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Sample records for dietary deficiency induces

  1. DIETARY FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED MICRONUCLEUS FORMATION IN MICE

    EPA Science Inventory


    Dietary folate deficiency enhances arsenic-induced micronucleus formation in mice.

    Folate deficiency increases background levels ofDNA damage and can enhance the mutagenicity of chemical agents. Duplicate experiments were performed to investigate the effect of dietary...

  2. Dietary zinc deficiency predisposes mice to the development of preneoplastic lesions in chemically-induced hepatocarcinogenesis.

    PubMed

    Romualdo, Guilherme Ribeiro; Goto, Renata Leme; Henrique Fernandes, Ana Angélica; Cogliati, Bruno; Barbisan, Luis Fernando

    2016-10-01

    Although there is a concomitance of zinc deficiency and high incidence/mortality for hepatocellular carcinoma in certain human populations, there are no experimental studies investigating the modifying effects of zinc on hepatocarcinogenesis. Thus, we evaluated whether dietary zinc deficiency or supplementation alter the development of hepatocellular preneoplastic lesions (PNL). Therefore, neonatal male Balb/C mice were submitted to a diethylnitrosamine/2-acetylaminefluorene-induced hepatocarcinogenesis model. Moreover, mice were fed adequate (35 mg/kg diet), deficient (3 mg/kg) or supplemented (180 mg/kg) zinc diets. Mice were euthanized at 12 (early time-point) or 24 weeks (late time-point) after introducing the diets. At the early time-point, zinc deficiency decreased Nrf2 protein expression and GSH levels while increased p65 and p53 protein expression and the number of PNL/area. At the late time-point, zinc deficiency also decreased GSH levels while increased liver genotoxicity, cell proliferation into PNL and PNL size. In contrast, zinc supplementation increased antioxidant defense at both time-points but not altered PNL development. Our findings are the first to suggest that zinc deficiency predisposes mice to the PNL development in chemically-induced hepatocarcinogenesis. The decrease of Nrf2/GSH pathway and increase of liver genotoxicity, as well as the increase of p65/cell proliferation, are potential mechanisms to this zinc deficiency-mediated effect.

  3. Dietary selenium deficiency exacerbates lipopolysaccharide-induced inflammatory response in mouse mastitis models.

    PubMed

    Wei, Zhengkai; Yao, Minjun; Li, Yimeng; He, Xuexiu; Yang, Zhengtao

    2014-12-01

    Selenium (Se) is an essential micronutrient that plays a critical role in anti-inflammatory processes and antioxidant defense system. In this study, we investigated the effects of dietary selenium deficiency on lipopolysaccharide (LPS)-induced mastitis in mouse models. Se content in the liver was assessed by fluorescent atomic absorption spectrometry. Glutathione peroxidase (GPx) activity in the blood, myeloperoxidase (MPO) activity, tumor necrosis actor alpha (TNF-α), and interleukin (IL)-1β in the supernatant of the mammary tissue were determined according to the corresponding kits. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions were evaluated by Western blotting. The results showed that the Se-deficient mouse model was successfully replicated, and selenium deficiency exacerbated mammary gland histopathology, increased the expressions of TNF-α and IL-1β, and facilitated the activation of iNOS and COX-2 in LPS-induced mouse mastitis. In conclusion, our studies demonstrated that selenium deficiency resulted in more severe inflammatory response in LPS-induced mouse mastitis.

  4. Dietary zinc deficiency fuels esophageal cancer development by inducing a distinct inflammatory signature

    PubMed Central

    Taccioli, C; Chen, H; Jiang, Y; Liu, XP; Huang, K; Smalley, KJ; Farber, JL; Croce, CM; Fong, LY

    2011-01-01

    Chronic inflammation is implicated in the pathogenesis of esophageal squamous cell cancer (ESCC). The causes of inflammation in ESCC, however, are undefined. Dietary zinc-deficiency (ZD) increases the risk of ESCC. We have previously shown that short-term ZD (6 weeks) in rats induces overexpression of the proinflammatory mediators S100a8 and S100a9 in the esophageal mucosa with accompanying esophageal epithelial hyperplasia. Here we report that prolonged ZD (21 weeks) in rats amplified this inflammation that when combined with non-carcinogenic low doses of the environmental carcinogen N-nitrosomethylbenzylamine (NMBA) elicited a 66.7% (16/24) incidence of ESCC. With zinc-sufficiency NMBA produced no cancers (0/21) (P<0.001). At tumor endpoint, the neoplastic ZD esophagus as compared with zinc-sufficient esophagus had an inflammatory gene signature with upregulation of numerous cancer-related inflammation genes (CXC and CC chemokines, chemokine receptors, cytokines, and Cox-2) in addition to S100a8 and S100a9. This signature was already activated in the earlier dysplastic stage. Additionally, time-course bioinformatics analysis of expression profiles at tumor endpoint and prior to NMBA exposure revealed that this sustained inflammation was due to ZD rather than carcinogen exposure. Importantly, zinc replenishment reversed this inflammatory signature at both the dysplastic and neoplastic stages of ESCC development, and prevented cancer formation. Thus, the molecular definition of ZD-induced inflammation as a critical factor in ESCC development has important clinical implications with regard to development and prevention of this deadly disease. PMID:22179833

