit-6, integrated into the Caenorhabditis elegans genome. In most of the 63 transformant strains, the plasmid sequences are integrated at random locations in the genome. However, in two strains the transgene integrated by homologous recombination into the endogenous vit-2 gene. In both cases the reciprocal exchange between the chromosome and the injected circular plasmid containing a promoter deletion led to switching of the plasmid-borne promoter and the endogenous promoter, with a reduction in vit-2 expression. Thus in nematodes, transforming DNA can integrate by homologous recombination to result in partial inactivation of the chromosomal locus. The simplicity of the event and its reasonably high frequency suggest that gene targeting by homologous recombination should be considered as a method for directed inactivation of C. elegans genes. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8506273

  19. Alteration of Caenorhabditis elegans gene expression by targeted transformation.

    PubMed

    Broverman, S; MacMorris, M; Blumenthal, T

    1993-05-15

    We have produced strains carrying a synthetic fusion of parts of two vitellogenin genes, vit-2 and vit-6, integrated into the Caenorhabditis elegans genome. In most of the 63 transformant strains, the plasmid sequences are integrated at random locations in the genome. However, in two strains the transgene integrated by homologous recombination into the endogenous vit-2 gene. In both cases the reciprocal exchange between the chromosome and the injected circular plasmid containing a promoter deletion led to switching of the plasmid-borne promoter and the endogenous promoter, with a reduction in vit-2 expression. Thus in nematodes, transforming DNA can integrate by homologous recombination to result in partial inactivation of the chromosomal locus. The simplicity of the event and its reasonably high frequency suggest that gene targeting by homologous recombination should be considered as a method for directed inactivation of C. elegans genes. PMID:8506273

  20. Alteration of gene expression in rat colon mucosa after exercise.

    PubMed

    Buehlmeyer, K; Doering, F; Daniel, H; Kindermann, B; Schulz, T; Michna, H

    2008-01-01

    The development of colon cancer is highly influenced by lifestyle factors such as nutrition and physical inactivity. Detailed biological mechanisms are thus far unclear. The purpose of this study was to investigate the effects of regular treadmill exercise on gene expression in rat colon mucosa. For this purpose, 6-week-old male Wistar rats completed a stress-free voluntary treadmill exercise period of 12 weeks. Sedentary rats served as a control group. In the colon mucosa, steady-state mRNA expression levels of approximately 10,000 genes were compared between both groups by micro-array analysis (MWG rat 10K array). A total of 8846 mRNAs were detected above background level. Regular exercise led to a decreased expression of 47 genes at a threshold-factor of 2.0. Three genes were found to be up-regulated in the exercise group. The identified genes encode proteins involved in signal transduction (n=11), transport (n=8), immune system (n=7), cytoskeleton (n=6), protein targeting (n=6), metabolism (n=5), transcription (n=3) and vascularization (n=2). Among the genes regulated by regular exercise, the betaine-homocysteine methyltransferase 2 (BHMT2) seems to be of particular interest. Physical activity may protect against aberrant methylation by repressing the BHMT2 gene and thus contribute to a decreased risk of developing colon cancer. We have also identified vascular endothelial growth factor (VEGF), angiopoietin-2 (ANG-2) and calcium-independent phospholipase a2 (iPL-A2), all of them with markedly reduced transcript levels in the mucosa of active rats. In summary, our experiment presents the first gene expression pattern in rat colon mucosa following regular treadmill activity and represents an important step in understanding the molecular mechanisms responsible for the preventive effect of physical activity on the development of colon cancer. PMID:18342145

  1. Functional profiling and gene expression analysis of chromosomal copy number alterations

    PubMed Central

    Conde, Lucía; Montaner, David; Burguet-Castell, Jordi; Tárraga, Joaquín; Al-Shahrour, Fátima; Dopazo, Joaquín

    2007-01-01

    Contrarily to the traditional view in which only one or a few key genes were supposed to be the causative factors of diseases, we discuss the importance of considering groups of functionally related genes in the study of pathologies characterised by chromosomal copy number alterations. Recent observations have reported the existence of regions in higher eukaryotic chromosomes (including humans) containing genes of related function that show a high degree of coregulation. Copy number alterations will consequently affect to clusters of functionally related genes, which will be the final causative agents of the diseased phenotype, in many cases. Therefore, we propose that the functional profiling of the regions affected by copy number alterations must be an important aspect to take into account in the understanding of this type of pathologies. To illustrate this, we present an integrated study of DNA copy number variations, gene expression along with the functional profiling of chromosomal regions in a case of multiple myeloma. PMID:17597935

  2. Structural alterations of the ribosomal RNA genes in leukemic cells.

    PubMed

    Smirnova, I A

    1992-01-01

    Cloned 6.7 kb EcoR1 fragment of mice rDNA was used as a hybridization probe for rDNA structure analysis in mice, rat and calf haemopoietic tumor and normal cells. EcoR1, BglII and Pst1 restriction fragment length polymorphism (RFLP) was found in neoplastic rDNA and was not revealed in normal ones. The rRNA gene rearrangements were observed not only in spacer region but in coding sequences of the genes. Leukemic cells reveal also rDNA amplification. A role of genetic rearrangements of rDNA for mechanisms of carcinogenesis is suggested. PMID:1342066

  3. Extreme obesity is associated with variation in genes related to the circadian rhythm of food intake and hypothalamic signaling.

    PubMed

    Mariman, Edwin C M; Bouwman, Freek G; Aller, Erik E J G; van Baak, Marleen A; Wang, Ping

    2015-06-01

    The hypothalamus is important for regulation of energy intake. Mutations in genes involved in the function of the hypothalamus can lead to early-onset severe obesity. To look further into this, we have followed a strategy that allowed us to identify rare and common gene variants as candidates for the background of extreme obesity from a relatively small cohort. For that we focused on subjects with a well-selected phenotype and on a defined gene set and used a rich source of genetic data with stringent cut-off values. A list of 166 genes functionally related to the hypothalamus was generated. In those genes complete exome sequence data from 30 extreme obese subjects (60 genomes) were screened for novel rare indel, nonsense, and missense variants with a predicted negative impact on protein function. In addition, (moderately) common variants in those genes were analyzed for allelic association using the general population as reference (false discovery rate<0.05). Six novel rare deleterious missense variants were found in the genes for BAIAP3, NBEA, PRRC2A, RYR1, SIM1, and TRH, and a novel indel variant in LEPR. Common variants in the six genes for MBOAT4, NPC1, NPW, NUCB2, PER1, and PRRC2A showed significant allelic association with extreme obesity. Our findings underscore the complexity of the genetic background of extreme obesity involving rare and common variants of genes from defined metabolic and physiologic processes, in particular regulation of the circadian rhythm of food intake and hypothalamic signaling. PMID:25805767

  4. POTENTIAL ALTERATIONS IN GENE EXPRESSION ASSOCIATED WITH CARCINOGEN EXPOSURE IN MYA ARENARIA

    EPA Science Inventory

    Gonadal cancers in soft-shell clams (Mya arenaria) have been found at high prevalences (20-40%) in populations in eastern Maine. The aetiology of these tumours is unknown. We hypothesized that gene expression would be altered in gonadal tumours and that examination of gene expres...

  5. Nursing frequency alters circadian patterns of mammary gene expression in lactating mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Milking frequency impacts lactation in dairy cattle and in rodent models of lactation. The role of circadian gene expression in this process is unknown. The hypothesis tested was that changing nursing frequency alters the circadian patterns of mammary gene expression. Mid-lactation CD1 mice were stu...

  6. Altered baseline brain activities before food intake in obese men: a resting state fMRI study.

    PubMed

    Zhang, Bin; Tian, Derun; Yu, Chunshui; Zhang, Jing; Tian, Xiao; von Deneen, Karen M; Zang, Yufeng; Walter, Martin; Liu, Yijun

    2015-01-01

    Obesity as a chronic disease has become a global epidemic. However, why obese individuals eat more still remains unclear. Recent functional neuroimaging studies have found abnormal brain activations in obese people. In the present study, we used resting state functional MRI to observe spontaneous blood-oxygen-level dependent (BOLD) signal fluctuations during both hunger and satiety states in 20 lean and 20 obese men. Using a regional homogeneity (ReHo) analysis method, we measured temporal homogeneity of the regional BOLD signals. We found that, before food intake, obese men had significantly increased synchronicity of activity in the left putamen relative to lean men. Decreased synchronicity of activity was found in the orbitofrontal cortex (OFC) and medial prefrontal cortex(MPFC) in the obese subjects. And, the ratings of hunger of the obese subjects were higher than those of the lean subjects before food intake. After food intake, we did not find the significant differences between the obese men and the lean men. In all participations, synchronicity of activity increased from the fasted to the satiated state in the OFC. The results indicated that OFC plays an important role in feeding behavior, and OFC signaling may be disordered in obesity. Obese men show less inhibitory control during fasting state. This study has provided strong evidence supporting the hypothesis that there is a hypo-functioning reward circuitry in obese individuals, in which the frontal cortex may fail to inhibit the striatum, and consequently lead to overeating and obesity. PMID:25459293

  7. High wholegrain barley β-glucan lowers food intake but does not alter small intestinal macronutrient digestibility in ileorectostomised rats.

    PubMed

    Belobrajdic, Damien P; Hino, Shingo; Kondo, Takashi; Jobling, Stephen A; Morell, Matthew K; Topping, David L; Morita, Tatsuya; Bird, Anthony R

    2016-09-01

    Using barley cultivars differing widely in β-glucan content, we aimed to determine their effects on small intestinal macronutrient digestion in 24 ileorectostomised rats. The rats were fed 1 of 4 experimental diets, each containing a different barley variety, for 11 d. The diets had a content of 0, 2.1, 2.6 and 4.3 g of β-glucan/100 g. Feed intake and faecal excretion of fat, protein, starch, and non-starch polysaccharides were determined in the final 5 d of the study and apparent macronutrient digestibility calculated. Higher dietary levels of β-glucan (2.6% and 4.3%) lowered feed intake (by 15 and 19%, respectively) but final body weight was only lowered by the 4.3% β-glucan diet relative to rats fed the 0% β-glucan diet (all ps < 0.05). Protein, lipid and starch digestibility was unrelated to the dietary β-glucan content. Higher dietary levels of barley β-glucan lower feed intake of ileorectostomised rats, which is independent of intestinal fermentation and unrelated to macronutrient digestibility. PMID:27282074

  8. Diet composition, not calorie intake, rapidly alters intrinsic excitability of hypothalamic AgRP/NPY neurons in mice

    PubMed Central

    Wei, Wei; Pham, Kevin; Gammons, Jesse W.; Sutherland, Daniel; Liu, Yanyun; Smith, Alana; Kaczorowski, Catherine C.; O’Connell, Kristen M.S.

    2015-01-01

    Obesity is a chronic condition resulting from a long-term pattern of poor diet and lifestyle. Long-term consumption of high-fat diet (HFD) leads to persistent activation and leptin resistance in AgRP neurons in the arcuate nucleus of the hypothalamus (ARH). Here, for the first time, we demonstrate acute effects of HFD on AgRP neuronal excitability and highlight a critical role for diet composition. In parallel with our earlier finding in obese, long-term HFD mice, we found that even brief HFD feeding results in persistent activation of ARH AgRP neurons. However, unlike long-term HFD-fed mice, AgRP neurons from short-term HFD-fed mice were still leptin-sensitive, indicating that the development of leptin-insensitivity is not a prerequisite for the increased firing rate of AgRP neurons. To distinguish between diet composition, caloric intake, and body weight, we compared acute and long-term effects of HFD and CD in pair-fed mice on AgRP neuronal spiking. HFD consumption in pair-fed mice resulted in a significant increase in AgRP neuronal spiking despite controls for weight gain and caloric intake. Taken together, our results suggest that diet composition may be more important than either calorie intake or body weight for electrically remodeling arcuate AgRP/NPY neurons. PMID:26592769

  9. The Transcriptional Response of Caenorhabditis elegans to Ivermectin Exposure Identifies Novel Genes Involved in the Response to Reduced Food Intake

    PubMed Central

    Laing, Steven T.; Ivens, Al; Butler, Victoria; Ravikumar, Sai P.; Laing, Roz; Woods, Debra J.; Gilleard, John S.

    2012-01-01

    We have examined the transcriptional response of Caenorhabditis elegans following exposure to the anthelmintic drug ivermectin (IVM) using whole genome microarrays and real-time QPCR. Our original aim was to identify candidate molecules involved in IVM metabolism and/or excretion. For this reason the IVM tolerant strain, DA1316, was used to minimise transcriptomic changes related to the phenotype of drug exposure. However, unlike equivalent work with benzimidazole drugs, very few of the induced genes were members of xenobiotic metabolising enzyme families. Instead, the transcriptional response was dominated by genes associated with fat mobilization and fatty acid metabolism including catalase, esterase, and fatty acid CoA synthetase genes. This is consistent with the reduction in pharyngeal pumping, and consequential reduction in food intake, upon exposure of DA1316 worms to IVM. Genes with the highest fold change in response to IVM exposure, cyp-37B1, mtl-1 and scl-2, were comparably up-regulated in response to short–term food withdrawal (4 hr) independent of IVM exposure, and GFP reporter constructs confirm their expression in tissues associated with fat storage (intestine and hypodermis). These experiments have serendipitously identified novel genes involved in an early response of C. elegans to reduced food intake and may provide insight into similar processes in higher organisms. PMID:22348077

  10. Gene flow in genetically altered crops helps progress transgenic turfgrass.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous useful traits are being imparted into transgenic and non-transgenic plants. Gene flow as indicated in a recent publication from the Council for Agricultural Science and Technology (CAST 2007) is the successful transfer of genetic information between different individuals, populations, and g...

  11. Kinetics of the cellular intake of a gene expression inducer at high concentrations.

    PubMed

    Tran, Huy; Oliveira, Samuel M D; Goncalves, Nadia; Ribeiro, Andre S

    2015-09-01

    From in vivo single-event measurements of the transient and steady-state transcription activity of a single-copy lac-ara-1 promoter in Escherichia coli, we characterize the intake kinetics of its inducer (IPTG) from the media. We show that the empirical data are well-fit by a model of intake assuming a bilayer membrane, with the passage through the second layer being rate-limiting, coupled to a stochastic, sub-Poissonian, multi-step transcription process. Using this model, we show that for a wide range of extracellular inducer levels (up to 1.25 mM) the intake process is diffusive-like, suggesting unsaturated membrane permeability. Inducer molecules travel from the periplasm to the cytoplasm in, on average, 31.7 minutes, strongly affecting cells' response time. The novel methodology followed here should aid the study of cellular intake mechanisms at the single-event level. PMID:26223179

  12. Identification of cancer-driver genes in focal genomic alterations from whole genome sequencing data.

    PubMed

    Jang, Ho; Hur, Youngmi; Lee, Hyunju

    2016-01-01

    DNA copy number alterations (CNAs) are the main genomic events that occur during the initiation and development of cancer. Distinguishing driver aberrant regions from passenger regions, which might contain candidate target genes for cancer therapies, is an important issue. Several methods for identifying cancer-driver genes from multiple cancer patients have been developed for single nucleotide polymorphism (SNP) arrays. However, for NGS data, methods for the SNP array cannot be directly applied because of different characteristics of NGS such as higher resolutions of data without predefined probes and incorrectly mapped reads to reference genomes. In this study, we developed a wavelet-based method for identification of focal genomic alterations for sequencing data (WIFA-Seq). We applied WIFA-Seq to whole genome sequencing data from glioblastoma multiforme, ovarian serous cystadenocarcinoma and lung adenocarcinoma, and identified focal genomic alterations, which contain candidate cancer-related genes as well as previously known cancer-driver genes. PMID:27156852

  13. Identification of cancer-driver genes in focal genomic alterations from whole genome sequencing data

    PubMed Central

    Jang, Ho; Hur, Youngmi; Lee, Hyunju

    2016-01-01

    DNA copy number alterations (CNAs) are the main genomic events that occur during the initiation and development of cancer. Distinguishing driver aberrant regions from passenger regions, which might contain candidate target genes for cancer therapies, is an important issue. Several methods for identifying cancer-driver genes from multiple cancer patients have been developed for single nucleotide polymorphism (SNP) arrays. However, for NGS data, methods for the SNP array cannot be directly applied because of different characteristics of NGS such as higher resolutions of data without predefined probes and incorrectly mapped reads to reference genomes. In this study, we developed a wavelet-based method for identification of focal genomic alterations for sequencing data (WIFA-Seq). We applied WIFA-Seq to whole genome sequencing data from glioblastoma multiforme, ovarian serous cystadenocarcinoma and lung adenocarcinoma, and identified focal genomic alterations, which contain candidate cancer-related genes as well as previously known cancer-driver genes. PMID:27156852

  14. Altered Expression of Diabetes-Related Genes in Alzheimer's Disease Brains: The Hisayama Study

    PubMed Central

    Hokama, Masaaki; Oka, Sugako; Leon, Julio; Ninomiya, Toshiharu; Honda, Hiroyuki; Sasaki, Kensuke; Iwaki, Toru; Ohara, Tomoyuki; Sasaki, Tomio; LaFerla, Frank M.; Kiyohara, Yutaka; Nakabeppu, Yusaku

    2014-01-01

    Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM. PMID:23595620

  15. Maternal and postweaning folic acid supplementation interact to influence body weight, insulin resistance, and food intake regulatory gene expression in rat offspring in a sex-specific manner.

    PubMed

    Huot, Pedro S P; Ly, Anna; Szeto, Ignatius M Y; Reza-López, Sandra A; Cho, Daniel; Kim, Young-In; Anderson, G Harvey

    2016-04-01

    Maternal intake of multivitamins or folic acid above the basal dietary requirement alters the growth and metabolic trajectory of rat offspring. We hypothesized that a modest increase in the folic acid content of maternal diets would alter the offspring's metabolic phenotype, and that these effects could be corrected by matching the folic acid content of the offspring's diet with that of the maternal diet. Female Sprague-Dawley rats were placed on a control or a 2.5× folic acid-supplemented diet prior to mating and during pregnancy and lactation. At weaning, pups from each maternal diet group were randomized to the control or to the 2.5× folic acid-supplemented diet for 25 weeks. Male pups from dams fed the folic acid-supplemented diet were 3.7% heavier than those from control-fed dams and had lower mRNA expression for leptin receptor Obrb isoform (Lepr) (11%) and Agouti-related protein (Agrp) (14%). In contrast, female pups from folic acid-supplemented dams were 5% lighter than those from control-fed dams and had lower proopiomelanocortin (Pomc) (42%), Lepr (32%), and Agrp (13%), but higher neuropeptide Y (Npy) (18%) mRNA expression. Folic acid supplementation ameliorated the alterations induced by maternal folic acid supplementation in male pups and led to the lowest insulin resistance, but the effects were smaller in female pups and led to the highest insulin resistance. In conclusion, maternal folic acid supplementation at 2.5× the control level was associated with alterations in body weight and hypothalamic gene expression in rat offspring in a sex-specific manner, and some of these effects were attenuated by postweaning folic acid supplementation. PMID:26989972

  16. Neurotoxocarosis alters myelin protein gene transcription and expression.

    PubMed

    Heuer, Lea; Beyerbach, Martin; Lühder, Fred; Beineke, Andreas; Strube, Christina

    2015-06-01

    Neurotoxocarosis is an infection of the central nervous system caused by migrating larvae of the common dog and cat roundworms (Toxocara canis and Toxocara cati), which are zoonotic agents. As these parasites are prevalent worldwide and neuropathological and molecular investigations on neurotoxocarosis are scare, this study aims to characterise nerve fibre demyelination associated with neurotoxocarosis on a molecular level. Transcription of eight myelin-associated genes (Cnp, Mag, Mbp, Mog, Mrf-1, Nogo-A, Plp1, Olig2) was determined in the mouse model during six time points of the chronic phase of infection using qRT-PCR. Expression of selected proteins was analysed by Western blotting or immunohistochemistry. Additionally, demyelination and neuronal damage were investigated histologically. Significant differences (p ≤ 0.05) between transcription rates of T. canis-infected and uninfected control mice were detected for all analysed genes while T. cati affected five of eight investigated genes. Interestingly, 2', 3 ´-cyclic nucleotide 3'-phosphodiesterase (Cnp) and myelin oligodendrocyte glycoprotein (Mog) were upregulated in both T. canis- and T. cati-infected mice preceding demyelination. Later, CNPase expression was additionally enhanced. As expected, myelin basic protein (Mbp) was downregulated in cerebra and cerebella of T. canis-infected mice when severe demyelination was present 120 days post infectionem (dpi). The transcriptional pattern observed in the present study appears to reflect direct traumatic and hypoxic effects of larval migration as well as secondary processes including host immune reactions, demyelination and attempts to remyelinate damaged areas. PMID:25773181

  17. Integrated Genomic and Transcriptional Profiling Identifies Chromosomal Loci with Altered Gene Expression in Cervical Cancer

    PubMed Central

    Wilting, Saskia M.; de Wilde, Jillian; Meijer, Chris J. L. M.; Berkhof, Johannes; Yi, Yajun; van Wieringen, Wessel N.; Braakhuis, Boudewijn J. M.; Meijer, Gerrit A.; Ylstra, Bauke; Snijders, Peter J. F.; Steenbergen, Renske D. M.

    2009-01-01

    For a better understanding of the consequences of recurrent chromosomal alterations in cervical carcinomas, we integrated genome-wide chromosomal and transcriptional profiles of 10 squamous cell carcinomas (SCCs), 5 adenocarcinomas (AdCAs) and 6 normal controls. Previous genomic profiling showed that gains at chromosome arms 1q, 3q, and 20q as well as losses at 8q, 10q, 11q, and 13q were common in cervical carcinomas. Altered regions spanned multiple megabases, and the extent to which expression of genes located there is affected remains unclear. Expression analysis of these previously chromosomally profiled carcinomas yielded 83 genes with significantly differential expression between carcinomas and normal epithelium. Application of differential gene locus mapping (DIGMAP) analysis and the array CGH expression integration tool (ACE-it) identified hotspots within large chromosomal alterations in which gene expression was altered as well. Chromosomal gains of the long arms of chromosome 1, 3, and 20 resulted in increased expression of genes located at 1q32.1-32.2, 3q13.32-23, 3q26.32-27.3, and 20q11.21-13.33, whereas a chromosomal loss of 11q22.3-25 was related to decreased expression of genes located in this region. Overexpression of DTX3L, PIK3R4, ATP2C1, and SLC25A36, all located at 3q21.1-23 and identified by DIGMAP, ACE-it or both, was confirmed in an independent validation sample set consisting of 12 SCCs and 13 normal ectocervical samples. In conclusion, integrated chromosomal and transcriptional profiling identified chromosomal hotspots at 1q, 3q, 11q, and 20q with altered gene expression within large commonly altered chromosomal regions in cervical cancer. PMID:18618715

  18. Polymorphisms in xenobiotic metabolizing genes, intakes of heterocyclic amines and red meat, and postmenopausal breast cancer

    PubMed Central

    Lee, Hae-Jeung; Wu, Kana; Cox, David G.; Hunter, David; Hankinson, Susan E.; Willett, Walter C.; Sinha, Rashmi; Cho, Eunyoung

    2013-01-01

    Heterocyclic amines (HCAs) are mutagenic compounds generated when meats are cooked at high temperature and for long duration. The findings from previous studies on the relation between HCAs and breast cancer are inconsistent, possibly due to genetic variations in the enzymes metabolizing HCAs. To evaluate whether the associations of intakes of estimated HCAs, meat-derived mutagenicity (MDM), and red meat with risk of postmenopausal breast cancer were modified by N-acetyltransferase 2 (NAT2) acetylator genotype or cytochrome P450 1A2 -164 A/C (CYP1A2) polymorphism, we conducted a nested case-control study with 579 cases and 981 controls within a prospective cohort, the Nurses’ Health Study (NHS). HCAs and MDM intakes were derived using a cooking method questionnaire administered in 1996. NAT2 acetylator genotype, the CYP1A2 polymorphism, and intakes of HCAs, MDM, and red meat were not associated with risk of postmenopausal breast cancer. There was also no interaction between NAT2 acetylator genotype or CYP1A2 polymorphism and HCAs and MDM and red meat intake in relation to breast cancer. These results do not support the hypothesis that genetic polymorphisms of xenobiotic enzymes involved in the metabolism of HCAs may modify the associations between intakes of red meat or meat-related mutagens and breast cancer risk. PMID:24099317

  19. Double replacement gene targeting for the production of a series of mouse strains with different prion protein gene alterations

    SciTech Connect

    Moore, R.C.; Redhead, N.J.; Selfridge, J.

    1995-09-01

    We have developed a double replacement gene targeting strategy which enables the production of a series of mouse strains bearing different subtle alterations to endogenous genes. This is a two-step process in which a region of the gene of interest is first replaced with a selectable marker to produce an inactivated allele, which is then re-targeted with a second vector to reconstruct the inactivated allele, concomitantly introducing an engineered mutation. Five independent embryonic stem cell lines have been produced bearing different targeted alterations to the prion protein gene, including one which raises the level of expression. We have constructed mice bearing the codon 101 proline to leucine substitution linked to the human familial prion disease, Gerstmann-Straussler-Scheinker syndrome. We anticipate that this procedure will have applications to the study of human inherited diseases and the development of therapies. 43 refs., 6 figs., 1 tab.

  20. Acquired copy number alterations of miRNA genes in acute myeloid leukemia are uncommon

    PubMed Central

    Ramsingh, Giridharan; Jacoby, Meagan A.; Shao, Jin; De Jesus Pizzaro, Rigoberto E.; Shen, Dong; Trissal, Maria; Getz, Angela H.; Ley, Timothy J.; Walter, Matthew J.

    2013-01-01

    Altered microRNA (miRNA) expression is frequently observed in acute myelogenous leukemia (AML) and has been implicated in leukemic transformation. Whether somatic copy number alterations (CNAs) are a frequent cause of altered miRNA gene expression is largely unknown. Herein, we used comparative genomic hybridization with a custom high-resolution miRNA-centric array and/or whole-genome sequence data to identify somatic CNAs involving miRNA genes in 113 cases of AML, including 50 cases of de novo AML, 18 cases of relapsed AML, 15 cases of secondary AML following myelodysplastic syndrome, and 30 cases of therapy-related AML. We identified a total of 48 somatic miRNA gene-containing CNAs that were not identified by routine cytogenetics in 20 patients (18%). All these CNAs also included one or more protein coding genes. We identified a single case with a hemizygous deletion of MIR223, resulting in the complete loss of miR-223 expression. Three other cases of AML were identified with very low to absent miR-223 expression, an miRNA gene known to play a key role in myelopoiesis. However, in these cases, no somatic genetic alteration of MIR223 was identified, suggesting epigenetic silencing. These data show that somatic CNAs specifically targeting miRNA genes are uncommon in AML. PMID:24009227

  1. Afforestation alters the composition of functional genes in soil and biogeochemical processes in South American grasslands.