  5. Dietary vitamin D3 deficiency alters intestinal mucosal defense and increases susceptibility to Citrobacter rodentium-induced colitis.

    PubMed

    Ryz, Natasha R; Lochner, Arion; Bhullar, Kirandeep; Ma, Caixia; Huang, Tina; Bhinder, Ganive; Bosman, Else; Wu, Xiujuan; Innis, Sheila M; Jacobson, Kevan; Vallance, Bruce A

    2015-11-01

    Vitamin D deficiency affects more that 1 billion people worldwide. Although thought to increase risk of bacterial infections, the importance of vitamin D on host defense against intestinal bacterial pathogens is currently unclear since injection of the active form of vitamin D, 1,25(OH)2D3, increased susceptibility to the enteric bacterial pathogen Citrobacter rodentium by suppressing key immune/inflammatory factors. To further characterize the role of vitamin D during bacteria-induced colitis, we fed weanling mice either vitamin D3-deficient or vitamin D3-sufficient diets for 5 wk and then challenged them with C. rodentium. Vitamin D3-deficient mice lost significantly more body weight, carried higher C. rodentium burdens, and developed worsened histological damage. Vitamin D3-deficient mice also suffered greater bacterial translocation to extra-intestinal tissues, including mesenteric lymph nodes, spleen, and liver. Intestinal tissues of infected vitamin D3-deficient mice displayed increased inflammatory cell infiltrates as well as significantly higher gene transcript levels of inflammatory mediators TNF-α, IL-1β, IL-6, TGF-β, IL-17A, and IL-17F as well as the antimicrobial peptide REG3γ. Notably, these exaggerated inflammatory responses accelerated the loss of commensal microbes and were associated with an impaired ability to detoxify bacterial lipopolysaccharide. Overall, these studies show that dietary-induced vitamin D deficiency exacerbates intestinal inflammatory responses to infection, also impairing host defense.

  6. Dietary vitamin D3 deficiency alters intestinal mucosal defense and increases susceptibility to Citrobacter rodentium-induced colitis

    PubMed Central

    Ryz, Natasha R.; Lochner, Arion; Bhullar, Kirandeep; Ma, Caixia; Huang, Tina; Bhinder, Ganive; Bosman, Else; Wu, Xiujuan; Innis, Sheila M.; Jacobson, Kevan

    2015-01-01

    Vitamin D deficiency affects more that 1 billion people worldwide. Although thought to increase risk of bacterial infections, the importance of vitamin D on host defense against intestinal bacterial pathogens is currently unclear since injection of the active form of vitamin D, 1,25(OH)2D3, increased susceptibility to the enteric bacterial pathogen Citrobacter rodentium by suppressing key immune/inflammatory factors. To further characterize the role of vitamin D during bacteria-induced colitis, we fed weanling mice either vitamin D3-deficient or vitamin D3-sufficient diets for 5 wk and then challenged them with C. rodentium. Vitamin D3-deficient mice lost significantly more body weight, carried higher C. rodentium burdens, and developed worsened histological damage. Vitamin D3-deficient mice also suffered greater bacterial translocation to extra-intestinal tissues, including mesenteric lymph nodes, spleen, and liver. Intestinal tissues of infected vitamin D3-deficient mice displayed increased inflammatory cell infiltrates as well as significantly higher gene transcript levels of inflammatory mediators TNF-α, IL-1β, IL-6, TGF-β, IL-17A, and IL-17F as well as the antimicrobial peptide REG3γ. Notably, these exaggerated inflammatory responses accelerated the loss of commensal microbes and were associated with an impaired ability to detoxify bacterial lipopolysaccharide. Overall, these studies show that dietary-induced vitamin D deficiency exacerbates intestinal inflammatory responses to infection, also impairing host defense. PMID:26336925

  7. Dietary component isorhamnetin is a PPARγ antagonist and ameliorates metabolic disorders induced by diet or leptin deficiency