    PubMed

    Berthrong, Sean T; Schadt, Christopher W; Piñeiro, Gervasio; Jackson, Robert B

    2009-10-01

    Soil microbes are highly diverse and control most soil biogeochemical reactions. We examined how microbial functional genes and biogeochemical pools responded to the altered chemical inputs accompanying land use change. We examined paired native grasslands and adjacent Eucalyptus plantations (previously grassland) in Uruguay, a region that lacked forests before European settlement. Along with measurements of soil carbon, nitrogen, and bacterial diversity, we analyzed functional genes using the GeoChip 2.0 microarray, which simultaneously quantified several thousand genes involved in soil carbon and nitrogen cycling. Plantations and grassland differed significantly in functional gene profiles, bacterial diversity, and biogeochemical pool sizes. Most grassland profiles were similar, but plantation profiles generally differed from those of grasslands due to differences in functional gene abundance across diverse taxa. Eucalypts decreased ammonification and N fixation functional genes by 11% and 7.9% (P < 0.01), which correlated with decreased microbial biomass N and more NH(4)(+) in plantation soils. Chitinase abundance decreased 7.8% in plantations compared to levels in grassland (P = 0.017), and C polymer-degrading genes decreased by 1.5% overall (P < 0.05), which likely contributed to 54% (P < 0.05) more C in undecomposed extractable soil pools and 27% less microbial C (P < 0.01) in plantation soils. In general, afforestation altered the abundance of many microbial functional genes, corresponding with changes in soil biogeochemistry, in part through altered abundance of overall functional gene types rather than simply through changes in specific taxa. Such changes in microbial functional genes correspond with altered C and N storage and have implications for long-term productivity in these soils. PMID:19700539

  2. Afforestation alters the composition of functional genes in soil and biogeochemical processes in South American grasslands

    SciTech Connect

    Berthrong, Sean T; Schadt, Christopher Warren; Pineiro, Gervasio; Jackson, Robert B

    2009-01-01

    Soil microbes are highly diverse and control most soil biogeochemical reactions. We examined how microbial functional genes and biogeochemical pools responded to the altered chemical inputs accompanying land use change. We examined paired native grasslands and adjacent Eucalyptus plantations (previously grassland) in Uruguay, a region that lacked forests before European settlement. Along with measurements of soil carbon, nitrogen, and bacterial diversity, we analyzed functional genes using the GeoChip 2.0 microarray, which simultaneously quantified several thousand genes involved in soil carbon and nitrogen cycling. Plantations and grassland differed significantly in functional gene profiles, bacterial diversity, and biogeochemical pool sizes. Most grassland profiles were similar, but plantation profiles generally differed from those of grasslands due to differences in functional gene abundance across diverse taxa. Eucalypts decreased ammonification and N fixation functional genes by 11% and 7.9% (P < 0.01), which correlated with decreased microbial biomass N and more NH{sub 4}{sup +} in plantation soils. Chitinase abundance decreased 7.8% in plantations compared to levels in grassland (P = 0.017), and C polymer-degrading genes decreased by 1.5% overall (P < 0.05), which likely contributed to 54% (P < 0.05) more C in undecomposed extractable soil pools and 27% less microbial C (P < 0.01) in plantation soils. In general, afforestation altered the abundance of many microbial functional genes, corresponding with changes in soil biogeochemistry, in part through altered abundance of overall functional gene types rather than simply through changes in specific taxa. Such changes in microbial functional genes correspond with altered C and N storage and have implications for long-term productivity in these soils.

  3. Effects of dietary intake and genetic factors on hypermethylation of the hMLH1 gene promoter in gastric cancer

    PubMed Central

    Nan, Hong-Mei; Song, Young-Jin; Yun, Hyo-Yung; Park, Joo-Seung; Kim, Heon

    2005-01-01

    AIM: Hypermethylation of the promoter of the hMLH1 gene, which plays an important role in mismatch repair during DNA replication, occurs in more than 30% of human gastric cancer tissues. The purpose of this study was to investigate the effects of environmental factors, genetic polymorphisms of major metabolic enzymes, and microsatellite instability on hypermethylation of the promoter of the hMLH1 gene in gastric cancer. METHODS: Data were obtained from a hospital-based, case-control study of gastric cancer. One hundred and ten gastric cancer patients and 220 age- and sex-matched control patients completed a structured questionnaire regarding their exposure to environmental risk factors. Hypermethylation of the hMLH1 gene promoter, polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2 and L-myc genes, microsatellite instability and mutations of p53 and Ki-ras genes were investigated. RESULTS: Both smoking and alcohol consumption were associated with a higher risk of gastric cancer with hypermethylation of the hMLH1 gene promoter. High intake of vegetables and low intake of potato were associated with increased likelihood of gastric cancer with hypermethylation of the hMLH1 gene promoter. Genetic polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2, and L-myc genes were not significantly associated with the risk of gastric cancer either with or without hypermethylation in the promoter of the hMLH1 gene. Hypermethylation of the hMLH1 promoter was significantly associated with microsatellite instability (MSI): 10 of the 14 (71.4%) MSI-positive tumors showed hypermethylation, whereas 28 of 94 (29.8%) the MSI-negative tumors were hypermethylated at the hMLH1 promoter region. Hypermethylation of the hMLH1 gene promoter was significantly inversely correlated with mutation of the p53 gene. CONCLUSION: These results suggest that cigarette smoking and alcohol consumption may influence the development of hMLH1-positive gastric cancer. Most dietary factors and

  4. Altered phenotypes in plants transformed with chimeric tobacco peroxidase genes

    SciTech Connect

    Lagrimini, L.M.

    1990-01-01

    Peroxidases have been implicated in a variety of secondary metabolic reactions including lignification, cross-linking of cell wall polysaccharides, oxidation of indole-3-acetic acid, regulation of cell elongation, wound-healing, phenol oxidation, and pathogen defense. However, due to the many different isoenzymes and even more potential substrates, it has proven difficult to verify actual physiological roles for peroxidase. We are studying the molecular biology of the tobacco peroxidase genes, and have utilized genetic engineering techniques to produce transgenic plants which differ only in their expression of an individual peroxidase isoenzyme. Many of the in planta functions for any individual isoenzyme may be predicted through the morphological and physiological analysis of transformed plants.

  5. Altered phenotypes in plants transformed with chimeric tobacco peroxidase genes

    SciTech Connect

    Lagrimini, L.M.

    1990-12-31

    Peroxidases have been implicated in a variety of secondary metabolic reactions including lignification, cross-linking of cell wall polysaccharides, oxidation of indole-3-acetic acid, regulation of cell elongation, wound-healing, phenol oxidation, and pathogen defense. However, due to the many different isoenzymes and even more potential substrates, it has proven difficult to verify actual physiological roles for peroxidase. We are studying the molecular biology of the tobacco peroxidase genes, and have utilized genetic engineering techniques to produce transgenic plants which differ only in their expression of an individual peroxidase isoenzyme. Many of the in planta functions for any individual isoenzyme may be predicted through the morphological and physiological analysis of transformed plants.

  6. Altered Cro repressors from engineered mutagenesis of a synthetic cro gene.

    PubMed

    Eisenbeis, S J; Nasoff, M S; Noble, S A; Bracco, L P; Dodds, D R; Caruthers, M H

    1985-02-01

    A portion of the gene coding for the Cro repressor protein of bacteriophage lambda has been chemically synthesized, incorporating base pair changes that generate restriction endonuclease sites without altering the amino acid coding sequence. These restriction endonuclease sites were used to remove small segments of the synthetic cro gene and the segments were replaced with duplexes carrying desired mutations. Altered Cro proteins produced by mutants constructed in this manner were then assayed for binding to lambda operator OR3 in vivo. Mutations directed into the region of the cro gene encoding the alpha-3 helix produced altered Cro proteins with a range of affinities for operator DNA. These changes suggest which amino acids play an important role in Cro-OR3 complex formation. PMID:3156377

  7. Timing of fat and liquid sugar intake alters substrate oxidation and food efficiency in male Wistar rats.

    PubMed

    Oosterman, Johanneke E; Foppen, Ewout; van der Spek, Rianne; Fliers, Eric; Kalsbeek, Andries; la Fleur, Susanne E

    2015-03-01

    In addition to the amount of ingested calories, both timing of food intake and meal composition are determinants of body weight gain. However, at present, it is unknown if the inappropriate timing of diet components is responsible for body weight gain. In the present study, we therefore studied a time-dependent effect of the diet composition on energy homeostasis. Male Wistar rats were subjected to chow ad libitum (chow group) or a choice diet with saturated fat, a 30% sugar solution, chow and tap water. The choice diet was provided either with all components ad libitum (AL), with ad libitum access to chow, tap water and a 30% sugar solution, but with access to saturated fat only during the light period (LF), or with ad libitum access to chow, tap water and saturated fat, but access to a 30% sugar solution only during the light period (LS). Caloric intake and body weight gain were monitored during 31 days. Energy expenditure was measured in the third week in calorimetric cages. All rats on a choice diet showed hyperphagia and gained more body weight compared to the chow group. Within the choice diet groups, rats on the LS diet were most food efficient (i.e. gained most body weight per ingested calorie) and showed a lower respiratory exchange ratio (RER) with an anti-phasic pattern, whereas no differences in locomotor activity or heat production were found. Collectively these data indicate that the timing of the diet composition affects food efficiency, most likely due to a shifted oxidation pattern, which can predispose for obesity. Further studies are underway to assess putative mechanisms involved in this dysregulation. PMID:25317718

  8. Gliadin intake alters the small intestinal mucosa in indomethacin-treated HLA-DQ8 transgenic mice.

    PubMed

    Mazzarella, Giuseppe; Bergamo, Paolo; Maurano, Francesco; Luongo, Diomira; Rotondi Aufiero, Vera; Bozzella, Giuseppina; Palmieri, Gianna; Troncone, Riccardo; Auricchio, Salvatore; David, Chella; Rossi, Mauro

    2014-08-01

    Celiac disease (CD) is an enteropathy caused by the ingestion of wheat gluten in genetically susceptible individuals. A complete understanding of the pathogenic mechanisms in CD has been hindered because of the lack of adequate in vivo models. In the present study, we explored the events after the intragastric administration of gliadin and of the albumin/globulin fraction from wheat in human leukocyte antigen-DQ8 transgenic mice (DQ8 mice) treated with indomethacin, an inhibitor of cyclooxygenases (COXs). After 10 days of treatment, mice showed a significant reduction of villus height, increased crypt depth, increased number of lamina propria-activated macrophages, and high basal interferon-γ secretion in mesenteric lymph nodes, all of which were specifically related to gliadin intake, whereas the albumin/globulin fraction of wheat was unable to induce similar changes. Cotreatment with NS-398, a specific inhibitor of COX-2, also induced the intestinal lesion. Enteropathy onset was further characterized by high levels of oxidative stress markers, similar to CD. Biochemical assessment of the small intestine revealed the specific activation of matrix metalloproteinases 2 and 9, high caspase-3 activity, and a significant increase of tissue transglutaminase protein levels associated with the intestinal lesion. Notably, after 30 days of treatment, enteropathic mice developed serum antibodies toward gliadin (IgA) and tissue transglutaminase (IgG). We concluded that gliadin intake in combination with COX inhibition caused a basal inflammatory status and an oxidative stress condition in the small intestine of DQ8 mice, thus triggering the mucosal lesion and, subsequently, an antigen-specific immunity. PMID:24924747

  9. Maternal tobacco use modestly alters correlated epigenome-wide placental DNA methylation and gene expression

    PubMed Central

    Suter, Melissa; Ma, Jun; Harris, Alan; Patterson, Lauren; Brown, Kathleen A; Shope, Cynthia; Showalter, Lori; Abramovici, Adi

    2011-01-01

    Several studies linking alterations in differential placental methylation with pregnancy disorders have implicated (de) regulation of the placental epigenome with fetal programming and later-in-life disease. We have previously demonstrated that maternal tobacco use is associated with alterations in promoter methylation of placental CYP1A1 and that these changes are correlated with CYP1A1 gene expression and fetal growth restriction. In this study we sought to expand our analysis of promoter methylation by correlating it to gene expression on a genome-wide scale. Employing side-by-side IlluminaHG-12 gene transcription with Infinium27K methylation arrays, we interrogated correlative changes in placental gene expression and DNA methylation associated with maternal tobacco smoke exposure at an epigenome-wide level and in consideration of signature gene pathways. We observed that the expression of 623 genes and the methylation of 1,024 CpG dinucleotides are significantly altered among smokers, with only 38 CpGs showing significant differential methylation (differing by a methylation level of ≥10%). We identified a significant Pearson correlation (≥0.7 or ≤-0.7) between placental transcriptional regulation and differential CpG methylation in only 25 genes among non-smokers but in 438 genes among smokers (18-fold increase, p < 0.0001), with a dominant effect among oxidative stress pathways. Differential methylation at as few as 6 sites was attributed to maternal smoking-mediated birth weight reduction in linear regression models with Bonferroni correction (p < 1.8 × 10−6). These studies suggest that a common perinatal exposure (such as maternal smoking) deregulates placental methylation in a CpG site-specific manner that correlates with meaningful alterations in gene expression along signature pathways. PMID:21937876

  10. Epigenetic and Genetic Alterations Affect the WWOX Gene in Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Ekizoglu, Seda; Bulut, Pelin; Karaman, Emin; Kilic, Erkan; Buyru, Nur

    2015-01-01

    Different types of genetic and epigenetic changes are associated with HNSCC. The molecular mechanisms of HNSCC carcinogenesis are still undergoing intensive investigation. WWOX gene expression is altered in many cancers and in a recent work reduced WWOX expression has been associated with miR-134 expression in HNSCC. In this study we investigated the WWOX messenger RNA expression levels in association with the promoter methylation of the WWOX gene and miR-134 expression levels in 80 HNSCC tumor and non-cancerous tissue samples. Our results show that WWOX expression is down-regulated especially in advanced-stage tumor samples or in tumors with SCC. This down-regulation was associated with methylation of the WWOX promoter region but not with miR-134 expression. There was an inverse correlation between the expression level and promoter methylation. We also analyzed whole exons and exon/intron boundries of the WWOX gene by direct sequencing. In our study group we observed 10 different alterations in the coding sequences and 18 different alterations in the non-coding sequences of the WWOX gene in HNSCC tumor samples. These results indicate that the WWOX gene can be functionally inactivated by promoter methylation, epigenetically or by mutations affecting the sequences coding for the enzymatic domain of the gene, functionally. We conclude that inactivation of WWOX gene contributes to the progression of HNSCC. PMID:25612104

  11. Geminivirus coat protein gene replacement alters insect specificity.

    PubMed

    Briddon, R W; Pinner, M S; Stanley, J; Markham, P G

    1990-07-01

    Chimeric clones have been constructed in which the coat protein encoded by DNA A of the bipartite genome of the geminivirus African cassava mosaic virus (ACMV) has been replaced by that of beet curly top virus (BCTV). Constructs containing the coding region inserted in either orientation were infectious when co-inoculated with ACMV DNA B onto Nicotiana benthamiana, producing symptoms typical of ACMV infection. The onset of symptom production was delayed relative to plants inoculated with parental ACMV clones and remission of symptoms was observed. When inserted in the correct orientation for expression from the ACMV coat protein promoter, the BCTV gene was expressed in plants and the coat protein synthesized encapsidated ssDNA of both ACMV genomic components. The BCTV leafhopper vector, Circulifer tenellus (Baker), transmitted both BCTV and the chimeric virus but not ACMV when injected with virus preparations and transferred to N. benthamiana seedlings. The results show that the specificity of leafhopper transmission from insect to plant resides with the coat protein. PMID:2353465

  12. Altered circadian clock gene expression in patients with schizophrenia.

    PubMed

    Johansson, Anne-Sofie; Owe-Larsson, Björn; Hetta, Jerker; Lundkvist, Gabriella B

    2016-07-01

    Impaired circadian rhythmicity has been reported in several psychiatric disorders. Schizophrenia is commonly associated with aberrant sleep-wake cycles and insomnia. It is not known if schizophrenia is associated with disturbances in molecular rhythmicity. We cultured fibroblasts from skin samples obtained from patients with chronic schizophrenia and from healthy controls, respectively, and analyzed the circadian expression during 48h of the clock genes CLOCK, BMAL1, PER1, PER2, CRY1, CRY2, REV-ERBα and DBP. In fibroblasts obtained from patients with chronic schizophrenia, we found a loss of rhythmic expression of CRY1 and PER2 compared to cells from healthy controls. We also estimated the sleep quality in these patients and found that most of them suffered from poor sleep in comparison with the healthy controls. In another patient sample, we analyzed mononuclear blood cells from patients with schizophrenia experiencing their first episode of psychosis, and found decreased expression of CLOCK, PER2 and CRY1 compared to blood cells from healthy controls. These novel findings show disturbances in the molecular clock in schizophrenia and have important implications in our understanding of the aberrant rhythms reported in this disease. PMID:27132483

  13. Effects of level of nutrient intake and age on mammalian target of rapamycin, insulin, and insulin-like growth factor-1 gene network expression in skeletal muscle of young Holstein calves.

    PubMed

    Wang, P; Drackley, J K; Stamey-Lanier, J A; Keisler, D; Loor, J J

    2014-01-01

    The molecular mechanisms by which level of nutrient intake enhances skeletal muscle growth in young ruminants are not fully understood. We examined mammalian target of rapamycin (mTOR), insulin, and insulin-like growth factor-1 (IGF-1) gene network expression in semitendinosus muscle tissue of young male Holstein calves fed a conventional milk replacer plus conventional starter (CON) or an enhanced milk replacer plus high-protein starter (ENH) for 5 wk followed by a conventional starter or a high-protein starter until 10 wk of age. Feeding ENH led to greater concentration of plasma IGF-1 and leptin and greater carcass protein and fat mass throughout the study. Despite the greater plasma IGF-1 and protein mass at wk 5, calves fed ENH had lower expression of IGF1R, INSR, and RPS6KB1 but greater expression of IRS1 and PDPK1 in muscle tissue. Except for IGF1R expression, which did not differ at wk 10, these differences persisted at wk 10, suggesting a long-term effect of greater nutrient intake on physiological and molecular mechanisms. Components of mTOR complex (mTORC)1 and mTORC2 (RICTOR and RPTOR) and FOXO1 expression decreased by wk 10 regardless of diet. Overall, the present data revealed that greater nutrient intake throughout the milk-fed and early postweaning phase alters body mass composition partly by altering hormonal and molecular profiles of genes associated with glucose and amino acid signaling. Those networks may play a crucial role in coordinating neonatal muscle growth and metabolism in response to level of nutrient intake. PMID:24210480

  14. Chronic alcohol exposure alters gene expression in HepG2 cells

    PubMed Central

    Pochareddy, Sirisha; Edenberg, Howard J.

    2011-01-01

    Background Liver is the primary site of alcohol metabolism and is highly vulnerable to injuries due to chronic alcohol abuse. Several molecular mechanisms, including oxidative stress and altered cellular metabolism, have been implicated in the development and progression of alcoholic liver disease. We sought to gain further insight into the molecular pathogenesis by studying the effects of ethanol exposure on global gene expression in HepG2 cells. Methods HepG2 cells were cultured in the presence or absence of 75 mM ethanol for nine days, with fresh media daily. Global gene expression changes were studied using Affymetrix GeneChip® Human Exon 1.0 ST Arrays. Gene expression differences were validated for thirteen genes by quantitative real-time RT-PCR. To identify biological pathways affected by ethanol treatment, differentially expressed genes were analyzed by Ingenuity Pathway Analysis software. Results Long term ethanol exposure altered the expression of 1093 genes (FDR ≤ 3%); many of these changes were modest. Long term ethanol exposure affected several pathways, including acute phase response, amino acid metabolism, carbohydrate metabolism and lipid metabolism. Conclusions Global measurements of gene expression show that a large number of genes are affected by chronic ethanol, although most show modest effect. These data provide insight into the molecular pathology resulting from extended alcohol exposure. PMID:22150570

  15. Altered Clock and Lipid Metabolism-Related Genes in Atherosclerotic Mice Kept with Abnormal Lighting Condition

    PubMed Central

    Zhu, Zhu; Hua, Bingxuan; Shang, Zhanxian; Yuan, Gongsheng; Xu, Lirong; Li, Ermin; Li, Xiaobo; Yan, Zuoqin; Qian, Ruizhe

    2016-01-01

    Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice. Methods. A mouse model of atherosclerosis with circadian clock genes expression disorder was established using ApoE-KO mice (ApoE-KO LD/DL mice) by altering exposure to light. C57 BL/6J mice (C57 mice) and ApoE-KO mice (ApoE-KO mice) exposed to normal day and night and normal diet served as control mice. According to zeitgeber time samples were acquired, to test atheromatous plaque formation, serum lipids levels and rhythmicity, clock genes, and lipid metabolism-related genes along with Sirtuin 1 (Sirt1) levels and rhythmicity. Results. Atherosclerosis plaques were formed in the aortic arch of ApoE-KO LD/DL mice. The serum lipids levels and oscillations in ApoE-KO LD/DL mice were altered, along with the levels and diurnal oscillations of circadian genes, lipid metabolism-associated genes, and Sirt1 compared with the control mice. Conclusions. Abnormal exposure to light aggravated plaque formation and exacerbated disorders of serum lipids and clock genes, lipid metabolism genes and Sirt1 levels, and circadian oscillation.

  16. Identification of Genes in Candida glabrata Conferring Altered Responses to Caspofungin, a Cell Wall Synthesis Inhibitor

    PubMed Central

    Rosenwald, Anne G.; Arora, Gaurav; Ferrandino, Rocco; Gerace, Erica L.; Mohammednetej, Maedeh; Nosair, Waseem; Rattila, Shemona; Subic, Amanda Zirzow; Rolfes, Ronda

    2016-01-01

    Candida glabrata is an important human fungal pathogen whose incidence continues to rise. Because many clinical isolates are resistant to azole drugs, the drugs of choice to treat such infections are members of the echinocandin family, although there are increasing reports of resistance to these drugs as well. In efforts to better understand the genetic changes that lead to altered responses to echinocandins, we screened a transposon-insertion library of mutants for strains to identify genes that are important for cellular responses to caspofungin, a member of this drug family. We identified 16 genes that, when disrupted, caused increased tolerance, and 48 genes that, when disrupted, caused increased sensitivity compared to the wild-type parental strain. Four of the genes identified as causing sensitivity are orthologs of Saccharomyces cerevisiae genes encoding proteins important for the cell wall integrity (CWI) pathway. In addition, several other genes are orthologs of the high affinity Ca2+ uptake system (HACS) complex genes. We analyzed disruption mutants representing all 64 genes under 33 different conditions, including the presence of cell wall disrupting agents and other drugs, a variety of salts, increased temperature, and altered pH. Further, we generated knockout mutants in different genes within the CWI pathway and the HACS complex, and found that they too exhibited phenotypes consistent with defects in cell wall construction. Our results indicate that small molecules that inhibit the CWI pathway, or that the HACS complex, may be an important means of increasing the efficacy of caspofungin. PMID:27449515

  17. Alterations in replication timing of cancer-related genes in malignant human breast cancer cells.

    PubMed

    Fritz, Andrew; Sinha, Seema; Marella, Narasimharao; Berezney, Ronald

    2013-05-01

    The replication timing of nine genes commonly involved in cancer was investigated in the MCF10 cell lines for human breast cancer progression. Six of these nine genes are part of a constellation of tumor suppressor genes that play a major role in familial human breast cancer (TP53, ATM, PTEN, CHK2, BRCA1, and BRCA2). Three other genes are involved in a large number of human cancers including breast as either tumor suppressors (RB1 and RAD51) or as an oncogene (cMYC). Five of these nine genes (TP53, RAD51, ATM, PTEN, and cMYC) show significant differences (P < 0.05) in replication timing between MCF10A normal human breast cells and the corresponding malignant MCF10CA1a cells. These differences are specific to the malignant state of the MCF10CA1a cells since there were no significant differences in the replication timing of these genes between normal MCF10A cells and the non-malignant cancer MCF10AT1 cells. Microarray analysis further demonstrated that three of these five genes (TP53, RAD51, and cMYC) showed significant changes in gene expression (≥2-fold) between normal and malignant cells. Our findings demonstrate an alteration in the replication timing of a small subset of cancer-related genes in malignant breast cancer cells. These alterations partially correlate with the major transcriptional changes characteristic of the malignant state in these cells. PMID:23161755

  18. Alteration of the retinoblastoma gene locus in radium-exposed individuals

    SciTech Connect

    Hardwick, J.P.; Schlenker, R.; Huberman, E.

    1991-01-01

    This study was performed to determine if the retinoblastoma suppressor gene was altered in individuals exposed to radium. We analyzed the Rb gene in 30 individuals, 17 of whom were exposed to radium either occupationally or iatrogenically. In the kidney DNA from four of nine radium-exposed individuals, the Rb gene was deleted. Three of these alterations in the Rb gene were internal deletions, which resulted in the absence of Rb mRNA accumulation. These results imply that the Rb gene is susceptible to radium-induced damage and confirm previous showing that radiation preferentially causes genomic deletions. The pronounced alterations in the non-tumorigenic femurs from radium-exposed individuals suggests that in the many years of exposure there was a selection of cells with alterations, presumably because of their growth advantage. Also it implies that deletions of one of the Rb alleles can be one of the events (perhaps an initial one) in the progression of radium-induced sarcomas. 11 refs., 2 figs.

  19. Dietary selenium intake increases exon-specific DNA methylation of p53 gene in rat liver and colon mucosa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The regulation of site-specific DNA methylation of tumor suppressor genes has been considered as a leading mechanism by which certain nutrients exert their anticancer property. Our previous studies suggest that dietary selenium (Se) may alter DNA methylation, and the purpose of this study was to inv...

  20. Dietary selenomethionine intake increases exon-specific DNA methylation of p53 gene in rat liver and colon mucosa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The regulation of site-specific DNA methylation of tumor suppressor genes has been considered as a leading mechanism by which certain nutrients exert their anticancer property. Our previous studies suggest that dietary selenium (Se) may alter DNA methylation, and the purpose of this study was to inv...

  1. Wheel running reduces high-fat diet intake, preference and mu-opioid agonist stimulated intake

    PubMed Central

    Liang, Nu-Chu; Bello, Nicholas T.; Moran, Timothy H.

    2015-01-01

    The ranges of mechanisms by which exercise affects energy balance remain unclear. One potential mechanism may be that exercise reduces intake and preference for highly palatable, energy dense fatty foods. The current study used a rodent wheel running model to determine whether and how physical activity affects HF diet intake/preference and reward signaling. Experiment 1 examined whether wheel running affected the ability of intracerebroventricular (ICV) µ opioid receptor agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO) to increase HF diet intake. Experiment 2 examined the effects of wheel running on the intake of and preference for a previously preferred HF diet. We also assessed the effects of wheel running and diet choice on mesolimbic dopaminergic and opioidergic gene expression. Experiment 1 revealed that wheel running decreased the ability of ICV DAMGO administration to stimulate HF diet intake. Experiment 2 showed that wheel running suppressed weight gain and reduced intake and preference for a previously preferred HF diet. Furthermore, the mesolimbic gene expression profile of wheel running rats was different from that of their sedentary paired-fed controls but similar to that of sedentary rats with large HF diet consumption. These data suggest that alterations in preference for palatable, energy dense foods play a role in the effects of exercise on energy homeostasis. The gene expression results also suggest that the hedonic effects of exercise may substitute for food reward to limit food intake and suppress weight gain. PMID:25668514

  2. Mitral valve prolapse is associated with altered extracellular matrix gene expression patterns.

    PubMed

    Greenhouse, David G; Murphy, Alison; Mignatti, Paolo; Zavadil, Jiri; Galloway, Aubrey C; Balsam, Leora B

    2016-07-15

    Mitral valve prolapse (MVP) is the leading indication for isolated mitral valve surgery in the United States. Disorganization of collagens and glycosaminoglycans in the valvular extracellular matrix (ECM) are histological hallmarks of MVP. We performed a transcriptome analysis to study the alterations in ECM-related gene expression in humans with sporadic MVP. Mitral valve specimens were obtained from individuals undergoing valve repair for MVP (n=7 patients) and from non-beating heart-tissue donors (n=3 controls). Purified RNA was subjected to whole-transcriptome microarray analysis. Microarray results were validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Gene ontology enrichment analysis was performed. 2046 unique genes showed significant differential expression (false discovery rate <0.5%). After demonstrating appropriate sample clustering, microarray results were globally validated using a subset of 22 differentially expressed genes by RT-qPCR (Pearson's correlation r=0.65, p=0.001). Gene ontology enrichment analyses performed with ErmineJ and DAVID Bioinformatics Database demonstrated overrepresentation of ECM components (p<0.05). Functional annotation clustering calculated enrichment of ECM-related ontology groups (enrichment score=4.1). ECM-related gene expression is significantly altered in MVP. Our study is consistent with the histologically observed alterations in collagen and mucopolysaccharide profiles of myxomatous mitral valves. Furthermore, whole-transcriptome analyses suggest dysregulation of multiple pathways, including TGF-beta signaling. PMID:27063507

  3. Identification of Gene Networks for Residual Feed Intake in Angus Cattle Using Genomic Prediction and RNA-seq

    PubMed Central

    Weber, Kristina L.; Welly, Bryan T.; Van Eenennaam, Alison L.; Young, Amy E.; Porto-Neto, Laercio R.; Reverter, Antonio; Rincon, Gonzalo

    2016-01-01

    Improvement in feed conversion efficiency can improve the sustainability of beef cattle production, but genomic selection for feed efficiency affects many underlying molecular networks and physiological traits. This study describes the differences between steer progeny of two influential Angus bulls with divergent genomic predictions for residual feed intake (RFI). Eight steer progeny of each sire were phenotyped for growth and feed intake from 8 mo. of age (average BW 254 kg, with a mean difference between sire groups of 4.8 kg) until slaughter at 14–16 mo. of age (average BW 534 kg, sire group difference of 28.8 kg). Terminal samples from pituitary gland, skeletal muscle, liver, adipose, and duodenum were collected from each steer for transcriptome sequencing. Gene expression networks were derived using partial correlation and information theory (PCIT), including differentially expressed (DE) genes, tissue specific (TS) genes, transcription factors (TF), and genes associated with RFI from a genome-wide association study (GWAS). Relative to progeny of the high RFI sire, progeny of the low RFI sire had -0.56 kg/d finishing period RFI (P = 0.05), -1.08 finishing period feed conversion ratio (P = 0.01), +3.3 kg^0.75 finishing period metabolic mid-weight (MMW; P = 0.04), +28.8 kg final body weight (P = 0.01), -12.9 feed bunk visits per day (P = 0.02) with +0.60 min/visit duration (P = 0.01), and +0.0045 carcass specific gravity (weight in air/weight in air—weight in water, a predictor of carcass fat content; P = 0.03). RNA-seq identified 633 DE genes between sire groups among 17,016 expressed genes. PCIT analysis identified >115,000 significant co-expression correlations between genes and 25 TF hubs, i.e. controllers of clusters of DE, TS, and GWAS SNP genes. Pathway analysis suggests low RFI bull progeny possess heightened gut inflammation and reduced fat deposition. This multi-omics analysis shows how differences in RFI genomic breeding values can impact other

  4. Identification of Gene Networks for Residual Feed Intake in Angus Cattle Using Genomic Prediction and RNA-seq.

    PubMed

    Weber, Kristina L; Welly, Bryan T; Van Eenennaam, Alison L; Young, Amy E; Porto-Neto, Laercio R; Reverter, Antonio; Rincon, Gonzalo

    2016-01-01

    Improvement in feed conversion efficiency can improve the sustainability of beef cattle production, but genomic selection for feed efficiency affects many underlying molecular networks and physiological traits. This study describes the differences between steer progeny of two influential Angus bulls with divergent genomic predictions for residual feed intake (RFI). Eight steer progeny of each sire were phenotyped for growth and feed intake from 8 mo. of age (average BW 254 kg, with a mean difference between sire groups of 4.8 kg) until slaughter at 14-16 mo. of age (average BW 534 kg, sire group difference of 28.8 kg). Terminal samples from pituitary gland, skeletal muscle, liver, adipose, and duodenum were collected from each steer for transcriptome sequencing. Gene expression networks were derived using partial correlation and information theory (PCIT), including differentially expressed (DE) genes, tissue specific (TS) genes, transcription factors (TF), and genes associated with RFI from a genome-wide association study (GWAS). Relative to progeny of the high RFI sire, progeny of the low RFI sire had -0.56 kg/d finishing period RFI (P = 0.05), -1.08 finishing period feed conversion ratio (P = 0.01), +3.3 kg^0.75 finishing period metabolic mid-weight (MMW; P = 0.04), +28.8 kg final body weight (P = 0.01), -12.9 feed bunk visits per day (P = 0.02) with +0.60 min/visit duration (P = 0.01), and +0.0045 carcass specific gravity (weight in air/weight in air-weight in water, a predictor of carcass fat content; P = 0.03). RNA-seq identified 633 DE genes between sire groups among 17,016 expressed genes. PCIT analysis identified >115,000 significant co-expression correlations between genes and 25 TF hubs, i.e. controllers of clusters of DE, TS, and GWAS SNP genes. Pathway analysis suggests low RFI bull progeny possess heightened gut inflammation and reduced fat deposition. This multi-omics analysis shows how differences in RFI genomic breeding values can impact other

  5. APOA5 gene variation modulates the effects of dietary fat intake on body mass index and obesity risk in the Framingham Heart Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diet is an important environmental factor interacting with our genes to modulate the likelihood of developing lipid disorders and consequently cardiovascular disease risk. Our objective was to study whether dietary intake modulates the association between APOA5 gene variation and body weight in a la...

  6. Identification of mechanosensitive genes during skeletal development: alteration of genes associated with cytoskeletal rearrangement and cell signalling pathways

    PubMed Central

    2014-01-01

    Background Mechanical stimulation is necessary for regulating correct formation of the skeleton. Here we test the hypothesis that mechanical stimulation of the embryonic skeletal system impacts expression levels of genes implicated in developmentally important signalling pathways in a genome wide approach. We use a mutant mouse model with altered mechanical stimulation due to the absence of limb skeletal muscle (Splotch-delayed) where muscle-less embryos show specific defects in skeletal elements including delayed ossification, changes in the size and shape of cartilage rudiments and joint fusion. We used Microarray and RNA sequencing analysis tools to identify differentially expressed genes between muscle-less and control embryonic (TS23) humerus tissue. Results We found that 680 independent genes were down-regulated and 452 genes up-regulated in humeri from muscle-less Spd embryos compared to littermate controls (at least 2-fold; corrected p-value ≤0.05). We analysed the resulting differentially expressed gene sets using Gene Ontology annotations to identify significant enrichment of genes associated with particular biological processes, showing that removal of mechanical stimuli from muscle contractions affected genes associated with development and differentiation, cytoskeletal architecture and cell signalling. Among cell signalling pathways, the most strongly disturbed was Wnt signalling, with 34 genes including 19 pathway target genes affected. Spatial gene expression analysis showed that both a Wnt ligand encoding gene (Wnt4) and a pathway antagonist (Sfrp2) are up-regulated specifically in the developing joint line, while the expression of a Wnt target gene, Cd44, is no longer detectable in muscle-less embryos. The identification of 84 genes associated with the cytoskeleton that are down-regulated in the absence of muscle indicates a number of candidate genes that are both mechanoresponsive and potentially involved in mechanotransduction, converting a

  7. Shared gene expression alterations in prostate cancer and histologically benign prostate from patients with prostate cancer.

    PubMed

    Kosari, Farhad; Cheville, John C; Ida, Cristiane M; Karnes, R Jeffrey; Leontovich, Alexey A; Sebo, Thomas J; Erdogan, Sibel; Rodriguez, Erika; Murphy, Stephen J; Vasmatzis, George

    2012-07-01

    Prostate cancer (PCa) field effect alterations provide important clues regarding the initiation of these tumors and suggest targets for prevention or biomarkers for early detection. However, biomarkers of PCa field effects that have passed independent validation are lacking, largely because these alterations are subtle and difficult to distinguish from unrelated small changes in gene expression. We hypothesized that shared expression alterations in PCa and benign prostates containing PCa (BPCs) would have a higher potential for independent validation than alterations identified in BPCs alone. Expression analyses were performed on 37 PCas and 36 unmatched BPCs and were contrasted with 28 benign prostates (BPs) from patients free of PCa. Most of the protein-coding genes and nonexonic RNAs selected according to the hypothesis were validated by quantitative RT-PCR in an independent set of 51 BPCs and BPs. A statistical model based on two markers distinguished BPCs from BPs in the RT-PCR set and in an external microarray (area under the curve = 0.84 and 0.90, respectively). In addition, genes with predominant expression in stroma were identified by expression profiling of pure stroma and epithelial cells. Pathway analysis identified dysregulated platelet-derived growth factor receptor signaling in BPC stroma. These results validate our approach for finding PCa field effect alterations and demonstrate a PCa transcriptome fingerprint in nonneoplastic cells in prostates containing cancer. PMID:22640805

  8. Inferring causal genomic alterations in breast cancer using gene expression data

    PubMed Central

    2011-01-01

    Background One of the primary objectives in cancer research is to identify causal genomic alterations, such as somatic copy number variation (CNV) and somatic mutations, during tumor development. Many valuable studies lack genomic data to detect CNV; therefore, methods that are able to infer CNVs from gene expression data would help maximize the value of these studies. Results We developed a framework for identifying recurrent regions of CNV and distinguishing the cancer driver genes from the passenger genes in the regions. By inferring CNV regions across many datasets we were able to identify 109 recurrent amplified/deleted CNV regions. Many of these regions are enriched for genes involved in many important processes associated with tumorigenesis and cancer progression. Genes in these recurrent CNV regions were then examined in the context of gene regulatory networks to prioritize putative cancer driver genes. The cancer driver genes uncovered by the framework include not only well-known oncogenes but also a number of novel cancer susceptibility genes validated via siRNA experiments. Conclusions To our knowledge, this is the first effort to systematically identify and validate drivers for expression based CNV regions in breast cancer. The framework where the wavelet analysis of copy number alteration based on expression coupled with the gene regulatory network analysis, provides a blueprint for leveraging genomic data to identify key regulatory components and gene targets. This integrative approach can be applied to many other large-scale gene expression studies and other novel types of cancer data such as next-generation sequencing based expression (RNA-Seq) as well as CNV data. PMID:21806811

  9. CRY1 circadian gene variant interacts with carbohydrate intake for insulin resistance in two independent populations: Mediterranean and North American

    PubMed Central

    Dashti, Hassan S.; Smith, Caren E.; Lee, Yu-Chi; Parnell, Laurence D.; Lai, Chao-Qiang; Arnett, Donna K.; Ordovás, José M.; Garaulet, Marta

    2014-01-01

    Dysregulation in the circadian system induced by variants of clock genes has been associated with type 2 diabetes. Evidence for the role of cryptochromes, core components of the system, in regulating glucose homeostasis is not supported by CRY1 candidate gene association studies for diabetes and insulin resistance in human, suggesting possible dietary influences. The purpose of this study was to test for interactions between a CRY1 polymorphism, rs2287161, and carbohydrate intake on insulin resistance in two independent populations: a Mediterranean (n=728) and an European origin North American population (n=820). Linear regression interaction models were performed in two populations to test for gene–diet interactions on fasting insulin and glucose and two insulin-related traits, homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). In addition, fixed effects meta-analyses for these interactions were performed. Cohort-specific interaction analyses showed significant interactions between the CRY1 variant and dietary carbohydrates for insulin resistance in both populations (p<0.05). Findings from the meta-analyses of carbohydrate–single nucleotide polymorphism interactions indicated that an increase in carbohydrate intake (% of energy intake) was associated with a significant increase in HOMA-IR (p=0.011), fasting insulin (p=0.007) and a decrease in QUICKI (p=0.028), only among individuals homozygous for the minor C allele. This novel finding supports the link between the circadian system and glucose metabolism and suggests the importance this CRY1 locus in developing personalized nutrition programs aimed at reducing insulin resistance and diabetes risk. PMID:24548145

  10. Gene Body Methylation can alter Gene Expression and is a Therapeutic Target in Cancer

    PubMed Central

    Yang, Xiaojing; Han, Han; De Carvalho, Daniel D.; Lay, Fides D.; Jones, Peter A.; Liang, Gangning

    2014-01-01

    SUMMARY DNA methylation in promoters is well known to silence genes and is the presumed therapeutic target of methylation inhibitors. Gene body methylation is positively correlated with expression yet its function is unknown. We show that 5-aza-2'-deoxycytidine treatment not only reactivates genes but decreases the over-expression of genes, many of which are involved in metabolic processes regulated by c-MYC. Down-regulation is caused by DNA demethylation of the gene bodies and restoration of high levels of expression requires remethylation by DNMT3B. Gene body methylation may therefore be an unexpected therapeutic target for DNA methylation inhibitors, resulting in the normalization of gene over-expression induced during carcinogenesis. Our results provide direct evidence for a causal relationship between gene body methylation and transcription. PMID:25263941

  11. Mutations in nuclear genes alter post-transcriptional regulation of mitochondrial genes.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nuclear gene products are required for the expression of mitochondrial genes and elaboration of functional mitochondrial protein complexes. To better understand the roles of these nuclear genes, we exploited the mitochondrial encoded S-type of cytoplasmic male sterility (CMS-S) and developed a nove...

  12. Predominant genera of fecal microbiota in children with atopic dermatitis are not altered by intake of probiotic bacteria Lactobacillus acidophilus NCFM and Bifidobacterium animalis subsp. lactis Bi-07.

    PubMed

    Larsen, Nadja; Vogensen, Finn K; Gøbel, Rikke; Michaelsen, Kim F; Abu Al-Soud, Waleed; Sørensen, Søren J; Hansen, Lars H; Jakobsen, Mogens

    2011-03-01

    The effect of probiotic bacteria Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 on the composition of the Lactobacillus group, Bifidobacterium and the total bacterial population in feces from young children with atopic dermatitis was investigated. The study included 50 children randomized to intake of one of the probiotic strain or placebo. Microbial composition was characterized by denaturing gradient gel electrophoresis, quantitative PCR and, in a subset of subjects, by pyrosequencing of the 16S rRNA gene. The core population of the Lactobacillus group was identified as Lactobacillus gasseri, Lactobacillus fermentum, Lactobacillus oris, Leuconostoc mesenteroides, while the bifidobacterial community included Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium longum and Bifidobacterium catenulatum. The fecal numbers of L. acidophilus and B. lactis increased significantly after intervention, indicating survival of the ingested bacteria. The levels of Bifidobacterium correlated positively (P=0.03), while the levels of the Lactobacillus group negatively (P=0.01) with improvement of atopic eczema evaluated by the Severity Scoring of Atopic Dermatitis index. This correlation was observed across the whole study cohort and not attributed to the probiotic intake. The main conclusion of the study is that administration of L. acidophilus NCFM and B. lactis Bi-07 does not affect the composition and diversity of the main bacterial populations in feces. PMID:21204871

  13. Alterations in inflammatory biomarkers and energy intake in cancer cachexia: a prospective study in patients with inoperable pancreatic cancer.

    PubMed

    Bye, Asta; Wesseltoft-Rao, Nima; Iversen, Per Ole; Skjegstad, Grete; Holven, Kirsten B; Ulven, Stine; Hjermstad, Marianne J

    2016-06-01

    Chronic systemic inflammatory response is proposed as an underlying mechanism for development of cancer cachexia. We conducted a prospective study to examine changes in inflammatory biomarkers during the disease course and the relationship between inflammatory biomarkers and cachexia in patients with inoperable pancreatic cancer. Twenty patients, median (range) age 67.5 (35-79) years, 5 females, were followed for median 5.5 (1-12) months. Cachexia was diagnosed according to the 2011 consensus-based classification system (weight loss >5 % past six months, BMI < 20 kg/m(2) and weight loss >2 %, or sarcopenia) and the modified Glasgow Prognostic score (mGPS) that combines CRP and albumin levels. Inflammatory biomarkers were measured by enzyme immunoassays. The patients had increased levels of most inflammatory biomarkers, albeit not all statistically significant, both at study entry and close to death, indicating ongoing inflammation. According to the consensus-based classification system, eleven (55 %) patients were classified as cachectic upon inclusion. They did not differ from non-cachectic patients with regard to inflammatory biomarkers or energy intake. According to the mGPS, seven (35 %) were defined as cachectic and had a higher IL-6 (p < 0.001) than the non-cachectic patients. They also had a slightly, but insignificantly longer survival than non-cachectic patients (p = 0.08). The mGPS should be considered as an additional framework for identification of cancer cachexia. PMID:27119533

  14. Curcumin Intake Affects miRNA Signature in Murine Melanoma with mmu-miR-205-5p Most Significantly Altered

    PubMed Central

    Rudzitis-Auth, Jeannette; Laschke, Matthias W.; Leidinger, Petra; Menger, Michael D.; Meese, Eckart; Mahlknecht, Ulrich

    2013-01-01

    Melanoma is the most aggressive form of skin cancer with estimated 48,000 deaths per year worldwide. The polyphenol curcumin derived from the plant Curcuma longa is well known for its anti-inflammatory and anti-cancerogenic properties. Accordingly, dietary intake of this compound may be suitable for melanoma prevention. However, how this compound affects basic cellular mechanisms in developing melanoma still remains elusive. Therefore, the aim of this study was to investigate for the first time the impact of oral curcumin administration on the miRNA signature of engrafting melanoma. For this purpose, the effects of a 4% curcumin diet were tested on melanoma, which were established by injection of murine B78H1 cells in the flank of C57BL/6 mice. Curcumin diet or standard chow (control) was administered two weeks prior to injection of tumor cells until termination of the experiment. High throughput chip-based array analysis was deployed to detect alterations in the miRNA signature of the tumors. Curcumin treatment significantly reduced the growth of the flank tumors. Furthermore the miRNA expression signature in tumors was substantially altered by curcumin intake with mmu-miR-205-5p over 100 times higher expressed when compared to controls. The expression levels of identified key miRNAs in the tumor samples were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). A comparable expression pattern of these miRNAs was also detected in other curcumin-treated melanoma cell lines under in vitro conditions. Putative targets of curcumin-induced up-regulated miRNAs were enriched in ‘o-glycan biosynthesis’, ‘endoplasmatic reticulum protein processing’ and different cancer-related pathways. Western Blot analyses revealed that of these targets anti-apoptotic B-cell CLL/lymphoma 2 (Bcl-2) and proliferating cell nuclear antigen (PCNA) were significantly down-regulated in curcumin-treated tumors. These findings demonstrate a profound alteration of the mi

  15. Curcumin intake affects miRNA signature in murine melanoma with mmu-miR-205-5p most significantly altered.

    PubMed

    Dahmke, Indra N; Backes, Christina; Rudzitis-Auth, Jeannette; Laschke, Matthias W; Leidinger, Petra; Menger, Michael D; Meese, Eckart; Mahlknecht, Ulrich

    2013-01-01

    Melanoma is the most aggressive form of skin cancer with estimated 48,000 deaths per year worldwide. The polyphenol curcumin derived from the plant Curcuma longa is well known for its anti-inflammatory and anti-cancerogenic properties. Accordingly, dietary intake of this compound may be suitable for melanoma prevention. However, how this compound affects basic cellular mechanisms in developing melanoma still remains elusive. Therefore, the aim of this study was to investigate for the first time the impact of oral curcumin administration on the miRNA signature of engrafting melanoma. For this purpose, the effects of a 4% curcumin diet were tested on melanoma, which were established by injection of murine B78H1 cells in the flank of C57BL/6 mice. Curcumin diet or standard chow (control) was administered two weeks prior to injection of tumor cells until termination of the experiment. High throughput chip-based array analysis was deployed to detect alterations in the miRNA signature of the tumors. Curcumin treatment significantly reduced the growth of the flank tumors. Furthermore the miRNA expression signature in tumors was substantially altered by curcumin intake with mmu-miR-205-5p over 100 times higher expressed when compared to controls. The expression levels of identified key miRNAs in the tumor samples were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). A comparable expression pattern of these miRNAs was also detected in other curcumin-treated melanoma cell lines under in vitro conditions. Putative targets of curcumin-induced up-regulated miRNAs were enriched in 'o-glycan biosynthesis', 'endoplasmatic reticulum protein processing' and different cancer-related pathways. Western Blot analyses revealed that of these targets anti-apoptotic B-cell CLL/lymphoma 2 (Bcl-2) and proliferating cell nuclear antigen (PCNA) were significantly down-regulated in curcumin-treated tumors. These findings demonstrate a profound alteration of the mi

  16. MicroRNA-Offset RNA Alters Gene Expression and Cell Proliferation

    PubMed Central

    Zhao, Jin; Schnitzler, Gavin R.; Iyer, Lakshmanan K.; Aronovitz, Mark J.; Baur, Wendy E.; Karas, Richard H.

    2016-01-01

    MicroRNA-offset RNAs (moRs) were first identified in simple chordates and subsequently in mouse and human cells by deep sequencing of short RNAs. MoRs are derived from sequences located immediately adjacent to microRNAs (miRs) in the primary miR (pri-miR). Currently moRs are considered to be simply a by-product of miR biosynthesis that lack biological activity. Here we show for the first time that a moR is biologically active. We demonstrate that endogenous or over-expressed moR-21 significantly alters gene expression and inhibits the proliferation of vascular smooth muscle cells (VSMC). In addition, we find that miR-21 and moR-21 may regulate different genes in a given pathway and can oppose each other in regulating certain genes. We report that there is a “seed region” of moR-21 as well as a “seed match region” in the target gene 3’UTR that are indispensable for moR-21-mediated gene down-regulation. We further demonstrate that moR-21-mediated gene repression is Argonaute 2 (Ago2) dependent. Taken together, these findings provide the first evidence that microRNA offset RNA alters gene expression and is biologically active. PMID:27276022

  17. Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas

    PubMed Central

    Wu, Kui; Zhang, Xin; Li, Fuqiang; Xiao, Dakai; Hou, Yong; Zhu, Shida; Liu, Dongbing; Ye, Xiaofei; Ye, Mingzhi; Yang, Jie; Shao, Libin; Pan, Hui; Lu, Na; Yu, Yuan; Liu, Liping; Li, Jin; Huang, Liyan; Tang, Hailing; Deng, Qiuhua; Zheng, Yue; Peng, Lihua; Liu, Geng; Gu, Xia; He, Ping; Gu, Yingying; Lin, Weixuan; He, Huiming; Xie, Guoyun; Liang, Han; An, Na; Wang, Hui; Teixeira, Manuel; Vieira, Joana; Liang, Wenhua; Zhao, Xin; Peng, Zhiyu; Mu, Feng; Zhang, Xiuqing; Xu, Xun; Yang, Huanming; Kristiansen, Karsten; Wang, Jian; Zhong, Nanshan; Wang, Jun; Pan-Hammarström, Qiang; He, Jianxing

    2015-01-01

    The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma. PMID:26647728

  18. Coactivation of GR and NFKB alters the repertoire of their binding sites and target genes

    PubMed Central

    Rao, Nagesha A.S.; McCalman, Melysia T.; Moulos, Panagiotis; Francoijs, Kees-Jan; Chatziioannou, Aristotelis; Kolisis, Fragiskos N.; Alexis, Michael N.; Mitsiou, Dimitra J.; Stunnenberg, Hendrik G.

    2011-01-01

    Glucocorticoid receptor (GR) exerts anti-inflammatory action in part by antagonizing proinflammatory transcription factors such as the nuclear factor kappa-b (NFKB). Here, we assess the crosstalk of activated GR and RELA (p65, major NFKB component) by global identification of their binding sites and target genes. We show that coactivation of GR and p65 alters the repertoire of regulated genes and results in their association with novel sites in a mutually dependent manner. These novel sites predominantly cluster with p65 target genes that are antagonized by activated GR and vice versa. Our data show that coactivation of GR and NFKB alters signaling pathways that are regulated by each factor separately and provide insight into the networks underlying the GR and NFKB crosstalk. PMID:21750107

  19. Alterations of the TP53 Gene in Gastric and Esophageal Carcinogenesis

    PubMed Central

    Bellini, Marilanda Ferreira; Cadamuro, Aline Cristina Targa; Succi, Maysa; Proença, Marcela Alcântara; Silva, Ana Elizabete

    2012-01-01

    TP53 genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability. The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation. Thus, this study highlights the participation of the main genetic alterations of the TP53 gene in esophageal and gastric carcinogenesis. Among these changes, high frequency of TP53 mutations, loss of heterozygosity (LOH), overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response. Furthermore, Single Nucleotide Polymorphisms (SNPs) of TP53 have been implicated in the development and prognosis of several cancers, mainly TP53 codon 72 polymorphism whose role has been extensively studied in relation to susceptibility for esophageal and gastric cancer development. PMID:22919278

  20. Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas.