    PubMed Central

    Zhang, Yu; Gu, Ming; Cai, Wujie; Yu, Lijing; Feng, Li; Zhang, Lu; Zang, Qingqing; Wang, Yahui; Wang, Dongshan; Chen, Hui; Tong, Qingchun; Ji, Guang; Huang, Cheng

    2016-01-01

    Studies on peroxisome proliferator-activated receptor (PPAR)-γ ligands have been focused on agonists. However, PPARγ activation may induce obesity and nonalcoholic fatty liver disease (NAFLD), one of the most challenging medical conditions. Here, we identified that isorhamnetin, a naturally occurring compound in fruits and vegetables and the metabolite of quercetin, is a novel antagonist of PPARγ. Isorhamnetin treatment inhibited the adipocyte differentiation induced by the PPARγ agonist rosiglitazone, reduced obesity development and ameliorated hepatic steatosis induced by both high-fat diet treatment and leptin deficiency. Our results suggest that dietary supplement of isorhamnetin may be beneficial to prevent obesity and steatosis and PPARγ antagonists may be useful to treat hepatic steatosis. PMID:26775807

  8. Dietary component isorhamnetin is a PPARγ antagonist and ameliorates metabolic disorders induced by diet or leptin deficiency.

    PubMed

    Zhang, Yu; Gu, Ming; Cai, Wujie; Yu, Lijing; Feng, Li; Zhang, Lu; Zang, Qingqing; Wang, Yahui; Wang, Dongshan; Chen, Hui; Tong, Qingchun; Ji, Guang; Huang, Cheng

    2016-01-18

    Studies on peroxisome proliferator-activated receptor (PPAR)-γ ligands have been focused on agonists. However, PPARγ activation may induce obesity and nonalcoholic fatty liver disease (NAFLD), one of the most challenging medical conditions. Here, we identified that isorhamnetin, a naturally occurring compound in fruits and vegetables and the metabolite of quercetin, is a novel antagonist of PPARγ. Isorhamnetin treatment inhibited the adipocyte differentiation induced by the PPARγ agonist rosiglitazone, reduced obesity development and ameliorated hepatic steatosis induced by both high-fat diet treatment and leptin deficiency. Our results suggest that dietary supplement of isorhamnetin may be beneficial to prevent obesity and steatosis and PPARγ antagonists may be useful to treat hepatic steatosis.

  9. Influence of dietary carbohydrate on zinc-deficiency-induced changes in oxidative defense mechanisms and tissue oxidative damage in rats.

    PubMed

    Kim, S H; Keen, C L

    1999-10-01

    The aim of this study was to determine the effect of dietary carbohydrate type on the expression of zinc (Zn) deficiency in rats with respect to tissue oxidative damage and defense mechanisms. Rats were fed diets containing adequate (+Zn) or low concentrations (-Zn) of Zn. Both fructose- and glucose-based diets were tested. Pair-fed controls were also studied to evaluate changes in the oxidative defense system which are secondary to Zn-deficiency-induced anorexia. Plasma and liver Zn concentrations and CuZn superoxide dismutase activities were lower in the -Zn rats than in the +Zn rats. Liver glutathione (GSH) and disulfide glutathione concentrations were higher in the -Zn rats than in the +Zn rats; this difference was most pronounced in the fructose groups. Liver and heart selenium glutathione peroxidase (Se-GSH-Px) activities were lower in the -Zn-fructose group than in the +Zn-fructose group. Liver Se-GSH-Px activity was higher in the fructose groups than in the glucose groups. Liver GSH reductase (GSH-Red) activity was lower in the -Zn-fructose group than in its control group. Liver glutamine synthetase activity was lower in the -Zn-glucose group and in the fructose groups than in the glucose control group. Liver thiobarbituric acid reactive substance (TBARS) production was similar among the groups. Collectively, these results support the concept that Zn deficiency can result in an impaired oxidant defense system. Based on the observation that pair-fed control animals also showed evidence of oxidative damage, we suggest that one factor that contributes to the effect of Zn deficiency is the reduction in caloric intake that occurs in these animals. Fructose feeding resulted in increased activities of several of the oxidant defense enzymes. Protein oxidative damage assessed by glutamine synthetase activity was increased by both Zn deficiency and fructose feeding.

  10. Dietary Fat Interacts with PCBs to Induce Changes in Lipid Metabolism in Mice Deficient in Low-Density Lipoprotein Receptor

    PubMed Central

    Hennig, Bernhard; Reiterer, Gudrun; Toborek, Michal; Matveev, Sergey V.; Daugherty, Alan; Smart, Eric; Robertson, Larry W.