    PubMed

    Wu, Kui; Zhang, Xin; Li, Fuqiang; Xiao, Dakai; Hou, Yong; Zhu, Shida; Liu, Dongbing; Ye, Xiaofei; Ye, Mingzhi; Yang, Jie; Shao, Libin; Pan, Hui; Lu, Na; Yu, Yuan; Liu, Liping; Li, Jin; Huang, Liyan; Tang, Hailing; Deng, Qiuhua; Zheng, Yue; Peng, Lihua; Liu, Geng; Gu, Xia; He, Ping; Gu, Yingying; Lin, Weixuan; He, Huiming; Xie, Guoyun; Liang, Han; An, Na; Wang, Hui; Teixeira, Manuel; Vieira, Joana; Liang, Wenhua; Zhao, Xin; Peng, Zhiyu; Mu, Feng; Zhang, Xiuqing; Xu, Xun; Yang, Huanming; Kristiansen, Karsten; Wang, Jian; Zhong, Nanshan; Wang, Jun; Pan-Hammarström, Qiang; He, Jianxing

    2015-01-01

    The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma. PMID:26647728

  1. Gene expression patterns underlying parasite-induced alterations in host behaviour and life history.

    PubMed

    Feldmeyer, Barbara; Mazur, Johanna; Beros, Sara; Lerp, Hannes; Binder, Harald; Foitzik, Susanne

    2016-01-01

    Many parasites manipulate their hosts' phenotype. In particular, parasites with complex life cycles take control of their intermediate hosts' behaviour and life history to increase transmission to their definitive host. The proximate mechanisms underlying these parasite-induced alterations are poorly understood. The cestode Anomotaenia brevis affects the behaviour, life history and morphology of parasitized Temnothorax nylanderi ants and indirectly of their unparasitized nestmates. To gain insights on how parasites alter host phenotypes, we contrast brain gene expression patterns of T. nylanderi workers parasitized with the cestode, their unparasitized nestmates and unparasitized workers from unparasitized colonies. Over 400 differentially expressed genes between the three groups were identified, with most uniquely expressed genes detected in parasitized workers. Among these are genes that can be linked to the increased lifespan of parasitized workers. Furthermore, many muscle (functionality) genes are downregulated in these workers, potentially causing the observed muscular deformations and their inactive behaviour. Alterations in lifespan and activity could be adaptive for the parasite by increasing the likelihood that infected workers residing in acorns are eaten by their definitive host, a woodpecker. Our transcriptome analysis reveals numerous gene expression changes in parasitized workers and their uninfected nestmates and indicates possible routes of parasite manipulation. Although causality still needs to be established, parasite-induced alterations in lifespan and host behaviour appear to be partly explained by morphological muscle atrophy instead of central nervous system interference, which is often the core of behavioural regulation. Results of this study will shed light upon the molecular basis of antagonistic species interactions. PMID:26615010

  2. Pioglitazone administration alters ovarian gene expression in aging obese lethal yellow mice

    PubMed Central

    Brannian, John D; Eyster, Kathleen M; Weber, Mitch; Diggins, Maureen

    2008-01-01

    Background Women with polycystic ovary syndrome (PCOS) are often treated with insulin-sensitizing agents, e.g. thiazolidinediones (TZD), which have been shown to reduce androgen levels and improved ovulatory function. Acting via peroxisome proliferator-activated receptor (PPAR) gamma, TZD alter the expression of a large variety of genes. Lethal yellow (LY; C57BL/6J Ay/a) mice, possessing a mutation (Ay) in the agouti gene locus, exhibit progressive obesity, reproductive dysfunction, and altered metabolic regulation similar to women with PCOS. The current study was designed to test the hypothesis that prolonged treatment of aging LY mice with the TZD, pioglitazone, alters the ovarian expression of genes that may impact reproduction. Methods Female LY mice received daily oral doses of either 0.01 mg pioglitazone (n = 4) or an equal volume of vehicle (DMSO; n = 4) for 8 weeks. At the end of treatment, ovaries were removed and DNA microarrays were used to analyze differential gene expression. Results Twenty-seven genes showed at least a two-fold difference in ovarian expression with pioglitazone treatment. These included leptin, angiopoietin, angiopoietin-like 4, Foxa3, PGE1 receptor, resistin-like molecule-alpha (RELM), and actin-related protein 6 homolog (ARP6). For most altered genes, pioglitazone changed levels of expression to those seen in untreated C57BL/6J(a/a) non-mutant lean mice. Conclusion TZD administration may influence ovarian function via numerous diverse mechanisms that may or may not be directly related to insulin/IGF signaling. PMID:18348723

  3. Immunosenescence is associated with altered gene expression and epigenetic regulation in primary and secondary immune organs

    PubMed Central

    Sidler, Corinne; Wóycicki, Rafał; Ilnytskyy, Yaroslav; Metz, Gerlinde; Kovalchuk, Igor; Kovalchuk, Olga

    2013-01-01

    Deterioration of the immune system (immunosenescence) with age is associated with an increased susceptibility to infection, autoimmune disease and cancer, and reduced responsiveness to vaccination. Immunosenescence entails a reduced supply of naïve T cells from the thymus and increased specialization of peripheral T cell clones. Both thymic involution and peripheral T cell homeostasis are thought to involve cellular senescence. In order to analyze this at the molecular level, we studied gene expression profiles, epigenetic status, and genome stability in the thymus and spleen of 1-, 4-, and 18-month-old Long Evans rats. In the thymus, altered gene expression, DNA and histone H3K9 hypomethylation, increased genome instability, and apoptosis were observed in 18-month-old animals compared to 1- and 4-month-old animals. In the spleen, alterations in gene expression and epigenetic regulation occurred already by the age of 4 months compared to 1 month and persisted in 18-month-old compared to 1-month-old rats. In both organs, these changes were accompanied by the altered composition of resident T cell populations. Our study suggests that both senescence and apoptosis may be involved in altered organ function. PMID:24151501

  4. 9 CFR 85.8 - Interstate movement of swine from a qualified negative gene-altered vaccinated herd.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Interstate movement of swine from a... (INCLUDING POULTRY) AND ANIMAL PRODUCTS PSEUDORABIES § 85.8 Interstate movement of swine from a qualified negative gene-altered vaccinated herd. Swine from a qualified negative gene-altered vaccinated herd,...

  5. 9 CFR 85.8 - Interstate movement of swine from a qualified negative gene-altered vaccinated herd.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Interstate movement of swine from a... (INCLUDING POULTRY) AND ANIMAL PRODUCTS PSEUDORABIES § 85.8 Interstate movement of swine from a qualified negative gene-altered vaccinated herd. Swine from a qualified negative gene-altered vaccinated herd,...

  6. 9 CFR 85.8 - Interstate movement of swine from a qualified negative gene-altered vaccinated herd.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Interstate movement of swine from a... (INCLUDING POULTRY) AND ANIMAL PRODUCTS PSEUDORABIES § 85.8 Interstate movement of swine from a qualified negative gene-altered vaccinated herd. Swine from a qualified negative gene-altered vaccinated herd,...

  7. Genes and small RNA transcripts exhibit dosage-dependent expression pattern in maize copy-number alterations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Copy-number alterations are widespread in animal and plant genomes, but their immediate impact on gene expression is still unclear. In animals, copy-number alterations usually exhibit dosage effects, except for sex chromosomes that tend to be dosage compensated. In plants, genes within small duplica...

  8. Investigation of major gene for milk yield, milking speed, dry matter intake, and body weight in dairy cattle.

    PubMed

    Karacaören, Burak; Kadarmideen, Haja N; Janss, Luc L G

    2006-01-01

    The main aim of this study was to determine if there exist any major gene for milk yield (MY), milking speed (MS), dry matter intake (DMI), and body weight (BW) recorded at various stages of lactation in first-lactation dairy cows (2543 observations from 320 cows) kept at the research farm of the Swiss Federal Institute of Technology between April 1994 and April 2004. Data were modelled based a simple repeatability covariance structure and analysed by using Bayesian segregation analyses. Gibbs sampling was used to make statistical inferences on posterior distributions; inferences were based on a single run of the Markov chain for each trait with 500,000 samples, with each 10th sample collected because of the high correlation among the samples. The posterior mean (+/-SD) of major gene variance was 2.61 (+/-2.46) for MY, 0.83 (+/-1.26) for MS, 4.37 (+/-2.34) for DMI, and 2056.43 (+/-665.67) for BW. Highest posterior density regions for 3 of the 4 traits did not include 0 (except MS), which supported the evidence for major gene. With additional tests for agreement with Mendelian transmission probabilities, we could only confirm the existence of a major gene for MY, but not for MS, DMI, and BW. Expected Mendelian transmission probabilities and their model fits were also compared. PMID:17132898

  9. Latent Herpes Simplex Virus Infection of Sensory Neurons Alters Neuronal Gene Expression

    PubMed Central

    Kramer, Martha F.; Cook, W. James; Roth, Frederick P.; Zhu, Jia; Holman, Holly; Knipe, David M.; Coen, Donald M.

    2003-01-01

    The persistence of herpes simplex virus (HSV) and the diseases that it causes in the human population can be attributed to the maintenance of a latent infection within neurons in sensory ganglia. Little is known about the effects of latent infection on the host neuron. We have addressed the question of whether latent HSV infection affects neuronal gene expression by using microarray transcript profiling of host gene expression in ganglia from latently infected versus mock-infected mouse trigeminal ganglia. 33P-labeled cDNA probes from pooled ganglia harvested at 30 days postinfection or post-mock infection were hybridized to nylon arrays printed with 2,556 mouse genes. Signal intensities were acquired by phosphorimager. Mean intensities (n = 4 replicates in each of three independent experiments) of signals from mock-infected versus latently infected ganglia were compared by using a variant of Student's t test. We identified significant changes in the expression of mouse neuronal genes, including several with roles in gene expression, such as the Clk2 gene, and neurotransmission, such as genes encoding potassium voltage-gated channels and a muscarinic acetylcholine receptor. We confirmed the neuronal localization of some of these transcripts by using in situ hybridization. To validate the microarray results, we performed real-time reverse transcriptase PCR analyses for a selection of the genes. These studies demonstrate that latent HSV infection can alter neuronal gene expression and might provide a new mechanism for how persistent viral infection can cause chronic disease. PMID:12915567

  10. Genetic polymorphisms in nitric oxide synthase genes modify the relationship between vegetable and fruit intake and risk of non-Hodgkin lymphoma

    PubMed Central

    Han, Xuesong; Zheng, Tongzhang; Lan, Qing; Zhang, Yaqun; Kilfoy, Briseis A.; Qin, Qin; Rothman, Nathaniel; Zahm, Shelia H.; Holford, Theodore R.; Leaderer, Brian; Zhang, Yawei

    2010-01-01

    Oxidative damage caused by reactive oxygen species (ROS) and other free radicals is involved in carcinogenesis. It has been suggested that high vegetable and fruit intake may reduce the risk of non-Hodgkin lymphoma (NHL) as vegetables and fruit are rich in antioxidants. The aim of this study is to evaluate the interaction of vegetable and fruit intake with genetic polymorphisms in oxidative stress pathway genes and NHL risk. This hypothesis was investigated in a population-based case-control study of NHL and NHL histological subtype in Connecticut women including 513 histologically confirmed incident cases and 591 randomly selected controls. Gene-vegetable/fruit joint effects were estimated using unconditional logistic regression model. The false discovery rate method was applied to adjust for multiple comparisons. Significant interactions with vegetable and fruit intake were mainly found for genetic polymorphisms on nitric oxide synthase (NOS) genes among those with diffuse large B-cell lymphoma (DLBCL) and Follicular lymphoma (FL). Two single nucleotide polymorphisms (SNPs) in the NOS1 gene were found to significantly modify the association between total vegetable and fruit intake and risk of NHL overall, as well as the risk of follicular lymphoma (FL). When vegetables, bean vegetables, cruciferous vegetables, green leafy vegetables, red vegetables, yellow/orange vegetables, fruit, and citrus fruit were examined separately, strong interaction effects were narrowed to vegetable intake among DLBCL patients. Our results suggest that genetic polymorphisms in oxidative stress pathway genes, especially in the nitric oxide synthase genes, modify the association between vegetable and fruit intake and risk of NHL. PMID:19423521

  11. Histological conversion of follicular lymphoma with structural alterations of t(14;18) and immunoglobin genes.

    PubMed

    Raghoebier, S; Broos, L; Kramer, M H; van Krieken, J H; Kluin-Nelemans, J C; van Ommen, G J; Kluin, P

    1995-10-01

    About half of the patients with follicular lymphoma will develop an aggressive B cell lymphoma with morphological changes in growth pattern and cellular morphology. Changes of the immunophenotype, especially of the expression of immunoglobulin (Ig) have been documented less frequently. Multiple tumor samples of two patients with follicular lymphoma who developed tumor progression, were studied by Southern blot analysis for rearrangements of the Ig genes and the oncogenes BCL2 and MYC. In both patients, the general pattern of Ig gene rearrangements, especially of the Ig light-chain genes, and the structure of the t(14;18) breakpoint as assessed by the polymerase chain reaction (PRC) and fine restriction mapping, remained unaltered with time. However, both within the functional Ig heavy-chain allele and around the t(14;18) breakpoint, extensive secondary alterations took place. This indicates clonal evolution rather than the appearance of an independent lymphoma. In the first case with progression from follicular lymphoma to Burkitt's lymphoma 3 years after diagnosis, alterations were especially present 3' of the t(14;18) breakpoint. In the second patient with a change from follicular to diffuse centroblastic lymphoma 4 years after diagnosis, subsequent class switches from IgM to IgG and to defective IgH expression were accompanied by deletion of C mu sequences and a rearrangement of the MYC gene, respectively. Additionally, in both patients alterations in individual restriction sites occurred, which most likely were due to somatic mutations within both the functional IgH and translocated allele. Our data indicate that complex alterations of both the functional and non-functional IgH allele may accompany tumor progression and may erroneously suggest the appearance of independent clones by Southern blot analysis. It remains to be established whether these alterations are causative events or the consequence of genetic instability and clonal evolution. PMID:7564520

  12. Global alteration in gene expression profiles of deciduas from women with idiopathic recurrent pregnancy loss

    PubMed Central

    Krieg, S.A.; Fan, X.; Hong, Y.; Sang, Q.-X.; Giaccia, A.; Westphal, L.M.; Lathi, R.B.; Krieg, A.J.; Nayak, N.R.

    2012-01-01

    Recurrent pregnancy loss (RPL) occurs in ∼5% of women. However, the etiology is still poorly understood. Defects in decidualization of the endometrium during early pregnancy contribute to several pregnancy complications, such as pre-eclampsia and intrauterine growth restriction (IUGR), and are believed to be important in the pathogenesis of idiopathic RPL. We performed microarray analysis to identify gene expression alterations in the deciduas of idiopathic RPL patients. Control patients had one antecedent term delivery, but were undergoing dilation and curettage for current aneuploid miscarriage. Gene expression differences were evaluated using both pathway and gene ontology (GO) analysis. Selected genes were validated using quantitative reverse transcription–polymerase chain reaction (qRT–PCR). A total of 155 genes were found to be significantly dysregulated in the deciduas of RPL patients (>2-fold change, P < 0.05), with 22 genes up-regulated and 133 genes down-regulated. GO analysis linked a large percentage of genes to discrete biological functions, including immune response (23%), cell signaling (18%) and cell invasion (17.1%), and pathway analysis revealed consistent changes in both the interleukin 1 (IL-1) and IL-8 pathways. All genes in the IL-8 pathway were up-regulated while genes in the IL-1 pathway were down-regulated. Although both pathways can promote inflammation, IL-1 pathway activity is important for normal implantation. Additionally, genes known to be critical for degradation of the extracellular matrix, including matrix metalloproteinase 26 and serine peptidase inhibitor Kazal-type 1, were also highly up-regulated. In this first microarray approach to decidual gene expression in RPL patients, our data suggest that dysregulation of genes associated with cell invasion and immunity may contribute significantly to idiopathic recurrent miscarriage. PMID:22505054

  13. Alterations in gene expression and DNA methylation during murine and human lung alveolar septation.

    PubMed

    Cuna, Alain; Halloran, Brian; Faye-Petersen, Ona; Kelly, David; Crossman, David K; Cui, Xiangqin; Pandit, Kusum; Kaminski, Naftali; Bhattacharya, Soumyaroop; Ahmad, Ausaf; Mariani, Thomas J; Ambalavanan, Namasivayam

    2015-07-01

    DNA methylation, a major epigenetic mechanism, may regulate coordinated expression of multiple genes at specific time points during alveolar septation in lung development. The objective of this study was to identify genes regulated by methylation during normal septation in mice and during disordered septation in bronchopulmonary dysplasia. In mice, newborn lungs (preseptation) and adult lungs (postseptation) were evaluated by microarray analysis of gene expression and immunoprecipitation of methylated DNA followed by sequencing (MeDIP-Seq). In humans, microarray gene expression data were integrated with genome-wide DNA methylation data from bronchopulmonary dysplasia versus preterm and term lung. Genes with reciprocal changes in expression and methylation, suggesting regulation by DNA methylation, were identified. In mice, 95 genes with inverse correlation between expression and methylation during normal septation were identified. In addition to genes known to be important in lung development (Wnt signaling, Angpt2, Sox9, etc.) and its extracellular matrix (Tnc, Eln, etc.), genes involved with immune and antioxidant defense (Stat4, Sod3, Prdx6, etc.) were also observed. In humans, 23 genes were differentially methylated with reciprocal changes in expression in bronchopulmonary dysplasia compared with preterm or term lung. Genes of interest included those involved with detoxifying enzymes (Gstm3) and transforming growth factor-β signaling (bone morphogenetic protein 7 [Bmp7]). In terms of overlap, 20 genes and three pathways methylated during mouse lung development also demonstrated changes in methylation between preterm and term human lung. Changes in methylation correspond to altered expression of a number of genes associated with lung development, suggesting that DNA methylation of these genes may regulate normal and abnormal alveolar septation. PMID:25387348

  14. Alterations in Gene Expression and DNA Methylation during Murine and Human Lung Alveolar Septation

    PubMed Central

    Cuna, Alain; Halloran, Brian; Faye-Petersen, Ona; Kelly, David; Crossman, David K.; Cui, Xiangqin; Pandit, Kusum; Kaminski, Naftali; Bhattacharya, Soumyaroop; Ahmad, Ausaf; Mariani, Thomas J.

    2015-01-01

    DNA methylation, a major epigenetic mechanism, may regulate coordinated expression of multiple genes at specific time points during alveolar septation in lung development. The objective of this study was to identify genes regulated by methylation during normal septation in mice and during disordered septation in bronchopulmonary dysplasia. In mice, newborn lungs (preseptation) and adult lungs (postseptation) were evaluated by microarray analysis of gene expression and immunoprecipitation of methylated DNA followed by sequencing (MeDIP-Seq). In humans, microarray gene expression data were integrated with genome-wide DNA methylation data from bronchopulmonary dysplasia versus preterm and term lung. Genes with reciprocal changes in expression and methylation, suggesting regulation by DNA methylation, were identified. In mice, 95 genes with inverse correlation between expression and methylation during normal septation were identified. In addition to genes known to be important in lung development (Wnt signaling, Angpt2, Sox9, etc.) and its extracellular matrix (Tnc, Eln, etc.), genes involved with immune and antioxidant defense (Stat4, Sod3, Prdx6, etc.) were also observed. In humans, 23 genes were differentially methylated with reciprocal changes in expression in bronchopulmonary dysplasia compared with preterm or term lung. Genes of interest included those involved with detoxifying enzymes (Gstm3) and transforming growth factor-β signaling (bone morphogenetic protein 7 [Bmp7]). In terms of overlap, 20 genes and three pathways methylated during mouse lung development also demonstrated changes in methylation between preterm and term human lung. Changes in methylation correspond to altered expression of a number of genes associated with lung development, suggesting that DNA methylation of these genes may regulate normal and abnormal alveolar septation. PMID:25387348

  15. A gene fusion at a homeobox locus: alterations in leaf shape and implications for morphological evolution.

    PubMed Central

    Chen, J J; Janssen, B J; Williams, A; Sinha, N

    1997-01-01

    Compound leaves are seen in many angiosperm genera and are thought to be either fundamentally different from simple leaves or elaborations of simple leaves. The knotted1-like homeobox (knox) genes are known to regulate plant development. When overexpressed in homologous or heterologous species, this family of genes can cause changes in leaf morphology, including excessive leaf compounding in tomato. We describe here an instance of a spontaneously arisen fusion between a gene encoding a metabolic enzyme and a homeodomain protein. We show that the fusion results in overexpression of the homeodomain protein and a change in morphology that approximates the changes caused by overexpression of the same gene under the control of the cauliflower mosaic virus 35S promoter in transgenic plants. Exon-shuffling events can account for the modularity of proteins. If the shuffled exons are associated with altered promoters, changes in gene expression patterns can result. Our results show that gene fusions of this nature can cause changes in expression patterns that lead to altered morphology. We suggest that such phenomena may have played a role in the evolution of form. PMID:9286107

  16. PRENATAL EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE ALTERS GENE EXPRESSION IN THE DEVELOPING MURINE HIPPOCAMPUS

    PubMed Central

    Mukhopadhyay, Partha; Horn, Kristin H.; Greene, Robert M.; Pisano, M. Michele

    2010-01-01

    Background Little is known about the effects of passive smoke exposures on the developing brain. Objective The purpose of the current study was to identify changes in gene expression in the murine hippocampus as a consequence of in utero exposure to sidestream cigarette smoke (an experimental equivalent of environmental tobacco smoke (ETS)) at exposure levels that do not result in fetal growth inhibition. Methods A whole body smoke inhalation exposure system was utilized to deliver ETS to pregnant C57BL/6J mice for six hours/day from gestational days 6–17 (gd 6–17) [for microarray] or gd 6–18.5 [for fetal phenotyping]. Results There were no significant effects of ETS exposure on fetal phenotype. However, 61 “expressed” genes in the gd 18.5 fetal hippocampus were differentially regulated (up- or down-regulated by 1.5 fold or greater) by maternal exposure to ETS. Of these 61 genes, 25 genes were upregulated while 36 genes were downregulated. A systems biology approach, including computational methodologies, identified cellular response pathways, and biological themes, underlying altered fetal programming of the embryonic hippocampus by in utero cigarette smoke exposure. Conclusions Results from the present study suggest that even in the absence of effects on fetal growth, prenatal smoke exposure can alter gene expression during the “early” period of hippocampal growth and may result in abnormal hippocampal morphology, connectivity, and function. PMID:19969065

  17. Altered gene expression profiles in the hippocampus and prefrontal cortex of type 2 diabetic rats

    PubMed Central

    2012-01-01

    Background There has been an increasing body of epidemiologic and biochemical evidence implying the role of cerebral insulin resistance in Alzheimer-type dementia. For a better understanding of the insulin effect on the central nervous system, we performed microarray-based global gene expression profiling in the hippocampus, striatum and prefrontal cortex of streptozotocin-induced and spontaneously diabetic Goto-Kakizaki rats as model animals for type 1 and type 2 diabetes, respectively. Results Following pathway analysis and validation of gene lists by real-time polymerase chain reaction, 30 genes from the hippocampus, such as the inhibitory neuropeptide galanin, synuclein gamma and uncoupling protein 2, and 22 genes from the prefrontal cortex, e.g. galanin receptor 2, protein kinase C gamma and epsilon, ABCA1 (ATP-Binding Cassette A1), CD47 (Cluster of Differentiation 47) and the RET (Rearranged During Transfection) protooncogene, were found to exhibit altered expression levels in type 2 diabetic model animals in comparison to non-diabetic control animals. These gene lists proved to be partly overlapping and encompassed genes related to neurotransmission, lipid metabolism, neuronal development, insulin secretion, oxidative damage and DNA repair. On the other hand, no significant alterations were found in the transcriptomes of the corpus striatum in the same animals. Changes in the cerebral gene expression profiles seemed to be specific for the type 2 diabetic model, as no such alterations were found in streptozotocin-treated animals. Conclusions According to our knowledge this is the first characterization of the whole-genome expression changes of specific brain regions in a diabetic model. Our findings shed light on the complex role of insulin signaling in fine-tuning brain functions, and provide further experimental evidence in support of the recently elaborated theory of type 3 diabetes. PMID:22369239

  18. Comparison of gene expression profiles altered by comfrey and riddelliine in rat liver

    PubMed Central

    Guo, Lei; Mei, Nan; Dial, Stacey; Fuscoe, James; Chen, Tao

    2007-01-01

    Background Comfrey (Symphytum officinale) is a perennial plant and has been consumed by humans as a vegetable, a tea and an herbal medicine for more than 2000 years. It, however, is hepatotoxic and carcinogenic in experimental animals and hepatotoxic in humans. Pyrrolizidine alkaloids (PAs) exist in many plants and many of them cause liver toxicity and/or cancer in humans and experimental animals. In our previous study, we found that the mutagenicity of comfrey was associated with the PAs contained in the plant. Therefore, we suggest that carcinogenicity of comfrey result from those PAs. To confirm our hypothesis, we compared the expression of genes and processes of biological functions that were altered by comfrey (mixture of the plant with PAs) and riddelliine (a prototype of carcinogenic PA) in rat liver for carcinogenesis in this study. Results Groups of 6 Big Blue Fisher 344 rats were treated with riddelliine at 1 mg/kg body weight by gavage five times a week for 12 weeks or fed a diet containing 8% comfrey root for 12 weeks. Animals were sacrificed one day after the last treatment and the livers were isolated for gene expression analysis. The gene expressions were investigated using Applied Biosystems Rat Whole Genome Survey Microarrays and the biological functions were analyzed with Ingenuity Analysis Pathway software. Although there were large differences between the significant genes and between the biological processes that were altered by comfrey and riddelliine, there were a number of common genes and function processes that were related to carcinogenesis. There was a strong correlation between the two treatments for fold-change alterations in expression of drug metabolizing and cancer-related genes. Conclusion Our results suggest that the carcinogenesis-related gene expression patterns resulting from the treatments of comfrey and riddelliine are very similar, and PAs contained in comfrey are the main active components responsible for carcinogenicity of

  19. Altered Circadian Rhythm and Metabolic Gene Profile in Rats Subjected to Advanced Light Phase Shifts

    PubMed Central

    Herrero, Laura; Valcarcel, Lorea; da Silva, Crhistiane Andressa; Albert, Nerea; Diez-Noguera, Antoni; Cambras, Trinitat; Serra, Dolors

    2015-01-01

    The circadian clock regulates metabolic homeostasis and its disruption predisposes to obesity and other metabolic diseases. However, the effect of phase shifts on metabolism is not completely understood. We examined whether alterations in the circadian rhythm caused by phase shifts induce metabolic changes in crucial genes that would predispose to obesity. Three-month-old rats were maintained on a standard diet under lighting conditions with chronic phase shifts consisting of advances, delays or advances plus delays. Serum leptin, insulin and glucose levels decreased only in rats subjected to advances. The expression of the clock gene Bmal 1 increased in the hypothalamus, white adipose tissue (WAT), brown adipose tissue (BAT) and liver of the advanced group compared to control rats. The advanced group showed an increase in hypothalamic AgRP and NPY mRNA, and their lipid metabolism gene profile was altered in liver, WAT and BAT. WAT showed an increase in inflammation and ER stress and brown adipocytes suffered a brown-to-white transformation and decreased UCP-1 expression. Our results indicate that chronic phase advances lead to significant changes in neuropeptides, lipid metabolism, inflammation and ER stress gene profile in metabolically relevant tissues such as the hypothalamus, liver, WAT and BAT. This highlights a link between alteration of the circadian rhythm and metabolism at the transcriptional level. PMID:25837425

  20. Ethanol-related alterations in gene expression patterns in the developing murine hippocampus.

    PubMed

    Mandal, Chanchal; Park, Kyoung Sun; Jung, Kyoung Hwa; Chai, Young Gyu

    2015-08-01

    It is well known that consuming alcohol prior to and during pregnancy can cause harm to the developing fetus. Fetal alcohol spectrum disorder is a term commonly used to describe a range of disabilities that may arise from prenatal alcohol exposure such as fetal alcohol syndrome, partial fetal alcohol syndrome, alcohol-related neurodevelopmental disorders, and alcohol-related birth defects. Here, we report that maternal binge alcohol consumption alters several important genes that are involved in nervous system development in the mouse hippocampus at embryonic day 18. Microarray analysis revealed that Nova1, Ntng1, Gal, Neurog2, Neurod2, and Fezf2 gene expressions are altered in the fetal hippocampus. Pathway analysis also revealed the association of the calcium signaling pathway in addition to other pathways with the differentially expressed genes during early brain development. Alteration of such important genes and dynamics of the signaling pathways may cause neurodevelopmental disorders. Our findings offer insight into the molecular mechanism involved in neurodevelopmental disorders associated with alcohol-related defects. PMID:26063602

  1. Altered Stra13 and Dec2 circadian gene expression in hypoxic cells

    SciTech Connect

    Guillaumond, Fabienne; Lacoche, Samuel; Dulong, Sandrine; Grechez-Cassiau, Aline; Filipski, Elisabeth; Li, Xiao-Mei; Levi, Francis; Berra, Edurne; Delaunay, Franck; Teboul, Michele

    2008-05-16

    The circadian system regulates rhythmically most of the mammalian physiology in synchrony with the environmental light/dark cycle. Alteration of circadian clock gene expression has been associated with tumour progression but the molecular links between the two mechanisms remain poorly defined. Here we show that Stra13 and Dec2, two circadian transcriptional regulators which play a crucial role in cell proliferation and apoptosis are overexpressed and no longer rhythmic in serum shocked fibroblasts treated with CoCl{sub 2,} a substitute of hypoxia. This effect is associated with a loss of circadian expression of the clock genes Rev-erb{alpha} and Bmal1, and the clock-controlled gene Dbp. Consistently, cotransfection assays demonstrate that STRA13 and DEC2 both antagonize CLOCK:BMAL1 dependent transactivation of the Rev-erb{alpha} and Dbp promoters. Using a transplantable osteosarcoma tumour model, we show that hypoxia is associated with altered circadian expression of Stra13, Dec2, Rev-erb{alpha}, Bmal1 and Dbp in vivo. These observations collectively support the notion that overexpression of Stra13 and Dec2 links hypoxia signalling to altered circadian clock gene expression.

  2. Carbohydrate intake.

    PubMed

    Leturque, Armelle; Brot-Laroche, Edith; Le Gall, Maude

    2012-01-01

    Carbohydrates represent more than 50% of the energy sources present in most human diets. Sugar intake is regulated by metabolic, neuronal, and hedonic factors, and gene polymorphisms are involved in determining sugar preference. Nutrigenomic adaptations to carbohydrate availability have been evidenced in metabolic diseases, in the persistence of lactose digestion, and in amylase gene copy number. Furthermore, dietary oligosaccharides, fermentable by gut flora, can modulate the microbiotal diversity to the benefit of the host. Genetic diseases linked to mutations in the disaccharidase genes (sucrase-isomaltase, lactase) and in sugar transporter genes (sodium/glucose cotransporter 1, glucose transporters 1 and 2) severely impact carbohydrate intake. These diseases are revealed upon exposure to food containing the offending sugar, and withdrawal of this sugar from the diet prevents disease symptoms, failure to thrive, and premature death. Tailoring the sugar composition of diets to optimize wellness and to prevent the chronic occurrence of metabolic diseases is a future goal that may yet be realized through continued development of nutrigenetics and nutrigenomics approaches. PMID:22656375

  3. FADS2 Genetic Variance in Combination with Fatty Acid Intake Might Alter Composition of the Fatty Acids in Brain.

    PubMed

    Rizzi, Thais S; van der Sluis, Sophie; Derom, Catherine; Thiery, Evert; van Kesteren, Ronald E; Jacobs, Nele; Van Gestel, Sofie; Vlietinck, Robert; Verhage, Matthijs; Heutink, Peter; Posthuma, Danielle

    2013-01-01

    Multiple lines of evidence suggest that fatty acids (FA) play an important role in cognitive function. However, little is known about the functional genetic pathways involved in cognition. The main goals of this study were to replicate previously reported interaction effects between breast feeding (BF) and FA desaturase (FADS) genetic variation on IQ and to investigate the possible mechanisms by which these variants might moderate BF effect, focusing on brain expression. Using a sample of 534 twins, we observed a trend in the moderation of BF effects on IQ by FADS2 variation. In addition, we made use of publicly available gene expression databases from both humans (193) and mice (93) and showed that FADS2 variants also correlate with FADS1 brain expression (P-value<1.1E-03). Our results provide novel clues for the understanding of the genetic mechanisms regulating FA brain expression and improve the current knowledge of the FADS moderation effect on cognition. PMID:23826354

  4. Altered Gene Expression Pattern in Peripheral Blood Mononuclear Cells in Patients with Acute Myocardial Infarction

    PubMed Central

    Kiliszek, Marek; Burzynska, Beata; Michalak, Marcin; Gora, Monika; Winkler, Aleksandra; Maciejak, Agata; Leszczynska, Agata; Gajda, Ewa; Kochanowski, Janusz; Opolski, Grzegorz

    2012-01-01

    Background Despite a substantial progress in diagnosis and therapy, acute myocardial infarction (MI) is a major cause of mortality in the general population. A novel insight into the pathophysiology of myocardial infarction obtained by studying gene expression should help to discover novel biomarkers of MI and to suggest novel strategies of therapy. The aim of our study was to establish gene expression patterns in leukocytes from acute myocardial infarction patients. Methods and Results Twenty-eight patients with ST-segment elevation myocardial infarction (STEMI) were included. The blood was collected on the 1st day of myocardial infarction, after 4–6 days, and after 6 months. Control group comprised 14 patients with stable coronary artery disease, without history of myocardial infarction. Gene expression analysis was performed with Affymetrix Human Gene 1.0 ST microarrays and GCS3000 TG system. Lists of genes showing altered expression levels (fold change >1.5, p<0.05) were submitted to Ingenuity Pathway Analysis. Gene lists from each group were examined for canonical pathways and molecular and cellular functions. Comparing acute phase of MI with the same patients after 6 months (stable phase) and with control group we found 24 genes with changed expression. In canonical analysis three pathways were highlighted: signaling of PPAR (peroxisome proliferator-activated receptor), IL-10 and IL-6 (interleukin 10 and 6). Conclusions In the acute phase of STEMI, dozens of genes from several pathways linked with lipid/glucose metabolism, platelet function and atherosclerotic plaque stability show altered expression. Up-regulation of SOCS3 and FAM20 genes in the first days of myocardial infarction is observed in the vast majority of patients. PMID:23185530

  5. Warming Alters Expressions of Microbial Functional Genes Important to Ecosystem Functioning

    PubMed Central

    Xue, Kai; Xie, Jianping; Zhou, Aifen; Liu, Feifei; Li, Dejun; Wu, Liyou; Deng, Ye; He, Zhili; Van Nostrand, Joy D.; Luo, Yiqi; Zhou, Jizhong

    2016-01-01

    Soil microbial communities play critical roles in ecosystem functioning and are likely altered by climate warming. However, so far, little is known about effects of warming on microbial functional gene expressions. Here, we applied functional gene array (GeoChip 3.0) to analyze cDNA reversely transcribed from total RNA to assess expressed functional genes in active soil microbial communities after nine years of experimental warming in a tallgrass prairie. Our results showed that warming significantly altered the community wide gene expressions. Specifically, expressed genes for degrading more recalcitrant carbon were stimulated by warming, likely linked to the plant community shift toward more C4 species under warming and to decrease the long-term soil carbon stability. In addition, warming changed expressed genes in labile C degradation and N cycling in different directions (increase and decrease), possibly reflecting the dynamics of labile C and available N pools during sampling. However, the average abundances of expressed genes in phosphorus and sulfur cycling were all increased by warming, implying a stable trend of accelerated P and S processes which might be a mechanism to sustain higher plant growth. Furthermore, the expressed gene composition was closely related to both dynamic (e.g., soil moisture) and stable environmental attributes (e.g., C4 leaf C or N content), indicating that RNA analyses could also capture certain stable trends in the long-term treatment. Overall, this study revealed the importance of elucidating functional gene expressions of soil microbial community in enhancing our understanding of ecosystem responses to warming. PMID:27199978

  6. Na+/H+ exchanger 1 deficiency alters gene expression in mouse brain.

    PubMed

    Zhou, Dan; Xue, Jin; Gavrialov, Orit; Haddad, Gabriel G

    2004-08-11

    Na(+)/H(+) exchanger 1 (NHE1) is well known to function as a major regulator of intracellular pH (pH(i)). It is activated by low pH(i) and exchanges extracellular Na(+) for intracellular H(+) to maintain cellular homeostasis. Despite the fact that we now have evidence suggesting other roles for NHE1, there has been no comprehensive study investigating its role as a signaling molecule. Toward this aim, we used in this study NHE1 null mutant mice and cDNA microarrays to investigate the effects of NHE1 on global gene expression in various regions of the brain, e.g., cortex, hippocampus, brain stem-diencephalon, and cerebellum. We found that a total of 35 to 79 genes were up- or downregulated in each brain region, with the majority being downregulated. The effect of NHE1 null mutation on gene expression is region specific, and only 11 genes were changed in all brain regions studied. Further analysis of the cis-regulatory regions of downregulated genes revealed that transcription suppressors, BCL6 and E4BP4, were probable candidates that mediated the inhibitory effect of NHE1 null mutation. One of the genes, MCT-13, was not only downregulated in the NHE1 null mutant brain but also in tissue cultures treated with an NHE1 inhibitor. We conclude that 1) a relatively small number of genes were altered in the NHE1 null mouse brain; 2) the effects of NHE1 null mutation on gene expression are region specific; and 3) several genes implicated in neurodegeneration have altered expression, potentially offering a molecular explanation for the phenotype of the NHE1 null mouse. PMID:15306696

  7. Chronic ultraviolet exposure-induced p53 gene alterations in sencar mouse skin carcinogenesis model

    SciTech Connect

    Tong, Ying; Smith, M.A.; Tucker, S.B.

    1997-06-27

    Alterations of the tumor suppressor gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10137 (27%) of SCCs and 12124 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C {r_arrow} A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C {r_arrow} T, two C {r_arrow} A, one C {r_arrow} G, and one A {r_arrow} T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin. 40 refs., 5 figs., 1 tab.

  8. Laminin-binding integrin gene copy number alterations in distinct epithelial-type cancers

    PubMed Central

    Harryman, William L; Pond, Erika; Singh, Parminder; Little, Andrew S; Eschbacher, Jennifer M; Nagle, Raymond B; Cress, Anne E

    2016-01-01

    Background: The laminin-binding integrin (LBI) family are cell adhesion molecules that are essential for invasion and metastasis of human epithelial cancers and cell adhesion mediated drug resistance. We investigated whether copy number alteration (CNA) or mutations of a five-gene signature (ITGB4, ITGA3, LAMB3, PLEC, and SYNE3), representing essential genes for LBI adhesion, would correlate with patient outcomes within human epithelial-type tumor data sets currently available in an open access format. Methods: We investigated the relative alteration frequency of an LBI signature panel (integrin β4 (ITGB4), integrin α3 (ITGA3), laminin β3 chain (LAMB3), plectin (PLEC), and nesprin 3 (SYNE3)), independent of the epithelial cancer type, within publically available and published data using cBioPortal and Oncomine software. We rank ordered the results using a 20% alteration frequency cut-off and limited the analysis to studies containing at least 100 samples. Kaplan-Meier survival curves were analyzed to determine if alterations in the LBI signature correlated with patient survival. The Oncomine data mining tool was used to compare the heat map expression of the LBI signature without SYNE3 (as this was not included in the Oncomine database) to drug resistance patterns. Results: Twelve different cancer types, representing 5,647 samples, contained at least a 20% alteration frequency of the five-gene LBI signature. The frequency of alteration ranged from 38.3% to 19.8%. Within the LBI signature, PLEC was the most commonly altered followed by LAMB3, ITGB4, ITGA3, and SYNE3 across all twelve cancer types. Within cancer types, there was little overlap of the individual amplified genes from each sample, suggesting different specific amplicons may alter the LBI adhesion structures. Of the twelve cancer types, overall survival was altered by CNA presence in bladder urothelial carcinoma (p=0.0143*) and cervical squamous cell carcinoma and endocervical adenocarcinoma (p=0

  9. Adipose and Muscle Tissue Gene Expression of Two Genes (NCAPG and LCORL) Located in a Chromosomal Region Associated with Cattle Feed Intake and Gain

    PubMed Central

    Lindholm-Perry, Amanda K.; Kuehn, Larry A.; Oliver, William T.; Sexten, Andrea K.; Miles, Jeremy R.; Rempel, Lea A.; Cushman, Robert A.; Freetly, Harvey C.

    2013-01-01

    A region on bovine chromosome 6 has been implicated in cattle birth weight, growth, and length. Non-SMC conodensin I complex subunit G (NCAPG) and ligand dependent nuclear receptor corepressor-like protein (LCORL) are positional candidate genes within this region. Previously identified genetic markers in both genes were associated with average daily gain (ADG) and average daily feed intake (ADFI) in a crossbred population of beef steers. These markers were also associated with hot carcass weight, ribeye area and adjusted fat thickness suggesting that they may have a role in lean muscle growth and/or fat deposition. The purpose of this study was to determine whether the transcript abundance of either of these genes in cattle adipose and muscle tissue was associated with variation in feed intake and average daily gain phenotypes. Transcript abundance for NCAPG and LCORL in adipose and muscle tissue was measured in heifers (adipose only), cows and steers using real-time polymerase chain reaction. In the adipose tissue from cows and heifers, a negative correlation between LCORL transcript abundance and ADFI were detected (P = 0.05). In the muscle tissue from cows, transcript abundance of NCAPG was associated with ADG (r = 0.26; P = 0.009). A positive correlation between LCORL transcript abundance from muscle tissue of steers and ADFI was detected (P = 0.04). LCORL protein levels in the muscle of steers were investigated and were associated with ADFI (P = 0.01). These data support our earlier genetic associations with ADFI and ADG within this region and represent the potential for biological activity of these genes in the muscle and adipose tissues of beef cattle; however, they also suggest that sex, age and/or nutrition-specific interactions may affect the expression of NCAPG and LCORL in these tissues. PMID:24278337

  10. Anti-Obesity and Anti-Hyperglycemic Effects of Cinnamaldehyde via altered Ghrelin Secretion and Functional impact on Food Intake and Gastric Emptying

    PubMed Central

    Camacho, Susana; Michlig, Stephanie; de Senarclens-Bezençon, Carole; Meylan, Jenny; Meystre, Julie; Pezzoli, Maurizio; Markram, Henry; le Coutre, Johannes

    2015-01-01

    Cinnamon extract is associated to different health benefits but the active ingredients or pathways are unknown. Cinnamaldehyde (CIN) imparts the characteristic flavor to cinnamon and is known to be the main agonist of transient receptor potential-ankyrin receptor 1 (TRPA1). Here, expression of TRPA1 in epithelial mouse stomach cells is described. After receiving a single-dose of CIN, mice significantly reduce cumulative food intake and gastric emptying rates. Co-localization of TRPA1 and ghrelin in enteroendocrine cells of the duodenum is observed both in vivo and in the MGN3-1 cell line, a ghrelin secreting cell model, where incubation with CIN up-regulates expression of TRPA1 and Insulin receptor genes. Ghrelin secreted in the culture medium was quantified following CIN stimulation and we observe that octanoyl and total ghrelin are significantly lower than in control conditions. Additionally, obese mice fed for five weeks with CIN-containing diet significantly reduce their cumulative body weight gain and improve glucose tolerance without detectable modification of insulin secretion. Finally, in adipose tissue up-regulation of genes related to fatty acid oxidation was observed. Taken together, the results confirm anti-hyperglycemic and anti-obesity effects of CIN opening a new approach to investigate how certain spice derived compounds regulate endogenous ghrelin release for therapeutic intervention. PMID:25605129

  11. Anti-obesity and anti-hyperglycemic effects of cinnamaldehyde via altered ghrelin secretion and functional impact on food intake and gastric emptying.

    PubMed

    Camacho, Susana; Michlig, Stephanie; de Senarclens-Bezençon, Carole; Meylan, Jenny; Meystre, Julie; Pezzoli, Maurizio; Markram, Henry; le Coutre, Johannes

    2015-01-01

    Cinnamon extract is associated to different health benefits but the active ingredients or pathways are unknown. Cinnamaldehyde (CIN) imparts the characteristic flavor to cinnamon and is known to be the main agonist of transient receptor potential-ankyrin receptor 1 (TRPA1). Here, expression of TRPA1 in epithelial mouse stomach cells is described. After receiving a single-dose of CIN, mice significantly reduce cumulative food intake and gastric emptying rates. Co-localization of TRPA1 and ghrelin in enteroendocrine cells of the duodenum is observed both in vivo and in the MGN3-1 cell line, a ghrelin secreting cell model, where incubation with CIN up-regulates expression of TRPA1 and Insulin receptor genes. Ghrelin secreted in the culture medium was quantified following CIN stimulation and we observe that octanoyl and total ghrelin are significantly lower than in control conditions. Additionally, obese mice fed for five weeks with CIN-containing diet significantly reduce their cumulative body weight gain and improve glucose tolerance without detectable modification of insulin secretion. Finally, in adipose tissue up-regulation of genes related to fatty acid oxidation was observed. Taken together, the results confirm anti-hyperglycemic and anti-obesity effects of CIN opening a new approach to investigate how certain spice derived compounds regulate endogenous ghrelin release for therapeutic intervention. PMID:25605129

  12. Role of Genetic Alterations in the NLRP3 and CARD8 Genes in Health and Disease

    PubMed Central

    Paramel, G. V.; Sirsjö, A.; Fransén, K.

    2015-01-01

    The complexity of a common inflammatory disease is influenced by multiple genetic and environmental factors contributing to the susceptibility of disease. Studies have reported that these exogenous and endogenous components may perturb the balance of innate immune response by activating the NLRP3 inflammasome. The multimeric NLRP3 complex results in the caspase-1 activation and the release of potent inflammatory cytokines, like IL-1β. Several studies have been performed on the association of the genetic alterations in genes encoding NLRP3 and CARD8 with the complex diseases with inflammatory background, like inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis, and type 1 diabetes. The aim of the present review is therefore to summarize the literature regarding genetic alterations in these genes and their association with health and disease. PMID:25788762

  13. Sequential Infection with Common Pathogens Promotes Human-like Immune Gene Expression and Altered Vaccine Response.

    PubMed

    Reese, Tiffany A; Bi, Kevin; Kambal, Amal; Filali-Mouhim, Ali; Beura, Lalit K; Bürger, Matheus C; Pulendran, Bali; Sekaly, Rafick-Pierre; Jameson, Stephen C; Masopust, David; Haining, W Nicholas; Virgin, Herbert W

    2016-05-11

    Immune responses differ between laboratory mice and humans. Chronic infection with viruses and parasites are common in humans, but are absent in laboratory mice, and thus represent potential contributors to inter-species differences in immunity. To test this, we sequentially infected laboratory mice with herpesviruses, influenza, and an intestinal helminth and compared their blood immune signatures to mock-infected mice before and after vaccination against yellow fever virus (YFV-17D). Sequential infection altered pre- and post-vaccination gene expression, cytokines, and antibodies in blood. Sequential pathogen exposure induced gene signatures that recapitulated those seen in blood from pet store-raised versus laboratory mice, and adult versus cord blood in humans. Therefore, basal and vaccine-induced murine immune responses are altered by infection with agents common outside of barrier facilities. This raises the possibility that we can improve mouse models of vaccination and immunity by selective microbial exposure of laboratory animals to mimic that of humans. PMID:27107939

  14. Polymorphic core promoter GA-repeats alter gene expression of the early embryonic developmental genes.

    PubMed

    Valipour, E; Kowsari, A; Bayat, H; Banan, M; Kazeminasab, S; Mohammadparast, S; Ohadi, M

    2013-12-01

    Protein complexes that bind to 'GAGA' DNA elements are necessary to replace nucleosomes to create a local chromatin environment that facilitates a variety of site-specific regulatory responses. Three to four elements are required for the disruption of a preassembled nucleosome. We have previously identified human protein-coding gene core promoters that are composed of exceptionally long GA-repeats. The functional implication of those GA-repeats is beginning to emerge in the core promoter of the human SOX5 gene, which is involved in multiple developmental processes. In the current study, we analyze the functional implication of GA-repeats in the core promoter of two additional genes, MECOM and GABRA3, whose expression is largely limited to embryogenesis. We report a significant difference in gene expression as a result of different alleles across those core promoters in the HEK-293 cell line. Across-species homology check for the GABRA3 GA-repeats revealed that those repeats are evolutionary conserved in mouse and primates (p<1 × 10(-8)). The MECOM core promoter GA-repeats are also conserved in numerous species, of which human has the longest repeat and complexity. We propose a novel role for GA-repeat core promoters to regulate gene expression in the genes involved in development and evolution. PMID:24055488

  15. Oxidative Stress Alters miRNA and Gene Expression Profiles in Villous First Trimester Trophoblasts

    PubMed Central

    Cross, Courtney E.; Tolba, Mai F.; Rondelli, Catherine M.; Xu, Meixiang; Abdel-Rahman, Sherif Z.

    2015-01-01

    The relationship between oxidative stress and miRNA changes in placenta as a potential mechanism involved in preeclampsia (PE) is not fully elucidated. We investigated the impact of oxidative stress on miRNAs and mRNA expression profiles of genes associated with PE in villous 3A first trimester trophoblast cells exposed to H2O2 at 12 different concentrations (0-1 mM) for 0.5, 4, 24, and 48 h. Cytotoxicity, determined using the SRB assay, was used to calculate the IC50 of H2O2. RNA was extracted after 4 h exposure to H2O2 for miRNA and gene expression profiling. H2O2 exerted a concentration- and time-dependent cytotoxicity on 3A trophoblast cells. Short-term exposure of 3A cells to low concentration of H2O2 (5% of IC50) significantly altered miRNA profile as evidenced by significant changes in 195 out of 595 evaluable miRNAs. Tool for annotations of microRNAs (TAM) analysis indicated that these altered miRNAs fall into 43 clusters and 34 families, with 41 functions identified. Exposure to H2O2 altered mRNA expression of 22 out of 84 key genes involved in dysregulation of placental development. In conclusion, short-term exposure of villous first trimester trophoblasts to low concentrations of H2O2 significantly alters miRNA profile and expression of genes implicated in placental development. PMID:26339600

  16. Relative Fluid Novelty Differentially Alters the Time Course of Limited-Access Ethanol and Water Intake in Selectively Bred High Alcohol Preferring Mice

    PubMed Central

    Linsenbardt, David N.; Boehm, Stephen L.

    2015-01-01

    Background The influence of previous alcohol (ethanol) drinking experience on increasing the rate and amount of future ethanol consumption might be a genetically-regulated phenomenon critical to the development and maintenance of repeated excessive ethanol abuse. We have recently found evidence supporting this view, wherein inbred C57BL/6J (B6) mice develop progressive increases in the rate of binge-ethanol consumption over repeated Drinking-in-the-Dark (DID) ethanol access sessions (i.e. ‘front-loading’). The primary goal of the present study was to evaluate identical parameters in High Alcohol Preferring (HAP) mice to determine if similar temporal alterations in limited-access ethanol drinking develop in a population selected for high ethanol preference/intake under continuous (24hr) access conditions. Methods Using specialized volumetric drinking devices, HAP mice received 14 daily 2 hour DID ethanol or water access sessions. A subset of these mice was then given one day access to the opposite assigned fluid on day 15. Home cage locomotor activity was recorded concomitantly on each day of these studies. The possibility of behavioral/metabolic tolerance was evaluated on day 16 using experimenter administered ethanol. Results The amount of ethanol consumed within the first 15 minutes of access increased markedly over days. However, in contrast to previous observations in B6 mice, ethanol front-loading was also observed on day 15 in mice that only had previous DID experience with water. Furthermore, a decrease in the amount of water consumed within the first 15 minutes of access compared to animals given repeated water access was observed on day 15 in mice with 14 previous days of ethanol access. Conclusions These data further illustrate the complexity and importance of the temporal aspects of limited-access ethanol consumption, and suggest that previous procedural/fluid experience in HAP mice selectively alters the time course of ethanol and water consumption

  17. Long-term alterations in vulnerability to addiction to drugs of abuse and in brain gene expression after early life ethanol exposure.

    PubMed

    Barbier, Estelle; Pierrefiche, Olivier; Vaudry, David; Vaudry, Hubert; Daoust, Martine; Naassila, Mickaël

    2008-12-01

    Exposure to ethanol early in life can have long-lasting implications on brain function and drug of abuse response later in life. The present study investigated in rats, the long-term consequences of pre- and postnatal (early life) ethanol exposure on drug consumption/reward and the molecular targets potentially associated with these behavioral alterations. Since a relationship has been demonstrated between heightened drugs intake and susceptibility to drugs-induced locomotor activity/sensitization, anxiolysis, we tested these behavioral responses, depending on the drug, in control and early life ethanol-exposed animals. Our results show that progeny exposed to early life ethanol displayed increased consumption of ethanol solutions and increased sensitivity to cocaine rewarding effects assessed in the conditioned place preference test. Offspring exposed to ethanol were more sensitive to the anxiolytic effect of ethanol and the increased sensitivity could, at least in part, explain the alteration in the consumption of ethanol for its anxiolytic effects. In addition, the sensitivity to hypothermic effects of ethanol and ethanol metabolism were not altered by early life ethanol exposure. The sensitization to cocaine (20 mg/kg) and to amphetamine (1.2 mg/kg) was increased after early life ethanol exposure and, could partly explain, an increase in the rewarding properties of psychostimulants. Gene expression analysis revealed that expression of a large number of genes was altered in brain regions involved in the reinforcing effects of drugs of abuse. Dopaminergic receptors and transporter binding sites were also down-regulated in the striatum of ethanol-exposed offspring. Such long-term neurochemical alterations in transmitter systems and in the behavioral responses to ethanol and other drugs of abuse may confer an increased liability for addiction in exposed offspring. PMID:18713641

  18. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.