    2005-01-01

    There is evidence that dietary fat can modify the cytotoxicity of polychlorinated biphenyls (PCBs) and that coplanar PCBs can induce inflammatory processes critical in the pathology of vascular diseases. To test the hypothesis that the interaction of PCBs with dietary fat is dependent on the type of fat, low-density lipoprotein receptor–deficient (LDL-R−/−) mice were fed diets enriched with either olive oil or corn oil for 4 weeks. Half of the animals from each group were injected with PCB-77. Vascular cell adhesion molecule-1 (VCAM-1) expression in aortic arches was non-detectable in the olive-oil–fed mice but was highly expressed in the presence of PCB-77. PCB treatment increased liver neutral lipids and decreased serum fatty acid levels only in mice fed the corn-oil–enriched diet. PCB treatment increased mRNA expression of genes involved in inflammation, apoptosis, and oxidative stress in all mice. Upon PCB treatment, mice in both olive- and corn-oil–diet groups showed induction of genes involved in fatty acid degradation but with up-regulation of different key enzymes. Genes involved in fatty acid synthesis were reduced only upon PCB treatment in corn-oil–fed mice, whereas lipid transport/export genes were altered in olive-oil–fed mice. These data suggest that dietary fat can modify changes in lipid metabolism induced by PCBs in serum and tissues. These findings have implications for understanding the interactions of nutrients with environmental contaminants on the pathology of inflammatory diseases such as atherosclerosis. PMID:15626652

  11. Dietary zinc deficiency induces oxidative stress and promotes tumor necrosis factor-α- and interleukin-1β-induced RANKL expression in rat bone.

    PubMed

    Suzuki, Takako; Katsumata, Shin-Ichi; Matsuzaki, Hiroshi; Suzuki, Kazuharu

    2016-03-01

    We investigated the effects of dietary zinc deficiency on oxidative stress and bone metabolism. Four-week-old male Wistar rats were randomly assigned to one of three groups for 4 weeks: a zinc-adequate group (30 ppm); a zinc-deficient group (1 ppm); and a pair-fed group (30 ppm) that was pair-fed to the zinc-deficient group. The iron content and the thiobarbituric acid reactive substance level in bone were higher in the zinc-deficient group than in the zinc-adequate and pair-fed groups. The mRNA expression level of osteoblastogenesis-related genes such as bone morphogenetic protein 2 and runt-related transcription factor 2 was lower in the zinc-deficient group than in the zinc-adequate and pair-fed groups. In contrast, the mRNA expression levels of tumor necrosis factor-α, interleukin-1β and osteoclastogenesis-related genes such as receptor activator of nuclear factor-κB ligand and nuclear factor of activated T cells cytoplasmic 1 were higher in the zinc-deficient group than in the zinc-adequate and pair-fed groups. These findings suggested that dietary zinc deficiency reduced osteoblastogenesis via a decrease in the expression of bone morphogenetic protein 2 and increased osteoclastogenesis via enhancement of the expression of receptor for activator of nuclear factor-κB ligand induced by oxidative stress-stimulated tumor necrosis factor-α and interleukin-1β.

  12. Dietary Composition Influences Incidence of Helicobacter pylori-Induced Iron Deficiency Anemia and Gastric Ulceration.

    PubMed

    Beckett, Amber C; Piazuelo, M Blanca; Noto, Jennifer M; Peek, Richard M; Washington, M Kay; Algood, Holly M Scott; Cover, Timothy L

    2016-12-01

    Epidemiologic studies have provided conflicting data regarding an association between Helicobacter pylori infection and iron deficiency anemia (IDA) in humans. Here, a Mongolian gerbil model was used to investigate a potential role of H. pylori infection, as well as a possible role of diet, in H. pylori-associated IDA. Mongolian gerbils (either H. pylori infected or uninfected) received a normal diet or one of three diets associated with increased H. pylori virulence: high-salt, low-iron, or a combination of a high-salt and low-iron diet. In an analysis of all infected animals compared to uninfected animals (independent of diet), H. pylori-infected gerbils had significantly lower hemoglobin values than their uninfected counterparts at 16 weeks postinfection (P < 0.0001). The mean corpuscular volume (MCV) and serum ferritin values were significantly lower in H. pylori-infected gerbils than in uninfected gerbils, consistent with IDA. Leukocytosis and thrombocytosis were also detected in infected gerbils, indicating the presence of a systemic inflammatory response. In comparison to uninfected gerbils, H. pylori-infected gerbils had a higher gastric pH, a higher incidence of gastric ulcers, and a higher incidence of fecal occult blood loss. Anemia was associated with the presence of gastric ulceration but not gastric cancer. Infected gerbils consuming diets with a high salt content developed gastric ulcers significantly more frequently than gerbils consuming a normal-salt diet, and the lowest hemoglobin levels were in infected gerbils consuming a high-salt/low-iron diet. These data indicate that H. pylori infection can cause IDA and that the composition of the diet influences the incidence and severity of H. pylori-induced IDA.