    PubMed

    Bueno, Raphael; Stawiski, Eric W; Goldstein, Leonard D; Durinck, Steffen; De Rienzo, Assunta; Modrusan, Zora; Gnad, Florian; Nguyen, Thong T; Jaiswal, Bijay S; Chirieac, Lucian R; Sciaranghella, Daniele; Dao, Nhien; Gustafson, Corinne E; Munir, Kiara J; Hackney, Jason A; Chaudhuri, Amitabha; Gupta, Ravi; Guillory, Joseph; Toy, Karen; Ha, Connie; Chen, Ying-Jiun; Stinson, Jeremy; Chaudhuri, Subhra; Zhang, Na; Wu, Thomas D; Sugarbaker, David J; de Sauvage, Frederic J; Richards, William G; Seshagiri, Somasekar

    2016-04-01

    We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (∼2%; 4/216) and TRAF7 (∼2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs. PMID:26928227

  19. Association of AMPK subunit gene polymorphisms with growth, feed intake, and feed efficiency in meat-type chickens.

    PubMed

    Jin, Sihua; Moujahid, El Mostafa El; Duan, Zhongyi; Zheng, Jiawei; Qu, Lujiang; Xu, Guiyun; Yang, Ning; Chen, Sirui

    2016-07-01

    Investigations on regulatory genes of feed intake will provide a rational scientific basis to improve future selection indices for more efficient chickens. In the present study, we investigated the association of 13 previously reported SNPs in the chicken adenosine monophosphate activated protein kinase (AMPK) subunits PRKAB1, PRKAG2, and PRKAG3 genes with body weight (BW), body weight gain (BWG), feed intake (FI), and feed conversion ratio (FCR) in two distinct yellow meat-type strains. Six SNPs with a very low minor allele frequency were removed by genotype quality control and data filtering. The experimental population comprised 796 pedigreed males from two strains with different genetic backgrounds, 335 chickens from N202 and 461 chickens from N301. BW at 49 (BW49) and 70 days of age (BW70) and FI (from 49 to 70 days of age) were determined individually. BWG and FCR were computed based on BW and FI in the interval between 49 to 70 days. The results indicated that PRKAB1 SNPs rs14094358 and rs14094362 were significantly associated with BW70, BWG, and FI in the N202 strain, and rs14094361 and rs14094363 were significantly associated with FI and FCR in the N301 strain (P < 0.05). In addition, the PRKAG2 SNP rs14133282 showed significant association with FI in N202, and rs13535812 was significantly associated with BW70 in N202 (P < 0.05). Moreover, the PRKAG3 SNP rs13595570 was significantly associated with BW in N202 (P < 0.05), and significantly associated with FI and FCR in N301 (P < 0.05). Additionally, a two-SNP haplotype comprising rs14094361 and rs14094362 in PRKAB1 was significantly associated with BWG in N202 (P < 0.05). Meanwhile, haplotypes based on two SNPs, rs14133282, and rs13535812, showed significant effects on FI in N202 (P < 0.05). Our findings therefore provide important evidence for association of AMPK subunits polymorphisms with body weight, feed intake, and feed efficiency that may be applied in meat-type chicken breeding programs. PMID

  20. Alteration of gene expression profiles in skeletal muscle of rats exposed to microgravity during a spaceflight

    NASA Technical Reports Server (NTRS)

    Taylor, Wayne E.; Bhasin, Shalender; Lalani, Rukhsana; Datta, Anuj; Gonzalez-Cadavid, Nestor F.

    2002-01-01

    To clarify the mechanism of skeletal muscle wasting during spaceflights, we investigated whether intramuscular gene expression profiles are affected, by using DNA microarray methods. Male rats sent on the 17-day NASA STS-90 Neurolab spaceflight were sacrificed 24 hours after return to earth (MG group). Ground control rats were maintained for 17 days in flight-simulated cages (CS group). Spaceflight induced a 19% and 23% loss of tibialis anterior and gastrocnemius muscle mass, respectively, as compared to ground controls. Muscle RNA was analyzed by the Clontech Atlas DNA expression array in four rats, with two MG/ CS pairs for the tibialis anterior, and one pair for the gastrocnemius. Alterations in gene expression were verified for selected genes by reverse-transcription PCR. In both muscles of MG rats, mRNAs for 12 genes were up-regulated by over 2-fold, and 38 were down-regulated compared to controls. There was inhibition of genes for cell proliferation and growth factor cascades, including cell cycle genes and signal transduction proteins, such as p21 Cip1, retinoblastoma (Rb), cyclins G1/S, -E and -D3, MAP kinase 3, MAD3, and ras related protein RAB2. These data indicate that following exposure to microgravity, there is downregulation of genes involved in regulation of muscle satellite cell replication.

  1. Lack of the Drosophila BEAF insulator proteins alters regulation of genes in the Antennapedia complex.

    PubMed

    Roy, Swarnava; Jiang, Nan; Hart, Craig M

    2011-02-01

    In a screen based on a rough eye phenotype caused by a dominant negative form of the BEAF-32A and BEAF-32B insulator proteins, we previously identified 17 proteins that genetically interact with BEAF. Eleven of these are developmental transcription factors, seven of which are encoded by the Antennapedia complex (ANT-C). While investigating potential reasons for the genetic interactions, we obtained evidence that BEAF plays a role in the regulation of genes in the ANT-C. BEAF does not localize near the transcription start sites of any genes in the ANT-C, indicating that BEAF does not locally affect regulation of these genes. Although BEAF affects chromatin structure or dynamics, we also found no evidence for a general change in binding to polytene chromosomes in the absence of BEAF. However, because we were unable to detect proteins encoded by ANT-C genes in salivary glands, the DREF and MLE proteins were used as proxies to examine binding. This does not rule out limited effects at particular binding sites or the possibility that BEAF might directly interact with certain transcription factors to affect their binding. In contrast, the embryonic expression levels and patterns of four examined ANT-C genes were altered (bcd, Dfd, ftz, pb). A control gene, Dref, was not affected. A full understanding of the regulation of ANT-C genes during development will have to take the role of BEAF into account. PMID:21132442

  2. Characteristics of nobiletin-mediated alteration of gene expression in cultured cell lines

    SciTech Connect

    Nemoto, Kiyomitsu; Ikeda, Ayaka; Yoshida, Chiaki; Kimura, Junko; Mori, Junki; Fujiwara, Hironori; Yokosuka, Akihito; Mimaki, Yoshihiro; Ohizumi, Yasushi; Degawa, Masakuni

    2013-02-15

    Highlights: ► Nobiletin-mediated alterations of gene expression were examined with DNA microarrays. ► Three organ-derived cell lines were treated with 100 μM nobiletin for 24 h. ► In all cell lines, 3 endoplasmic reticulum stress-responsive genes were up-regulated. ► Some cell cycle-regulating and oxidative stress-promoting genes were down-regulated. ► These alterations may contribute to nobiletin-mediated biological effects. -- Abstract: Nobiletin, a polymethoxylated flavonoid that is highly contained in the peels of citrus fruits, exerts a wide variety of beneficial effects, including anti-proliferative effects in cancer cells, repressive effects in hyperlipidemia and hyperglycemia, and ameliorative effects in dementia at in vitro and in vivo levels. In the present study, to further understand the mechanisms of these actions of nobiletin, the nobiletin-mediated alterations of gene expression in three organ-derived cell lines – 3Y1 rat fibroblasts, HuH-7 human hepatocarcinoma cells, and SK-N-SH human neuroblastoma cells – were first examined with DNA microarrays. In all three cell lines, treatments with nobiletin (100 μM) for 24 h resulted in more than 200% increases in the expression levels of five genes, including the endoplasmic reticulum stress-responsive genes Ddit3, Trib3, and Asns, and in less than 50% decreases in the expression levels of seven genes, including the cell cycle-regulating genes Ccna2, Ccne2, and E2f8 and the oxidative stress-promoting gene Txnip. It was also confirmed that in each nobiletin-treated cell line, the levels of the DDIT3 (DNA-damage-inducible transcript 3, also known as CHOP and GADD153) and ASNS (asparagine synthetase) proteins were increased, while the level of the TXNIP (thioredoxin-interacting protein, also known as VDUP1 and TBP-2) protein was decreased. All these findings suggest that nobiletin exerts a wide variety of biological effects, at least partly, through induction of endoplasmic reticulum stress and

  3. PRENATAL ALCOHOL EXPOSURE ALTERS STEADY-STATE AND ACTIVATED GENE EXPRESSION IN THE ADULT RAT BRAIN

    PubMed Central

    Stepien, Katarzyna A.; Lussier, Alexandre A.; Neumann, Sarah M.; Pavlidis, Paul; Kobor, Michael S.; Weinberg, Joanne

    2016-01-01

    Background Prenatal alcohol exposure (PAE) is associated with alterations in numerous physiological systems, including the stress and immune systems . We have previously shown that PAE increases the course and severity of arthritis in an adjuvant-induced arthritis (AA) model. While the molecular mechanisms underlying these effects are not fully known, changes in neural gene expression are emerging as important factors in the etiology of PAE effects. As the prefrontal cortex (PFC) and hippocampus (HPC) play key roles in neuroimmune function, PAE-induced alterations to their transcriptome may underlie abnormal steady-state functions and responses to immune challenge. The current study examined brains from adult PAE and control females from our recent AA study to determine whether PAE causes long-term alterations in gene expression and whether these mediate the altered severity and course of arthritis in PAE females Methods Adult females from PAE, pair-fed [PF], and ad libitum-fed control [C]) groups were injected with either saline or complete Freund’s adjuvant. Animals were terminated at the peak of inflammation or during resolution (days 16 and 39 post-injection, respectively); cohorts of saline-injected PAE, PF and C females were terminated in parallel. Gene expression was analyzed in the PFC and HPC using whole genome mRNA expression microarrays. Results Significant changes in gene expression in both the PFC and HPC were found in PAE compared to controls in response to ethanol exposure alone (saline-injected females), including genes involved in neurodevelopment, apoptosis, and energy metabolism. Moreover, in response to inflammation (adjuvant-injected females), PAE animals showed unique expression patterns, while failing to exhibit the activation of genes and regulators involved in the immune response observed in control and pair-fed animals. Conclusions These results support the hypothesis that PAE affects neuroimmune function at the level of gene expression

  4. Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress.

    PubMed

    Li, Sisi; Papale, Ligia A; Zhang, Qi; Madrid, Andy; Chen, Li; Chopra, Pankaj; Keleş, Sündüz; Jin, Peng; Alisch, Reid S

    2016-02-01

    Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders, including anxiety and post-traumatic stress disorder. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Recently, we found a hippocampal increase of 5hmC in the glucocorticoid receptor gene (Nr3c1) following acute stress, warranting a deeper investigation of stress-related 5hmC levels. Here we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate the first genome-wide profile of hippocampal 5hmC following exposure to acute restraint stress and a one-hour recovery. This approach found a genome-wide disruption in 5hmC associated with acute stress response, primarily in genic regions, and identified known and potentially novel stress-related targets that have a significant enrichment for neuronal ontological functions. Integration of these data with hippocampal gene expression data from these same mice found stress-related hydroxymethylation correlated to altered transcript levels and sequence motif predictions indicated that 5hmC may function by mediating transcription factor binding to these transcripts. Together, these data reveal an environmental impact on this newly discovered epigenetic mark in the brain and represent a critical step toward understanding stress-related epigenetic mechanisms that alter gene expression and can lead to the development of psychiatric disorders. PMID:26598390

  5. Target genes discovery through copy number alteration analysis in human hepatocellular carcinoma.

    PubMed

    Gu, De-Leung; Chen, Yen-Hsieh; Shih, Jou-Ho; Lin, Chi-Hung; Jou, Yuh-Shan; Chen, Chian-Feng

    2013-12-21

    High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma (HCC) cohorts confirmed previously identified frequently mutated somatic genes, such as TP53, CTNNB1 and AXIN1, and identified several novel genes with moderate mutation frequencies, including ARID1A, ARID2, MLL, MLL2, MLL3, MLL4, IRF2, ATM, CDKN2A, FGF19, PIK3CA, RPS6KA3, JAK1, KEAP1, NFE2L2, C16orf62, LEPR, RAC2, and IL6ST. Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling, Wnt/β-catenin signaling, JAK/STAT signaling, and oxidative stress play critical roles in HCC tumorigenesis. Nevertheless, because there are few druggable genes used in HCC therapy, the identification of new therapeutic targets through integrated genomic approaches remains an important task. Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain, copy number alteration (CNA) analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons, homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression. Moreover, integration of CNAs with other high-throughput genomic data, such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models, provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients. PMID:24379610

  6. The effect of dietary fat intake on hepatic gene expression in LG/J AND SM/J mice

    PubMed Central

    2014-01-01

    Background The liver plays a major role in regulating metabolic homeostasis and is vital for nutrient metabolism. Identifying the genetic factors regulating these processes could lead to a greater understanding of how liver function responds to a high-fat diet and how that response may influence susceptibilities to obesity and metabolic syndrome. In this study we examine differences in hepatic gene expression between the LG/J and SM/J inbred mouse strains and how gene expression in these strains is affected by high-fat diet. LG/J and SM/J are known to differ in their responses to a high-fat diet for a variety of obesity- and diabetes-related traits, with the SM/J strain exhibiting a stronger phenotypic response to diet. Results Dietary intake had a significant effect on gene expression in both inbred lines. Genes up-regulated by a high-fat diet were involved in biological processes such as lipid and carbohydrate metabolism; protein and amino acid metabolic processes were down regulated on a high-fat diet. A total of 259 unique transcripts exhibited a significant diet-by-strain interaction. These genes tended to be associated with immune function. In addition, genes involved in biochemical processes related to non-alcoholic fatty liver disease (NAFLD) manifested different responses to diet between the two strains. For most of these genes, SM/J had a stronger response to the high-fat diet than LG/J. Conclusions These data show that dietary fat impacts gene expression levels in SM/J relative to LG/J, with SM/J exhibiting a stronger response. This supports previous data showing that SM/J has a stronger phenotypic response to high-fat diet. Based upon these findings, we suggest that SM/J and its cross with the LG/J strain provide a good model for examining non-alcoholic fatty liver disease and its role in metabolic syndrome. PMID:24499025

  7. Stress and inflammatory gene networks in bovine liver are altered by plane of dietary energy during late pregnancy.

    PubMed

    Khan, M Jawad; Jacometo, Carolina B; Riboni, Mario Vailati; Trevisi, Erminio; Graugnard, Daniel E; Corrêa, Marcio N; Loor, Juan J

    2015-09-01

    fed the lower-energy diet experienced a gradual increase in the inflammatory response. The lack of differences between groups in voluntary feed intake and lactation capacity suggests that nutritional management prepartum triggers different mechanisms that affect ER and oxidative stress along with inflammation. Although no clinical disorders were detected, these alterations expose animals to the development of immuno-metabolic disorders. PMID:25939883

  8. JC virus induces altered patterns of cellular gene expression: Interferon-inducible genes as major transcriptional targets

    SciTech Connect

    Verma, Saguna; Ziegler, Katja; Ananthula, Praveen; Co, Juliene K.G.; Frisque, Richard J.; Yanagihara, Richard; Nerurkar, Vivek R. . E-mail: nerurkar@pbrc.hawaii.edu

    2006-02-20

    Human polyomavirus JC (JCV) infects 80% of the population worldwide. Primary infection, typically occurring during childhood, is asymptomatic in immunocompetent individuals and results in lifelong latency and persistent infection. However, among the severely immunocompromised, JCV may cause a fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Virus-host interactions influencing persistence and pathogenicity are not well understood, although significant regulation of JCV activity is thought to occur at the level of transcription. Regulation of the JCV early and late promoters during the lytic cycle is a complex event that requires participation of both viral and cellular factors. We have used cDNA microarray technology to analyze global alterations in gene expression in JCV-permissive primary human fetal glial cells (PHFG). Expression of more than 400 cellular genes was altered, including many that influence cell proliferation, cell communication and interferon (IFN)-mediated host defense responses. Genes in the latter category included signal transducer and activator of transcription 1 (STAT1), interferon stimulating gene 56 (ISG56), myxovirus resistance 1 (MxA), 2'5'-oligoadenylate synthetase (OAS), and cig5. The expression of these genes was further confirmed in JCV-infected PHFG cells and the human glioblastoma cell line U87MG to ensure the specificity of JCV in inducing this strong antiviral response. Results obtained by real-time RT-PCR and Western blot analyses supported the microarray data and provide temporal information related to virus-induced changes in the IFN response pathway. Our data indicate that the induction of an antiviral response may be one of the cellular factors regulating/controlling JCV replication in immunocompetent hosts and therefore constraining the development of PML.

  9. Rat embryo fibroblast cells expressing human papillomavirus 1a genes exhibit altered growth properties and tumorigenicity.

    PubMed Central

    Green, M; Brackmann, K H; Loewenstein, P M

    1986-01-01

    Human papillomavirus 1a (HPV1a) induces benign tumors (papillomas or warts) in humans under natural conditions of infection but has not been found to replicate significantly in cell culture or in experimental animals. To establish model systems to study the oncogenic properties and expression of HPV genes, we established cell lines by cotransfecting the 3Y1 rat fibroblast cell line with HPV1a DNA constructs containing an intact early gene region and the Tn5 neomycin resistance gene. Most cell lines selected for expression of the neomycin resistance gene by treatment with the antibiotic G-418 contained viral DNA in a high-molecular-weight form. The growth characteristics of several cell lines containing high copy numbers of HPV1a DNA were studied further. They were shown to differ from the parental cell line and from G-418-resistant cell lines that did not incorporate viral DNA in the following properties: morphological alteration, increased cell density at confluence, growth in 0.5% serum, efficient anchorage-independent growth in soft agar, and rapid formation of tumors in nude mice. Those cell lines that possessed altered growth properties and tumorigenicity were found to express abundant quantities of polyadenylated virus-specific RNA species in the cytoplasm. Images PMID:3023676

  10. Altered epigenetic regulation of homeobox genes in human oral squamous cell carcinoma cells

    SciTech Connect

    Marcinkiewicz, Katarzyna M.; Gudas, Lorraine J.

    2014-01-01

    To gain insight into oral squamous cell carcinogenesis, we performed deep sequencing (RNAseq) of non-tumorigenic human OKF6-TERT1R and tumorigenic SCC-9 cells. Numerous homeobox genes are differentially expressed between OKF6-TERT1R and SCC-9 cells. Data from Oncomine, a cancer microarray database, also show that homeobox (HOX) genes are dysregulated in oral SCC patients. The activity of Polycomb repressive complexes (PRC), which causes epigenetic modifications, and retinoic acid (RA) signaling can control HOX gene transcription. HOXB7, HOXC10, HOXC13, and HOXD8 transcripts are higher in SCC-9 than in OKF6-TERT1R cells; using ChIP (chromatin immunoprecipitation) we detected PRC2 protein SUZ12 and the epigenetic H3K27me3 mark on histone H3 at these genes in OKF6-TERT1R, but not in SCC-9 cells. In contrast, IRX1, IRX4, SIX2 and TSHZ3 transcripts are lower in SCC-9 than in OKF6-TERT1R cells. We detected SUZ12 and the H3K27me3 mark at these genes in SCC-9, but not in OKF6-TERT1R cells. SUZ12 depletion increased HOXB7, HOXC10, HOXC13, and HOXD8 transcript levels and decreased the proliferation of OKF6-TERT1R cells. Transcriptional responses to RA are attenuated in SCC-9 versus OKF6-TERT1R cells. SUZ12 and H3K27me3 levels were not altered by RA at these HOX genes in SCC-9 and OKF6-TERT1R cells. We conclude that altered activity of PRC2 is associated with dysregulation of homeobox gene expression in human SCC cells, and that this dysregulation potentially plays a role in the neoplastic transformation of oral keratinocytes. - Highlights: • RNAseq elucidates differences between non-tumorigenic and tumorigenic oral keratinocytes. • Changes in HOX mRNA in SCC-9 vs. OKF6-TERT1R cells are a result of altered epigenetic regulation. • RNAseq shows that retinoic acid (RA) influences gene expression in both OKF6-TERT1R and SCC-9 cells.

  11. Alterations in Hepatic FGF21, Co-Regulated Genes, and Upstream Metabolic Genes in Response to Nutrition, Ketosis and Inflammation in Peripartal Holstein Cows

    PubMed Central

    Akbar, Haji; Batistel, Fernanda; Drackley, James K.; Loor, Juan J.

    2015-01-01

    In rodents, fibroblast growth factor 21 (FGF21) has emerged as a key metabolic regulator produced by liver. To gather preliminary data on the potential importance of FGF1, co-regulated genes, and upstream metabolic genes, we examined the hepatic mRNA expression in response to nutrition and inflammation in dairy cows. In experiment 1, induction of ketosis through feed restriction on d 5 postpartum upregulated FGF21, its co-receptor KLB, and PPARA but only elicited a numerical increase in serum FGF21 concentration. In experiment 2, cows in control (CON) or receiving 50 g/d of L-carnitine (C50) from -14 through 21 d had increased FGF21, PPARA, and NFIL3 on d 10 compared with d 2 postpartum. In contrast, compared with CON and C50, 100 g/d L-carnitine (C100) resulted in lower FGF21, KLB, ANGPTL4, and ARNTL expression on d 10. In experiment 3, cows were fed during the dry period either a higher-energy (OVE; 1.62 Mcal/kg DM) or lower-energy (CON; 1.34 Mcal/kg DM) diet and received 0 (OVE:N, CON:N) or 200 μg of LPS (OVE:Y, CON:Y) into the mammary gland at d 7 postpartum. For FGF21 mRNA expression in CON, the LPS challenge (CON:Y) prevented a decrease in expression between d 7 and 14 postpartum such that cows in CON:N had a 4-fold lower expression on d 14 compared with d 7. The inflammatory stimulus induced by LPS in CON:Y resulted in upregulation of PPARA on d 14 to a similar level as cows in OVE:N. In OVE:Y, expression of PPARA was lower than CON:N on d 7 and remained unchanged on d 14. On d 7, LPS led to a 4-fold greater serum FGF21 only in OVE but not in CON cows. In fact, OVE:Y reached the same serum FGF21 concentration as CON:N, suggesting a carryover effect of dietary energy level on signaling mechanisms within liver. Overall, results indicate that nutrition, ketosis, and inflammation during the peripartal period can alter hepatic FGF21, co-regulated genes, and upstream metabolic genes to various extents. The functional outcome of these changes merits further study

  12. Alterations in Mc1r gene expression are associated with regressive pigmentation in Astyanax cavefish.

    PubMed

    Stahl, Bethany A; Gross, Joshua B

    2015-11-01

    Diverse changes in coloration across distant taxa are mediated through alterations in certain highly conserved pigmentation genes. Among these genes, Mc1r is a frequent target for mutation, and many documented alterations involve coding sequence changes. We investigated whether regulatory mutations in Mc1r may also contribute to pigmentation loss in the blind Mexican cavefish, Astyanax mexicanus. This species comprises multiple independent cave populations that have evolved reduced (or absent) melanic pigmentation as a consequence of living in darkness for millions of generations. Among the most salient cave-associated traits, complete absence (albinism) or reduced levels of pigmentation (brown) have long been the focus of degenerative pigmentation research in Astyanax. These two Mendelian traits have been linked to specific coding mutations in Oca2 (albinism) and Mc1r (brown). However, four of the seven caves harboring the brown phenotype exhibit unaffected coding sequences compared to surface fish. Thus, diverse genetic changes involving the same genes likely impact reduced pigmentation among cavefish populations. Using both sequence and expression analyses, we show that certain cave-dwelling populations harboring the brown mutation have substantial alterations to the putative Mc1r cis-regulatory region. Several of these sequence mutations in the Mc1r 5' region were present across multiple, independent cave populations. This study suggests that pigmentation reduction in Astyanax cavefish evolves through a combination of both coding and cis-regulatory mutations. Moreover, this study represents one of the first attempts to identify regulatory alterations linked to regressive changes in cave-dwelling populations of A. mexicanus. PMID:26462499

  13. Altered surfactant protein A gene expression and protein metabolism associated with repeat exposure to inhaled endotoxin.

    PubMed

    George, Caroline L S; White, Misty L; O'Neill, Marsha E; Thorne, Peter S; Schwartz, David A; Snyder, Jeanne M

    2003-12-01

    Chronically inhaled endotoxin, which is ubiquitous in many occupational and domestic environments, can adversely affect the respiratory system resulting in an inflammatory response and decreased lung function. Surfactant-associated protein A (SP-A) is part of the lung innate immune system and may attenuate the inflammatory response in various types of lung injury. Using a murine model to mimic occupational exposures to endotoxin, we hypothesized that SP-A gene expression and protein would be elevated in response to repeat exposure to inhaled grain dust and to purified lipopolysaccharide (LPS). Our results demonstrate that repeat exposure to inhaled endotoxin, either in the form of grain dust or purified LPS, results in increased whole lung SP-A gene expression and type II alveolar epithelial cell hyperplasia, whereas SP-A protein levels in lung lavage fluid are decreased. Furthermore, these alterations in SP-A gene activity and protein metabolism are dependent on an intact endotoxin signaling system. PMID:12922979

  14. Altered circadian rhythm of the clock genes in fibrotic livers induced by carbon tetrachloride.

    PubMed

    Chen, Peng; Kakan, Xiamusiya; Zhang, Jianfa

    2010-04-16

    Disruption in circadian rhythms either by mutation in mice or by shiftwork in people, is associated with an increased risk for the development of multiple organ diseases. In turn, organ disease may influence the function of clock genes and peripheral circadian systems. Here we showed that hepatic fibrosis induced by carbon tetrachloride in mice leads to alterations in the circadian rhythms of hepatic clock genes. Especially, we found an impaired daily Cry2 rhythm in the fibrotic livers, with markedly decreased levels during the day time while compared with control livers. Associatively, the expressions of two important clock-regulated genes peroxisome proliferator-activated receptor alpha and cytochrome P450 oxidoreductase lost circadian rhythm with significantly decreased levels during the light-dark (12/12h) cycle in fibrotic livers. PMID:20233594

  15. Intracellular Streptococcus pyogenes in human macrophages display an altered gene expression profile.

    PubMed

    Hertzén, Erika; Johansson, Linda; Kansal, Rita; Hecht, Alexander; Dahesh, Samira; Janos, Marton; Nizet, Victor; Kotb, Malak; Norrby-Teglund, Anna

    2012-01-01

    Streptococcus pyogenes is an important human pathogen, which has recently gained recognition as an intracellular microorganism during the course of severe invasive infections such as necrotizing fasciitis. Although the surface anchored M protein has been identified as a pivotal factor affecting phagosomal maturation and S. pyogenes survival within macrophages, the overall transcriptional profile required for the pathogen to adapt and persist intracellularly is as of yet unknown. To address this, the gene expression profile of S. pyogenes within human macrophages was determined and compared to that of extracellular bacteria using customized microarrays and real-time qRT-PCR. In order to model the early phase of infection involving adaptation to the intracellular compartment, samples were collected 2h post-infection. Microarray analysis revealed that the expression of 145 streptococcal genes was significantly altered in the intracellular environment. The majority of differentially regulated genes were associated with metabolic and energy-dependent processes. Key up-regulated genes in early phase intracellular bacteria were ihk and irr, encoding a two-component gene regulatory system (TCS). Comparison of gene expression of selected genes at 2h and 6h post-infection revealed a dramatic shift in response regulators over time with a down-regulation of ihk/irr genes concurring with an up-regulation of the covR/S TCS. In re-infection assays, intracellular bacteria from the 6h time point exhibited significantly greater survival within macrophages than did bacteria collected at the 2h time point. An isogenic S. pyogenes mutant deficient in ihk/irr displayed significantly reduced bacterial counts when compared to wild-type bacteria following infection of macrophages. The findings illustrate how gene expression of S. pyogenes during the intracellular life cycle is fine-tuned by temporal expression of specific two-component systems. PMID:22511985

  16. Alterations in the K-ras and p53 genes in rat lung tumors

    SciTech Connect

    Belinsky, S.A.; Swafford, D.S.; Finch, G.L.; Mitchell, C.E.

    1997-06-01

    Activation of the K-ras protooncogene and inactivation of the p53 tumor suppressor gene are events common to many types of human cancers. Molecular epidemiology studies have associated mutational profiles in these genes with specific exposures. The purpose of this paper is to review investigations that have examined the role of the K-ras and p53 genes in lung tumors induced in the F344 rat by mutagenic and nonmutagenic exposures. Mutation profiles within the K-ras and p53 genes, if present in rat lung tumors, would help to define some of the molecular mechanisms underlying cancer induction by various environmental agents. Pulmonary adenocarcinomas or squamous cell carcinomas were induced by tetranitromethane (TNM), 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), beryllium metal, plutonium-239, X-ray, diesel exhaust, or carbon black. These agents were chosen because the tumors they produced could arise via different types of DNA damage. Mutation of the K-ras gene was determined by approaches that included DNA transfection, direct sequencing, mismatch hybridization, and restriction fragment length polymorphism analysis. The frequency for mutation of the K-ras gene was exposure dependent. The transition mutations formed could have been derived from deamination of cytosine. Alteration in the p53 gene was assessed by immunohistochemical analysis for p53 protein and single-strand conformation polymorphism (SSCP) analysis of exons 4 to 9. None of the 93 adenocarinomas examined was immunoreactive toward the anti-p53 antibody CM1. In contrast, 14 of 71 squamous cell carcinomas exhibited nuclear p53 immunoreactivity with no correlation to type of exposure. However, SSCP analysis only detected mutations in 2 of 14 squamous cell tumors that were immunoreactive, suggesting that protein stabilization did not stem from mutations within the p53 gene. Thus, the p53 gene does not appear to be involved in the genesis of most rat lung tumors. 2 figs., 2 tabs., 48 refs.

  17. Altered Clock Gene Expression in Obese Visceral Adipose Tissue Is Associated with Metabolic Syndrome

    PubMed Central

    C. Figueroa, Ana Lucia; Aranda, Gloria; Momblan, Dulce; Carmona, Francesc; Gomis, Ramon

    2014-01-01

    Clock gene expression was associated with different components of metabolic syndrome (MS) in human adipose tissue. However, no study has been done to compare the expression of clock genes in visceral adipose tissue (VAT) from lean and obese subjects and its clinical implications. Therefore, we studied in lean and obese women the endogenous 24 h expression of clock genes in isolated adipocytes and its association with MS components. VAT was obtained from lean (BMI 21–25 kg/m2; n = 21) and morbidly obese women (BMI >40 kg/m2; n = 28). The 24 h pattern of clock genes was analyzed every 6 hours using RT-PCR. Correlation of clinical data was studied by Spearman analysis. The 24 h pattern of clock genes showed that obesity alters the expression of CLOCK, BMAL1, PER1, CRY2 and REV-ERB ALPHA in adipocytes with changes found in CRY2 and REV-ERB ALPHA throughout the 24 h period. The same results were confirmed in VAT and stromal cells (SC) showing an upregulation of CRY2 and REV-ERB ALPHA from obese women. A positive correlation was observed for REV-ERB ALPHA gene expression with BMI and waist circumference in the obese population. Expression of ROR ALPHA was correlated with HDL levels and CLOCK with LDL. Obese subjects with MS exhibited positive correlation in the PER2 gene with LDL cholesterol, whereas REV-ERB ALPHA was correlated with waist circumference. We identified CRY2 and REV-ERB ALPHA as the clock genes upregulated in obesity during the 24 h period and that REV-ERB ALPHA is an important gene associated with MS. PMID:25365257

  18. Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens

    PubMed Central

    Zhao, Changjiu; Eisinger, Brian Earl; Driessen, Terri M.; Gammie, Stephen C.

    2014-01-01

    Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions. PMID:25414651

  19. Intracellular Streptococcus pyogenes in Human Macrophages Display an Altered Gene Expression Profile

    PubMed Central

    Hertzén, Erika; Johansson, Linda; Kansal, Rita; Hecht, Alexander; Dahesh, Samira; Janos, Marton; Nizet, Victor; Kotb, Malak; Norrby-Teglund, Anna

    2012-01-01

    Streptococcus pyogenes is an important human pathogen, which has recently gained recognition as an intracellular microorganism during the course of severe invasive infections such as necrotizing fasciitis. Although the surface anchored M protein has been identified as a pivotal factor affecting phagosomal maturation and S. pyogenes survival within macrophages, the overall transcriptional profile required for the pathogen to adapt and persist intracellularly is as of yet unknown. To address this, the gene expression profile of S. pyogenes within human macrophages was determined and compared to that of extracellular bacteria using customized microarrays and real-time qRT-PCR. In order to model the early phase of infection involving adaptation to the intracellular compartment, samples were collected 2h post-infection. Microarray analysis revealed that the expression of 145 streptococcal genes was significantly altered in the intracellular environment. The majority of differentially regulated genes were associated with metabolic and energy-dependent processes. Key up-regulated genes in early phase intracellular bacteria were ihk and irr, encoding a two-component gene regulatory system (TCS). Comparison of gene expression of selected genes at 2h and 6h post-infection revealed a dramatic shift in response regulators over time with a down-regulation of ihk/irr genes concurring with an up-regulation of the covR/S TCS. In re-infection assays, intracellular bacteria from the 6h time point exhibited significantly greater survival within macrophages than did bacteria collected at the 2h time point. An isogenic S. pyogenes mutant deficient in ihk/irr displayed significantly reduced bacterial counts when compared to wild-type bacteria following infection of macrophages. The findings illustrate how gene expression of S. pyogenes during the intracellular life cycle is fine-tuned by temporal expression of specific two-component systems. PMID:22511985

  20. NF-Y activates genes of metabolic pathways altered in cancer cells

    PubMed Central

    Benatti, Paolo; Chiaramonte, Maria Luisa; Lorenzo, Mariangela; Hartley, John A.; Hochhauser, Daniel; Gnesutta, Nerina; Mantovani, Roberto; Imbriano, Carol; Dolfini, Diletta

    2016-01-01

    The trimeric transcription factor NF-Y binds to the CCAAT box, an element enriched in promoters of genes overexpressed in tumors. Previous studies on the NF-Y regulome identified the general term metabolism as significantly enriched. We dissect here in detail the targeting of metabolic genes by integrating analysis of NF-Y genomic binding and profilings after inactivation of NF-Y subunits in different cell types. NF-Y controls de novo biosynthetic pathways of lipids, teaming up with the master SREBPs regulators. It activates glycolytic genes, but, surprisingly, is neutral or represses mitochondrial respiratory genes. NF-Y targets the SOCG (Serine, One Carbon, Glycine) and Glutamine pathways, as well as genes involved in the biosynthesis of polyamines and purines. Specific cancer-driving nodes are generally under NF-Y control. Altogether, these data delineate a coherent strategy to promote expression of metabolic genes fuelling anaerobic energy production and other anabolic pathways commonly altered in cancer cells. PMID:26646448

  1. Long-Term Oil Contamination Alters the Molecular Ecological Networks of Soil Microbial Functional Genes.

    PubMed

    Liang, Yuting; Zhao, Huihui; Deng, Ye; Zhou, Jizhong; Li, Guanghe; Sun, Bo

    2016-01-01

    With knowledge on microbial composition and diversity, investigation of within-community interactions is a further step to elucidate microbial ecological functions, such as the biodegradation of hazardous contaminants. In this work, microbial functional molecular ecological networks were studied in both contaminated and uncontaminated soils to determine the possible influences of oil contamination on microbial interactions and potential functions. Soil samples were obtained from an oil-exploring site located in South China, and the microbial functional genes were analyzed with GeoChip, a high-throughput functional microarray. By building random networks based on null model, we demonstrated that overall network structures and properties were significantly different between contaminated and uncontaminated soils (P < 0.001). Network connectivity, module numbers, and modularity were all reduced with contamination. Moreover, the topological roles of the genes (module hub and connectors) were altered with oil contamination. Subnetworks of genes involved in alkane and polycyclic aromatic hydrocarbon degradation were also constructed. Negative co-occurrence patterns prevailed among functional genes, thereby indicating probable competition relationships. The potential "keystone" genes, defined as either "hubs" or genes with highest connectivities in the network, were further identified. The network constructed in this study predicted the potential effects of anthropogenic contamination on microbial community co-occurrence interactions. PMID:26870020

  2. Long-Term Oil Contamination Alters the Molecular Ecological Networks of Soil Microbial Functional Genes

    PubMed Central

    Liang, Yuting; Zhao, Huihui; Deng, Ye; Zhou, Jizhong; Li, Guanghe; Sun, Bo

    2016-01-01

    With knowledge on microbial composition and diversity, investigation of within-community interactions is a further step to elucidate microbial ecological functions, such as the biodegradation of hazardous contaminants. In this work, microbial functional molecular ecological networks were studied in both contaminated and uncontaminated soils to determine the possible influences of oil contamination on microbial interactions and potential functions. Soil samples were obtained from an oil-exploring site located in South China, and the microbial functional genes were analyzed with GeoChip, a high-throughput functional microarray. By building random networks based on null model, we demonstrated that overall network structures and properties were significantly different between contaminated and uncontaminated soils (P < 0.001). Network connectivity, module numbers, and modularity were all reduced with contamination. Moreover, the topological roles of the genes (module hub and connectors) were altered with oil contamination. Subnetworks of genes involved in alkane and polycyclic aromatic hydrocarbon degradation were also constructed. Negative co-occurrence patterns prevailed among functional genes, thereby indicating probable competition relationships. The potential “keystone” genes, defined as either “hubs” or genes with highest connectivities in the network, were further identified. The network constructed in this study predicted the potential effects of anthropogenic contamination on microbial community co-occurrence interactions. PMID:26870020

  3. Identification of a chromosome 18q gene that is altered in colorectal cancers

    SciTech Connect

    Fearon, E.R.; Nigro, J.M.; Simons, J.W.; Ruppert, J.M.; Preisinger, A.C.; Vogelstein, B.; Cho, K.R.; Kern, S.E.; Hamilton, S.R. ); Thomas, G. )

    1990-01-05

    A contiguous stretch of DNA comprising 370 kilobase pairs (kb) has now been cloned from a region of chromosome 18q suspected to reside near this gene. Potential exons in the 370-kb region were defined by human-rodent sequence identities, and the expression of potential exons was assessed by an exon-connection strategy based on the polymerase chain reaction. Expressed exons were used as probes for cDNA screening to obtain clones that encoded a portion of a gene termed DCC; this cDNA was encoded by at least eight exons within the 370-kb genomic region. The predicted amino acid sequence of the cDNA specified a protein with sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested. Somatic mutations within the DCC gene observed in colorectal cancers included a homozygous deletion of the 5{prime} end of the gene, a point mutation within one of the introns, and ten examples of DNA insertions within a 0.17-kb fragment immediately downstream of one of the exons. The DCC gene may play a role in the pathogenesis of human colorectal neoplasia, perhaps through alteration of the normal cell-cell interactions controlling growth.

  4. Impact of ovariohysterectomy and food intake on body composition, physical activity, and adipose gene expression in cats.

    PubMed

    Belsito, K R; Vester, B M; Keel, T; Graves, T K; Swanson, K S

    2009-02-01

    physical activity levels and several genes associated with lipid metabolism (decreased lipoprotein lipase), food intake (decreased leptin expression), and insulin insensitivity (increased interleukin-6). By identifying these changes, targets for nutritional intervention or lifestyle management have been identified that may curb the risk of obesity and related disorders in spayed cats. PMID:18997063

  5. Embryonic Atrazine Exposure Elicits Alterations in Genes Associated with Neuroendocrine Function in Adult Male Zebrafish.

    PubMed

    Wirbisky, Sara E; Sepúlveda, Maria S; Weber, Gregory J; Jannasch, Amber S; Horzmann, Katharine A; Freeman, Jennifer L

    2016-09-01

    The developmental origins of health and disease (DOHaD) hypothesis states that exposure to environmental stressors early in life can elicit genome and epigenome changes resulting in an increased susceptibility of a disease state during adulthood. Atrazine, a common agricultural herbicide used throughout the Midwestern United States, frequently contaminates potable water supplies and is a suspected endocrine disrupting chemical. In our previous studies, zebrafish was exposed to 0, 0.3, 3, or 30 parts per billion (μg/l) atrazine through embryogenesis, rinsed, and allowed to mature to adulthood. A decrease in spawning was observed with morphological alterations in offspring. In addition, adult females displayed an increase in ovarian progesterone and follicular atresia, alterations in levels of a serotonin metabolite and serotonin turnover in brain tissue, and transcriptome changes in brain and ovarian tissue supporting neuroendocrine alterations. As reproductive dysfunction is also influenced by males, this study assessed testes histology, hormone levels, and transcriptomic profiles of testes and brain tissue in the adult males. The embryonic atrazine exposure resulted in no alterations in body or testes weight, gonadosomatic index, testes histology, or levels of 11-ketotestosterone or testosterone. To further investigate potential alterations, transcriptomic profiles of adult male testes and brain tissue was completed. This analysis demonstrated alterations in genes associated with abnormal cell and neuronal growth and morphology; molecular transport, quantity, and production of steroid hormones; and neurotransmission with an emphasis on the hypothalamus-pituitary-adrenal and hypothalamus-pituitary-thyroid axes. Overall, this data indicate future studies should focus on additional neuroendocrine endpoints to determine potential functional impairments. PMID:27413107

  6. Molecular classification of thyroid lesions by combined testing for miRNA gene expression and somatic gene alterations

    PubMed Central

    Wylie, Dennis; Beaudenon‐Huibregtse, Sylvie; Haynes, Brian C.; Giordano, Thomas J.

    2016-01-01

    Abstract Multiple molecular markers contribute to the pathogenesis of thyroid cancer and can provide valuable information to improve disease diagnosis and patient management. We performed a comprehensive evaluation of miRNA gene expression in diverse thyroid lesions (n = 534) and developed predictive models for the classification of thyroid nodules, alone or in combination with genotyping. Expression profiling by reverse transcription‐quantitative polymerase chain reaction in surgical specimens (n = 257) identified specific miRNAs differentially expressed in 17 histopathological categories. Eight supervised machine learning algorithms were trained to discriminate benign from malignant lesions and evaluated for accuracy and robustness. The selected models showed invariant area under the receiver operating characteristic curve (AUC) in cross‐validation (0.89), optimal AUC (0.94) in an independent set of preoperative thyroid nodule aspirates (n = 235), and classified 92% of benign lesions as low risk/negative and 92% of malignant lesions as high risk/positive. Surgical and preoperative specimens were further tested for the presence of 17 validated oncogenic gene alterations in the BRAF, RAS, RET or PAX8 genes. The miRNA‐based classifiers complemented and significantly improved the diagnostic performance of the 17‐mutation panel (p < 0.001 for McNemar's tests). In a subset of resected tissues (n = 54) and in an independent set of thyroid nodules with indeterminate cytology (n = 42), the optimized ThyraMIR Thyroid miRNA Classifier increased diagnostic sensitivity by 30–39% and correctly classified 100% of benign nodules negative by the 17‐mutation panel. In contrast, testing with broad targeted next‐generation sequencing panels decreased diagnostic specificity by detecting additional mutations of unknown clinical significance in 19–39% of benign lesions. Our results demonstrate that, independent of mutational status, mi

  7. Molecular classification of thyroid lesions by combined testing for miRNA gene expression and somatic gene alterations.

    PubMed

    Wylie, Dennis; Beaudenon-Huibregtse, Sylvie; Haynes, Brian C; Giordano, Thomas J; Labourier, Emmanuel

    2016-04-01

    Multiple molecular markers contribute to the pathogenesis of thyroid cancer and can provide valuable information to improve disease diagnosis and patient management. We performed a comprehensive evaluation of miRNA gene expression in diverse thyroid lesions (n = 534) and developed predictive models for the classification of thyroid nodules, alone or in combination with genotyping. Expression profiling by reverse transcription-quantitative polymerase chain reaction in surgical specimens (n = 257) identified specific miRNAs differentially expressed in 17 histopathological categories. Eight supervised machine learning algorithms were trained to discriminate benign from malignant lesions and evaluated for accuracy and robustness. The selected models showed invariant area under the receiver operating characteristic curve (AUC) in cross-validation (0.89), optimal AUC (0.94) in an independent set of preoperative thyroid nodule aspirates (n = 235), and classified 92% of benign lesions as low risk/negative and 92% of malignant lesions as high risk/positive. Surgical and preoperative specimens were further tested for the presence of 17 validated oncogenic gene alterations in the BRAF, RAS, RET or PAX8 genes. The miRNA-based classifiers complemented and significantly improved the diagnostic performance of the 17-mutation panel (p < 0.001 for McNemar's tests). In a subset of resected tissues (n = 54) and in an independent set of thyroid nodules with indeterminate cytology (n = 42), the optimized ThyraMIR Thyroid miRNA Classifier increased diagnostic sensitivity by 30-39% and correctly classified 100% of benign nodules negative by the 17-mutation panel. In contrast, testing with broad targeted next-generation sequencing panels decreased diagnostic specificity by detecting additional mutations of unknown clinical significance in 19-39% of benign lesions. Our results demonstrate that, independent of mutational status, miRNA expression profiles are strongly

  8. Berry intake changes hepatic gene expression and DNA methylation patterns associated with high-fat diet.

    PubMed

    Heyman-Lindén, Lovisa; Seki, Yoshinori; Storm, Petter; Jones, Helena A; Charron, Maureen J; Berger, Karin; Holm, Cecilia

    2016-01-01

    The liver is a critical organ for regulation of energy homeostasis and fatty liver disease is closely associated with obesity and insulin resistance. We have previously found that lingonberries, blackcurrants and bilberries prevent, whereas açai berries exacerbate, the development of hepatic steatosis and obesity in the high-fat (HF)-fed C57BL/6J mouse model. In this follow-up study, we investigated the mechanisms behind these effects. Genome-wide hepatic gene expression profiling indicates that the protective effects of lingonberries and bilberries are accounted for by several-fold downregulation of genes involved in acute-phase and inflammatory pathways (e.g. Saa1, Cxcl1, Lcn2). In contrast, açai-fed mice exhibit marked upregulation of genes associated with steatosis (e.g. Cfd, Cidea, Crat) and lipid and cholesterol biosynthesis, which is in line with the exacerbation of HF-induced hepatic steatosis in these mice. In silico transcription factor analysis together with immunoblot analysis identified NF-κB, STAT3 and mTOR as upstream regulators involved in mediating the observed transcriptional effects. To gain further insight into mechanisms involved in the gene expression changes, the HELP-tagging assay was used to identify differentially methylated CpG sites. Compared to the HF control group, lingonberries induced genome-wide hypermethylation and specific hypermethylation of Ncor2, encoding the corepressor NCoR/SMRT implicated in the regulation of pathways of metabolic homeostasis and inflammation. We conclude that the beneficial metabolic effects of lingonberries and bilberries are associated with downregulation of inflammatory pathways, whereas for blackcurrants, exerting similar metabolic effects, different mechanisms of action appear to dominate. NF-κB, STAT3 and mTOR are potential targets of the health-promoting effects of berries. PMID:26423886

  9. Simulated microgravity alters the expression of key genes involved in fracture healing

    NASA Astrophysics Data System (ADS)

    McCabe, N. Patrick; Androjna, Caroline; Hill, Esther; Globus, Ruth K.; Midura, Ronald J.

    2013-11-01

    Fracture healing in animal models has been shown to be altered in both ground based analogs of spaceflight and in those exposed to actual spaceflight. The molecular mechanisms behind altered fracture healing as a result of chronic exposure to microgravity remain to be elucidated. This study investigates temporal gene expression of multiple factors involved in secondary fracture healing, specifically those integral to the development of a soft tissue callus and the transition to that of hard tissue. Skeletally mature female rats were subjected to a 4 week period of simulated microgravity and then underwent a closed femoral fracture procedure. Thereafter, they were reintroduced to the microgravity and allowed to heal for a 1 or 2 week period. A synchronous group of weight bearing rats was used as a normal fracture healing control. Utilizing Real-Time quantitative PCR on mRNA from fracture callus tissue, we found significant reductions in the levels of transcripts associated with angiogenesis, chondrogenesis, and osteogenesis. These data suggest an altered fracture healing process in a simulated microgravity environment, and these alterations begin early in the healing process. These findings may provide mechanistic insight towards developing countermeasure protocols to mitigate these adaptations.

  10. Calcium homeostasis is altered in skeletal muscle of spontaneously hypertensive rats: cytofluorimetric and gene expression analysis.

    PubMed

    Liantonio, Antonella; Camerino, Giulia M; Scaramuzzi, Antonia; Cannone, Maria; Pierno, Sabata; De Bellis, Michela; Conte, Elena; Fraysse, Bodvael; Tricarico, Domenico; Conte Camerino, Diana

    2014-10-01

    Hypertension is often associated with skeletal muscle pathological conditions related to function and metabolism. The mechanisms underlying the development of these pathological conditions remain undefined. Because calcium homeostasis is a biomarker of muscle function, we assessed whether it is altered in hypertensive muscles. We measured resting intracellular calcium and store-operated calcium entry (SOCE) in fast- and slow-twitch muscle fibers from normotensive Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs) by cytofluorimetric technique and determined the expression of SOCE gene machinery by real-time PCR. Hypertension caused a phenotype-dependent dysregulation of calcium homeostasis; the resting intracellular calcium of extensor digitorum longus and soleus muscles of SHRs were differently altered with respect to the related muscle of normotensive animals. In addition, soleus muscles of SHR showed reduced activity of the sarcoplasmic reticulum and decreased sarcolemmal calcium permeability at rest and after SOCE activation. Accordingly, we found an alteration of the expression levels of some SOCE components, such as stromal interaction molecule 1, calcium release-activated calcium modulator 1, and transient receptor potential canonical 1. The hypertension-induced alterations of calcium homeostasis in the soleus muscle of SHRs occurred with changes of some functional outcomes as excitability and resting chloride conductance. We provide suitable targets for therapeutic interventions aimed at counterbalancing muscle performance decline in hypertension, and propose the reported calcium-dependent parameters as indexes to predict how the antihypertensive drugs could influence muscle function. PMID:25084345

  11. Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma

    PubMed Central

    Totoki, Yasushi; Yoshida, Akihiko; Hosoda, Fumie; Nakamura, Hiromi; Hama, Natsuko; Ogura, Koichi; Yoshida, Aki; Fujiwara, Tomohiro; Arai, Yasuhito; Toguchida, Junya; Tsuda, Hitoshi; Miyano, Satoru; Kawai, Akira

    2014-01-01

    Chondrosarcoma is the second most frequent malignant bone tumor. However, the etiological background of chondrosarcomagenesis remains largely unknown, along with details on molecular alterations and potential therapeutic targets. Massively parallel paired-end sequencing of whole genomes of 10 primary chondrosarcomas revealed that the process of accumulation of somatic mutations is homogeneous irrespective of the pathological subtype or the presence of IDH1 mutations, is unique among a range of cancer types, and shares significant commonalities with that of prostate cancer. Clusters of structural alterations localized within a single chromosome were observed in four cases. Combined with targeted resequencing of additional cartilaginous tumor cohorts, we identified somatic alterations of the COL2A1 gene, which encodes an essential extracellular matrix protein in chondroskeletal development, in 19.3% of chondrosarcoma and 31.7% of enchondroma cases. Epigenetic regulators (IDH1 and YEATS2) and an activin/BMP signal component (ACVR2A) were recurrently altered. Furthermore, a novel FN1-ACVR2A fusion transcript was observed in both chondrosarcoma and osteochondromatosis cases. With the characteristic accumulative process of somatic changes as a background, molecular defects in chondrogenesis and aberrant epigenetic control are primarily causative of both benign and malignant cartilaginous tumors. PMID:25024164

  12. A Polymorphism in the 5′-Untranslated Region of the Porcine Cholecystokinin Type A Receptor Gene Affects Feed Intake and Growth

    PubMed Central

    Houston, R. D.; Haley, C. S.; Archibald, A. L.; Cameron, N. D.; Plastow, G. S.; Rance, K. A.

    2006-01-01

    The location and utilization of quantitative trait loci (QTL) and candidate genes with significant effects on economically important traits are becoming increasingly important in livestock breeding programs. The porcine cholecystokinin type A receptor (CCKAR) is a candidate gene for performance traits, due to its known role in the physiological control of feed intake, satiety, and obesity. We investigated the association of CCKAR polymorphisms with feeding, growth, and efficiency traits in an F2 population derived from a cross between Meishan and Large White founder animals and in lines of Large White pigs that had been divergently selected on the basis of lean growth efficiency traits. In the F2 population, CCKAR genotype was significantly associated with daily feed intake and average daily gain. The effects of the polymorphisms were then assessed in a larger-scale analysis of segregating commercial lines. A newly discovered single-nucleotide polymorphism (SNP) within the 5′-untranslated region (5′-UTR) had highly significant effects on feed intake, average daily gain, and days to 110 kg, which were not seen for a previously reported SNP within the CCKAR gene. Furthermore, we provide evidence that the novel SNP disrupts the binding of the YY1 transcription factor, which raises the possibility that it is the causal variant. The 5′-UTR SNP could be utilized as a molecular genetic test for increased feed intake, faster lean growth, and reduced days to market weight in segregating commercial lines. PMID:16951077

  13. Somatic Copy Number Alterations at Oncogenic Loci Show Diverse Correlations with Gene Expression

    PubMed Central

    Roszik, Jason; Wu, Chang-Jiun; Siroy, Alan E.; Lazar, Alexander J.; Davies, Michael A; Woodman, Scott E; Kwong, Lawrence N

    2016-01-01

    Somatic copy number alterations (SCNAs) affecting oncogenic drivers have a firmly established role in promoting cancer. However, no agreed-upon standard exists for calling locus-specific amplifications and deletions in each patient sample. Here, we report the correlative analysis of copy number amplitude and length with gene expression across 6,109 samples from The Cancer Genome Atlas (TCGA) dataset across 16 cancer types. Using specificity, sensitivity, and precision-based scores, we assigned optimized amplitude and length cutoffs for nine recurrent SCNAs affecting known oncogenic drivers, using mRNA expression as a functional readout. These cutoffs captured the majority of SCNA-driven, highly-expression-altered samples. The majority of oncogenes required only amplitude cutoffs, as high amplitude samples were almost invariably focal; however, CDKN2A and PTEN uniquely required both amplitude and length cutoffs as primary predictors. For PTEN, these extended to downstream AKT activation. In contrast, SCNA genes located peri-telomerically or in fragile sites showed poor expression-copy number correlations. Overall, our analyses identify optimized amplitude and length cutoffs as efficient predictors of gene expression changes for specific oncogenic SCNAs, yet warn against one-size-fits-all interpretations across all loci. Our results have implications for cancer data analyses and the clinic, where copy number and mutation data are increasingly used to personalize cancer therapy. PMID:26787600

  14. Clock genes and behavioral responses to light are altered in a mouse model of diabetic retinopathy.

    PubMed

    Lahouaoui, Hasna; Coutanson, Christine; Cooper, Howard M; Bennis, Mohamed; Dkhissi-Benyahya, Ouria

    2014-01-01

    There is increasing evidence that melanopsin-expressing ganglion cells (ipRGCs) are altered in retinal pathologies. Using a streptozotocin-induced (STZ) model of diabetes, we investigated the impact of diabetic retinopathy on non-visual functions by analyzing ipRGCs morphology and light-induced c-Fos and Period 1-2 clock genes in the central clock (SCN). The ability of STZ-diabetic mice to entrain to light was challenged by exposure animals to 1) successive light/dark (LD) cycle of decreasing or increasing light intensities during the light phase and 2) 6-h advance of the LD cycle. Our results show that diabetes induces morphological changes of ipRGCs, including soma swelling and dendritic varicosities, with no reduction in their total number, associated with decreased c-Fos and clock genes induction by light in the SCN at 12 weeks post-onset of diabetes. In addition, STZ-diabetic mice exhibited a reduction of overall locomotor activity, a decrease of circadian sensitivity to light at low intensities, and a delay in the time to re-entrain after a phase advance of the LD cycle. These novel findings demonstrate that diabetes alters clock genes and behavioral responses of the circadian timing system to light and suggest that diabetic patients may show an increased propensity for circadian disturbances, in particular when they are exposed to chronobiological challenges. PMID:25006976

  15. Somatic Copy Number Alterations at Oncogenic Loci Show Diverse Correlations with Gene Expression

    NASA Astrophysics Data System (ADS)

    Roszik, Jason; Wu, Chang-Jiun; Siroy, Alan E.; Lazar, Alexander J.; Davies, Michael A.; Woodman, Scott E.; Kwong, Lawrence N.

    2016-01-01

    Somatic copy number alterations (SCNAs) affecting oncogenic drivers have a firmly established role in promoting cancer. However, no agreed-upon standard exists for calling locus-specific amplifications and deletions in each patient sample. Here, we report the correlative analysis of copy number amplitude and length with gene expression across 6,109 samples from The Cancer Genome Atlas (TCGA) dataset across 16 cancer types. Using specificity, sensitivity, and precision-based scores, we assigned optimized amplitude and length cutoffs for nine recurrent SCNAs affecting known oncogenic drivers, using mRNA expression as a functional readout. These cutoffs captured the majority of SCNA-driven, highly-expression-altered samples. The majority of oncogenes required only amplitude cutoffs, as high amplitude samples were almost invariably focal; however, CDKN2A and PTEN uniquely required both amplitude and length cutoffs as primary predictors. For PTEN, these extended to downstream AKT activation. In contrast, SCNA genes located peri-telomerically or in fragile sites showed poor expression-copy number correlations. Overall, our analyses identify optimized amplitude and length cutoffs as efficient predictors of gene expression changes for specific oncogenic SCNAs, yet warn against one-size-fits-all interpretations across all loci. Our results have implications for cancer data analyses and the clinic, where copy number and mutation data are increasingly used to personalize cancer therapy.

  16. Tumor promoters alter gene expression and protein phosphorylation in avian cells in culture

    SciTech Connect

    Laszlo, A.; Radke, K.; Chin, S.; Bissell, M.J.

    1981-10-01

    We have investigated the effect of 12-O-tetradecanoylphorbol 13-acetate (TPA) on the synthesis and modification of polypeptides in normal avian cells and cells infected by wild-type and temperature-sensitive Rous sarcoma virus (RSV). Using two-dimensional gel electrophoresis, we have detected alterations in both the abundance of cellular polypeptides and in their phosphorylation that seem unique to TPA treatment. However, the state of phosphorylation of the major putative substrate for the action of the src gene-associated protein kinase, the 34- to 36-kilodalton protein, was not altered. Moreover, examination of the phosphorylated amino acid content of total cellular phosphoproteins revealed that the response to TPA was not associated with detectable increases in their phosphotyrosine content. These results make it unlikely that TPA acts by the activation of the phosphorylating activity of the cellular proto-src gene or by the activation of other cellular phosphotyrosine-specific kinases. We have shown previously that temperature-sensitive RSV-infected cells at nonpermissive temperature demonstrate an increased sensitivity to TPA treatment (Bissell, M.J., Hatie, C. and Calfin, M. (1979) Proc. Natl. Acad. Sci. USA 76, 348-352). Our present results indicate that this is not due to reactivation of the phosphorylating activity of the defective src gene product or to its leakiness, and they lend support to the notion of multistep viral carcinogenesis.

  17. Prickle1 stunts limb growth through alteration of cell polarity and gene expression

    PubMed Central

    Yang, Tian; Bassuk, Alexander G.; Fritzsch, Bernd

    2014-01-01

    Background Wnt/PCP signaling plays a critical role in multiple developmental processes, including limb development. Wnt5a, a ligand of the PCP pathway, signals through the Ror2/Vangl2 or the Vangl2/Ryk complex to regulate limb development along the proximal-distal axis in mice. Based on the interaction between Van Gogh and Prickle in Drosophila, we hypothesized the vertebrate Prickle1 have similar function as Vangl2 in limb development. Results We show Prickle1 is expressed in the skeletal condensates that will differentiate into chondrocytes and later form bones. Disrupted Prickle1 function in Prickle1C251X/C251X mouse mutants alters expression of genes such as Bmp4, Fgf8, Vangl2 and Wnt5a. These expression changes correlate with shorter and wider bones in the limbs and loss of one phalangeal segment in digits 2-5 of Prickle1C251X mutants. These growth defects along the proximal-distal axis are also associated with increased cell death in the growing digit tip, reduced cell death in the interdigital membrane and disrupted chondrocyte polarity. Conclusions We suggest Prickle1 is part of the Wnt5a/PCP signaling, regulating cell polarity and affecting expression of multiple factors to stunt limb growth through altered patterns of gene expression, including the PCP genes Wnt5a and Vangl2. PMID:23913870

  18. Repeated methylphenidate treatment in adolescent rats alters gene regulation in the striatum.

    PubMed

    Brandon, Cindy L; Steiner, Heinz

    2003-09-01

    Methylphenidate is a psychostimulant which inhibits the dopamine transporter and produces dopamine overflow in the striatum, similar to the effects of cocaine. Excessive dopamine action is often associated with changes in gene expression in dopamine-receptive neurons. Little is known about methylphenidate's effects on gene regulation. We investigated whether a methylphenidate treatment regimen known to produce behavioural changes would alter gene expression in the striatum. Using in situ hybridization histochemistry, we assessed the effects of acute and repeated methylphenidate treatment on the expression of immediate-early genes (c-fos, zif 268) and neuropeptides (dynorphin, substance P, enkephalin) in adolescent rats. Acute methylphenidate treatment (0-10 mg/kg, i.p.) produced a dose-dependent increase in the expression of c-fos and zif 268. These effects were most pronounced in the dorsal striatum at middle to caudal striatal levels, and were found for doses as low as 2 mg/kg. Repeated treatment with methylphenidate (10 mg/kg/day, 7 days) increased the expression of dynorphin, which was highly correlated with the acute immediate-early gene response across different striatal regions. Moreover, after repeated methylphenidate treatment, cocaine-induced expression of c-fos and zif 268, as well as of substance P, was significantly attenuated throughout the striatum. These effects of repeated methylphenidate treatment mirror those produced by repeated treatment with cocaine or other psychostimulants and are considered to reflect drug-induced neuroadaptations. Thus, our findings demonstrate that acute and repeated methylphenidate treatment can produce molecular alterations similar to other psychostimulants. PMID:14511337

  19. Cyclic Equibiaxial Tensile Strain Alters Gene Expression of Chondrocytes via Histone Deacetylase 4 Shuttling

    PubMed Central

    Chen, Chongwei; Wei, Xiaochun; Lv, Zhi; Sun, Xiaojuan; Wang, Shaowei; Zhang, Yang; Jiao, Qiang; Wang, Xiaohu; Li, Yongping; Wei, Lei

    2016-01-01

    Objectives This paper aims to investigate whether equibiaxial tensile strain alters chondrocyte gene expression via controlling subcellular localization of histone deacetylase 4 (HDAC4). Materials and Methods Murine chondrocytes transfected with GFP-HDAC4 were subjected to 3 h cyclic equibiaxial tensile strain (CTS, 6% strain at 0.25 Hz) by a Flexcell® FX-5000™ Tension System. Fluorescence microscope and western blot were used to observe subcellular location of HDAC4. The gene expression was analyzed by real-time RT-PCR. The concentration of Glycosaminoglycans in culture medium was quantified by bimethylmethylene blue dye; Collagen II protein was evaluated by western blot. Cells phenotype was identified by immunohistochemistry. Cell viability was evaluated by live-dead cell detect kit. Okadaic acid, an inhibitor of HDAC4 nuclear relocation, was used to further validate whether HDAC4 nuclear relocation plays a role in gene expression in response to tension stimulation. Results 87.5% of HDAC4 was located in the cytoplasm in chondrocytes under no loading condition, but it was relocated to the nucleus after CTS. RT-PCR analysis showed that levels of mRNA for aggrecan, collagen II, LK1 and SOX9 were all increased in chondrocytes subjected to CTS as compared to no loading control chondrocytes; in contrast, the levels of type X collagen, MMP-13, IHH and Runx2 gene expression were decreased in the chondrocytes subjected to CTS as compared to control chondrocytes. Meanwhile, CTS contributed to elevation of glycosaminoglycans and collagen II protein, but did not change collagen I production. When Okadaic acid blocked HDAC4 relocation from the cytoplasm to nucleus, the changes of the chondrocytes induced by CTS were abrogated. There was no chondrocyte dead detected in this study in response to CTS. Conclusions CTS is able to induce HDAC4 relocation from cytoplasm to nucleus. Thus, CTS alters chondrocytes gene expression in association with the relocation of HDAC4 induced

  20. RNA-Seq identifies key reproductive gene expression alterations in response to cadmium exposure.

    PubMed

    Hu, Hanyang; Lu, Xing; Cen, Xiang; Chen, Xiaohua; Li, Feng; Zhong, Shan

    2014-01-01

    Cadmium is a common toxicant that is detrimental to many tissues. Although a number of transcriptional signatures have been revealed in different tissues after cadmium treatment, the genes involved in the cadmium caused male reproductive toxicity, and the underlying molecular mechanism remains unclear. Here we observed that the mice treated with different amount of cadmium in their rodent chow for six months exhibited reduced serum testosterone. We then performed RNA-seq to comprehensively investigate the mice testicular transcriptome to further elucidate the mechanism. Our results showed that hundreds of genes expression altered significantly in response to cadmium treatment. In particular, we found several transcriptional signatures closely related to the biological processes of regulation of hormone, gamete generation, and sexual reproduction, respectively. The expression of several testosterone synthetic key enzyme genes, such as Star, Cyp11a1, and Cyp17a1, were inhibited by the cadmium exposure. For better understanding of the cadmium-mediated transcriptional regulatory mechanism of the genes, we computationally analyzed the transcription factors binding sites and the mircoRNAs targets of the differentially expressed genes. Our findings suggest that the reproductive toxicity by cadmium exposure is implicated in multiple layers of deregulation of several biological processes and transcriptional regulation in mice. PMID:24982889

  1. Alteration of select gene expression patterns in individuals infected with HIV-1.

    PubMed

    Serrao, Erik; Wang, Chia-Hao; Frederick, Toinette; Lee, Chi-Lin; Anthony, Patricia; Arribas-Layton, David; Baker, Kerry; Millstein, Joshua; Kovacs, Andrea; Neamati, Nouri

    2014-04-01

    Multiple human proteins have been shown to both support and restrict viral replication, and confirmation of virus-associated changes in the expression of these genes is relevant for future therapeutic efforts. In this study a well-characterized panel of 49 individuals either infected with HIV-1 or uninfected was compiled and analyzed for the effect of HIV infection status, viral load, and antiretroviral treatment on specific gene expression. mRNA was extracted and reverse transcribed from purified CD4+ cells, and quantitative real-time PCR was utilized to scrutinize differences in the expression of four host genes that have been demonstrated to either stimulate (HSP90 and LEDGF/p75) or restrict (p21/WAF1 and APOBEC3G) proviral integration. HIV infection status was associated with slight to moderate alterations in the expression of all four genes. After adjusting for age, mRNA expression levels of HSP90, LEDGF/p75 and APOBEC3G were found to all be decreased in infected patients compared to healthy controls by 1.43-, 1.26-, and 4.71-fold, respectively, while p21/WAF1 expression was increased 2.35-fold. Furthermore, individuals receiving raltegravir exhibited a 1.28-fold reduction in LEDGF/p75 compared to those on non-raltegravir antiretroviral treatment. Identification of these and similar HIV-induced changes in gene expression may be valuable for delineating the extent of host cell molecular mechanisms stimulating viral replication. PMID:24482297

  2. Chromosomal position shift of a regulatory gene alters the bacterial phenotype.

    PubMed

    Gerganova, Veneta; Berger, Michael; Zaldastanishvili, Elisabed; Sobetzko, Patrick; Lafon, Corinne; Mourez, Michael; Travers, Andrew; Muskhelishvili, Georgi

    2015-09-30

    Recent studies strongly suggest that in bacterial cells the order of genes along the chromosomal origin-to-terminus axis is determinative for regulation of the growth phase-dependent gene expression. The prediction from this observation is that positional displacement of pleiotropic genes will affect the genetic regulation and hence, the cellular phenotype. To test this prediction we inserted the origin-proximal dusB-fis operon encoding the global regulator FIS in the vicinity of replication terminus on both arms of the Escherichia coli chromosome. We found that the lower fis gene dosage in the strains with terminus-proximal dusB-fis operons was compensated by increased fis expression such that the intracellular concentration of FIS was homeostatically adjusted. Nevertheless, despite unchanged FIS levels the positional displacement of dusB-fis impaired the competitive growth fitness of cells and altered the state of the overarching network regulating DNA topology, as well as the cellular response to environmental stress, hazardous substances and antibiotics. Our finding that the chromosomal repositioning of a regulatory gene can determine the cellular phenotype unveils an important yet unexplored facet of the genetic control mechanisms and paves the way for novel approaches to manipulate bacterial physiology. PMID:26170236

  3. RNA-Seq Identifies Key Reproductive Gene Expression Alterations in Response to Cadmium Exposure

    PubMed Central

    Hu, Hanyang; Lu, Xing; Cen, Xiang; Chen, Xiaohua; Li, Feng; Zhong, Shan

    2014-01-01

    Cadmium is a common toxicant that is detrimental to many tissues. Although a number of transcriptional signatures have been revealed in different tissues after cadmium treatment, the genes involved in the cadmium caused male reproductive toxicity, and the underlying molecular mechanism remains unclear. Here we observed that the mice treated with different amount of cadmium in their rodent chow for six months exhibited reduced serum testosterone. We then performed RNA-seq to comprehensively investigate the mice testicular transcriptome to further elucidate the mechanism. Our results showed that hundreds of genes expression altered significantly in response to cadmium treatment. In particular, we found several transcriptional signatures closely related to the biological processes of regulation of hormone, gamete generation, and sexual reproduction, respectively. The expression of several testosterone synthetic key enzyme genes, such as Star, Cyp11a1, and Cyp17a1, were inhibited by the cadmium exposure. For better understanding of the cadmium-mediated transcriptional regulatory mechanism of the genes, we computationally analyzed the transcription factors binding sites and the mircoRNAs targets of the differentially expressed genes. Our findings suggest that the reproductive toxicity by cadmium exposure is implicated in multiple layers of deregulation of several biological processes and transcriptional regulation in mice. PMID:24982889

  4. Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene

    PubMed Central

    Shu, Weiguo; Cho, Julie Y.; Jiang, Yuhui; Zhang, Minhua; Weisz, Donald; Elder, Gregory A.; Schmeidler, James; De Gasperi, Rita; Sosa, Miguel A. Gama; Rabidou, Donald; Santucci, Anthony C.; Perl, Daniel; Morrisey, Edward; Buxbaum, Joseph D.

    2005-01-01

    Neurobiology of speech and language has previously been studied in the KE family, in which half of the members have severe impairment in both speech and language. The gene responsible for the phenotype was mapped to chromosome 7q31 and identified as the FOXP2 gene, coding for a transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain. Because of linkage studies implicating 7q31 in autism, where language impairment is a component of the disorder, and in specific language impairment, FOXP2 has also been considered as a potential susceptibility locus for the language deficits in autism and/or specific language impairment. In this study, we characterized mice with a disruption in the murine Foxp2 gene. Disruption of both copies of the Foxp2 gene caused severe motor impairment, premature death, and an absence of ultrasonic vocalizations that are elicited when pups are removed from their mothers. Disruption of a single copy of the gene led to modest developmental delay but a significant alteration in ultrasonic vocalization in response to such separation. Learning and memory appear normal in the heterozygous animals. Cerebellar abnormalities were observed in mice with disruptions in Foxp2, with Purkinje cells particularly affected. Our findings support a role for Foxp2 in cerebellar development and in a developmental process that subsumes social communication functions in diverse organisms. PMID:15983371

  5. KGF alters gene expression in human airway epithelia: potential regulation of the inflammatory response.

    PubMed

    Prince, L S; Karp, P H; Moninger, T O; Welsh, M J

    2001-07-17

    Keratinocyte growth factor (KGF) regulates several functions in adult and developing lung epithelia; it causes proliferation, stimulates secretion of fluid and electrolytes, enhances repair, and may minimize injury. To gain insight into the molecular processes influenced by KGF, we applied KGF to primary cultures of well-differentiated human airway epithelia and used microarray hybridization to assess the abundance of gene transcripts. Of 7,069 genes tested, KGF changed expression levels of 910. Earlier studies showed that KGF causes epithelial proliferation, and as expected, treatment altered expression of numerous genes involved in cell proliferation. We found that KGF stimulated transepithelial Cl(-) transport, but the number of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) transcripts fell. Although transcripts for ClC-1 and ClC-7 Cl(-) channels increased, KGF failed to augment transepithelial Cl(-) transport in CF epithelia, suggesting that KGF-stimulated Cl(-) transport in differentiated airway epithelia depends on the CFTR Cl(-) channel. Interestingly, KGF decreased transcripts for many interferon (IFN)-induced genes. IFN causes trafficking of Stat dimers to the nucleus, where they activate transcription of IFN-induced genes. We found that KGF prevented the IFN-stimulated trafficking of Stat1 from the cytosol to the nucleus, suggesting a molecular mechanism for KGF-mediated suppression of the IFN-signaling pathway. These results suggest that in addition to stimulating proliferation and repair of damaged airway epithelia, KGF stimulates Cl(-) transport and may dampen the response of epithelial cells to inflammatory mediators. PMID:11459923

  6. Intake of High-intensity Sweeteners alters the Ability of Sweet Taste to Signal Caloric Consequences: Implications for the Learned Control of Energy and Body Weight Regulation

    PubMed Central

    Davidson, Terry L.; Martin, Ashley A.; Clark, Kiely; Swithers, Susan E.

    2012-01-01

    Recent results from both human epidemiological and experimental studies with animals suggest that intake of non-caloric sweeteners may promote, rather than protect against, weight gain and other disturbances of energy regulation. However, without a viable mechanism to explain how consumption of non-caloric sweeteners can increase energy intake and body weight, the persuasiveness of such results has been limited. Using a rat model, the present research showed that intake of non-caloric sweeteners reduces the effectiveness of learned associations between sweet tastes and postingestive caloric outcomes (Experiment 1) and that interfering with this association may impair the ability of rats to regulate their intake of sweet, but not nonsweet, high-fat and high-calorie food (Experiment 2). The results support the hypothesis that consuming noncaloric sweeteners may promote excessive intake and body weight gain by weakening a predictive relationship between sweet taste and the caloric consequences of eating. PMID:21424985

  7. Altered amygdalar resting-state connectivity in depression is explained by both genes and environment.

    PubMed

    Córdova-Palomera, Aldo; Tornador, Cristian; Falcón, Carles; Bargalló, Nuria; Nenadic, Igor; Deco, Gustavo; Fañanás, Lourdes

    2015-10-01

    Recent findings indicate that alterations of the amygdalar resting-state fMRI connectivity play an important role in the etiology of depression. While both depression and resting-state brain activity are shaped by genes and environment, the relative contribution of genetic and environmental factors mediating the relationship between amygdalar resting-state connectivity and depression remain largely unexplored. Likewise, novel neuroimaging research indicates that different mathematical representations of resting-state fMRI activity patterns are able to embed distinct information relevant to brain health and disease. The present study analyzed the influence of genes and environment on amygdalar resting-state fMRI connectivity, in relation to depression risk. High-resolution resting-state fMRI scans were analyzed to estimate functional connectivity patterns in a sample of 48 twins (24 monozygotic pairs) informative for depressive psychopathology (6 concordant, 8 discordant and 10 healthy control pairs). A graph-theoretical framework was employed to construct brain networks using two methods: (i) the conventional approach of filtered BOLD fMRI time-series and (ii) analytic components of this fMRI activity. Results using both methods indicate that depression risk is increased by environmental factors altering amygdalar connectivity. When analyzing the analytic components of the BOLD fMRI time-series, genetic factors altering the amygdala neural activity at rest show an important contribution to depression risk. Overall, these findings show that both genes and environment modify different patterns the amygdala resting-state connectivity to increase depression risk. The genetic relationship between amygdalar connectivity and depression may be better elicited by examining analytic components of the brain resting-state BOLD fMRI signals. PMID:26096943

  8. Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects

    PubMed Central

    Duric, Vanja; Banasr, Mounira; Stockmeier, Craig A.; Simen, Arthur A.; Newton, Samuel S.; Overholser, James C.; Jurjus, George J.; Dieter, Lesa; Duman, Ronald S.

    2012-01-01

    Major depressive disorder (MDD) has been linked to changes in function and activity of the hippocampus, one of the central limbic regions involved in regulation of emotions and mood. The exact cellular and molecular mechanisms underlying hippocampal plasticity in response to stress are yet to be fully characterized. In this study, we examined the genetic profile of micro-dissected subfields of post-mortem hippocampus from subjects diagnosed with MDD and comparison subjects matched for sex, race and age. Gene expression profiles of the dentate gyrus and CA1 were assessed by 48K human HEEBO whole genome microarrays and a subgroup of identified genes was confirmed by real-time polymerase chain reaction (qPCR). Pathway analysis revealed altered expression of several gene families, including cytoskeletal proteins involved in rearrangement of neuronal processes. Based on this and evidence of hippocampal neuronal atrophy in MDD, we focused on the expression of cytoskeletal, synaptic and glutamate receptor genes. Our findings demonstrate significant dysregulation of synaptic function/structure related genes SNAP25, DLG2 (SAP93), and MAP1A, and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor subunit genes GLUR1 and GLUR3. Several of these human target genes were similarly dysregulated in a rat model of chronic unpredictable stress and the effects reversed by antidepressant treatment. Together, these studies provide new evidence that disruption of synaptic and glutamatergic signalling pathways contribute to the pathophysiology underlying MDD and provide interesting targets for novel therapeutic interventions. PMID:22339950

  9. OMP gene deletion results in an alteration in odorant-induced mucosal activity patterns.

    PubMed

    Youngentob, S L; Kent, P F; Margolis, F L

    2003-12-01

    Previous behavioral work, using a complex five-odorant identification task, demonstrated that olfactory marker protein (OMP) is critically involved in odor processing to the extent that its loss results in an alteration in odorant quality perception. Exactly how the lack of OMP exerts its influence on the perception of odorant quality is unknown. However, there is considerable neurophysiological evidence that different odorants produce different spatiotemporal patterns of neural activity at the level of the mucosa and that these patterns predict the psychophysically determined perceptual relationship among odorants. In this respect, OMP gene deletion is known to result in a constellation of physiologic defects (i.e., marked reduction in the electroolfactogram (EOG) and altered response and recovery kinetics) that would be expected to alter the odorant-induced spatiotemporal activity patterns that are characteristic of different odorants. This, in turn, would be expected to alter the spatiotemporal patterning of information that results from the mucosal projection onto the bulb, thereby changing odorant quality perception. To test the hypothesis that odorant-induced mucosal activity patterns are altered in mice lacking the gene for OMP, we optically recorded the fluorescent changes in response to odorant stimulation from both the septum and turbinates of both OMP-null and control mice using a voltage-sensitive dye (di-4-ANEPPS Molecular Probes, Eugene, OR) and a Dalsa 120 x 120, 12-bit CCD camera. To maintain continuity with the previous behavioral work, the odorants 2-propanol, citral, carvone, ethylacetoacetate, and propyl acetate were again used. Each odorant was randomly presented to each mucosal surface in a Latin-Square design. The results of this study demonstrated that, for both mouse strains, there do indeed exist different spatiotemporal activity patterns for different odorants. More importantly, however, these patterns significantly differed between OMP

  10. Maternal but not fetal FADS gene variants modify the association between maternal long-chain PUFA intake in pregnancy and birth weight.

    PubMed

    Moltó-Puigmartí, Carolina; van Dongen, Martien C J M; Dagnelie, Pieter C; Plat, Jogchum; Mensink, Ronald P; Tan, Frans E S; Heinrich, Joachim; Thijs, Carel

    2014-09-01

    Several studies have shown a positive association between maternal fish intake in pregnancy and pregnancy duration and child birth weight (BW), probably due to fish n-3 (ω-3) long-chain polyunsaturated fatty acids (LC-PUFAs). n-3 LC-PUFAs can also be synthesized endogenously, and their synthesis depends on single nucleotide polymorphisms (SNPs) in the fatty acid desaturase (FADS) gene encoding for FADS. We assessed the associations of maternal docosahexaenoic acid (DHA) intake in pregnancy with pregnancy duration and BW and investigated whether these associations are modified by maternal or fetal FADS SNP genotypes. We hypothesized that we would find stronger associations in minor allele homozygous mothers or fetuses due to their lower n-3 LC-PUFA endogenous synthesis and hence higher dependence on dietary supply. Data on maternal diet, pregnancy duration, and BW were available for 2622 mother-child pairs from the KOALA (Kind, Ouders en gezondheid: Aandacht voor Leefstijl en Aanleg) Birth Cohort Study. The rs174556 FADS SNP was genotyped in 1516 mothers and 1515 children. Associations and gene-diet interactions were tested with linear regression adjusting for potential confounders, including intake of other PUFAs. Women at the 75th percentile of DHA intake had 0.7-d longer pregnancies (P = 0.016) and 28-g heavier infants (P = 0.039) than did women at the 25th percentile of intake. Associations with arachidonic acid intake were of the same order but in the opposite direction. Mothers who were homozygous for the minor allele had 2-d shorter pregnancies (P = 0.035) and infants who were nearly 140 g lighter (P = 0.006) than did mothers who were major allele homozygotes. Post hoc analyses revealed that they had higher prepregnancy BMI (P = 0.020). Among the women homozygous for the minor allele, those at the 75th percentile of DHA intake had 226-g heavier infants than those at the 25th percentile of intake (P = 0.030), whereas DHA intake was not significantly