  13. Behavioral Abnormality Induced by Enhanced Hypothalamo-Pituitary-Adrenocortical Axis Activity under Dietary Zinc Deficiency and Its Usefulness as a Model.

    PubMed

    Takeda, Atsushi; Tamano, Haruna; Nishio, Ryusuke; Murakami, Taku

    2016-07-16

    Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after the increase in glucocorticoid secretion. A major target of glucocorticoids is the hippocampus and their actions are often associated with disturbance of glutamatergic neurotransmission, which may be linked to behavioral abnormality, such as depressive symptoms and aggressive behavior under zinc deficiency. Glucocorticoid-mediated disturbance of glutamatergic neurotransmission in the hippocampus is also involved in the pathophysiology of, not only psychiatric disorders, such as depression, but also neurodegenerative disorders, e.g., Alzheimer's disease. The evidence suggests that zinc-deficient animals are models for behavioral and psychological symptoms of dementia (BPSD), as well as depression. To understand validity to apply zinc-deficient animals as a behavioral abnormality model, this paper deals with the effect of antidepressive drugs and herbal medicines on hippocampal dysfunctions and behavioral abnormality, which are induced by enhanced HPA axis activity under dietary zinc deficiency.

  14. Relationship between abnormal sperm morphology induced by dietary zinc deficiency and lipid composition in testes of growing rats.

    PubMed

    Merrells, Krystal J; Blewett, Heather; Jamieson, Jennifer A; Taylor, Carla G; Suh, Miyoung

    2009-07-01

    The present study investigated the effect of dietary Zn deficiency during sexual maturation on sperm integrity and testis phospholipid fatty acid composition. Male weanling Sprague-Dawley rats were randomised into four dietary groups for 3 weeks: Zn control (ZC; 30 mg Zn/kg); Zn marginally deficient (ZMD; 9 mg Zn/kg); Zn deficient (ZD; < 1 mg Zn/kg); pair fed (PF; 30 mg Zn/kg) to the ZD group. Morphology of cauda epididymal sperm and lipid profiles of testis phospholipids were analysed. The rats fed the ZD diet had a lower testis weight (P < 0.02). Seminal vesicles and prostate weight were also lower in the ZD and PF groups. Rats fed the ZD diet, but not the ZMD diet, had 34-35 % more abnormal spermatozoa and 24 % shorter sperm tail length than the ZC and PF rats (P < 0.001). Testis cholesterol concentration was higher in the ZD rats compared with the ZC and PF rats (P < 0.04). Testes were highly enriched with n-6 fatty acids by showing n-6 : n-3 fatty acid ratios of 27:1 in phosphatidylcholine (PC) and 23:1 in phosphatidylethanolamine (PE). The dominant fatty acid in testes was docosapentaenoic acid (22 : 5n-6), comprising 15 and 24 % of PC and PE, respectively. This fatty acid was significantly lower in the ZD rats, whereas 18 : 2n-6 was higher compared with the rats in the other diet groups. These results demonstrate that severe Zn deficiency adversely affects sperm integrity and modulates testis fatty acid composition by interrupting essential fatty acid metabolism. This suggests that Zn deficiency-associated abnormal testicular function is perhaps preceded by altered membrane fatty acid composition, especially of a major fatty acid, 22 : 5n-6.

  15. Effects of cigarette smoke and ethanol intake on mouse oesophageal mucosa changes induced by dietary zinc deficiency and deoxycholic acid supplementation.

    PubMed

    Zapaterini, Joyce R; de Moura, Nelci A; Ribeiro, Daniel A; Rodrigues, Maria A M; Barbisan, Luis F

    2012-08-01

    The noxious effects of dietary zinc deficiency (ZD) and deoxycholic bile acid (DCA) supplementation in the oesophagus were investigated. The additional influence of cigarette smoke and ethanol intake on the changes in the oesophageal mucosa induced by dietary ZD plus DCA was also assessed. Male C57BL/6 mice were allocated into four groups: Group 1 was fed control diet and groups 2-4 were fed ZD plus DCA diet. After 5 weeks, groups 3 and 4 were exposed to 10% ethanol intake or cigarette smoke for 15 weeks, respectively. All animals were euthanized at the end of week 20, and the oesophagus, lung, liver and colon were collected and analysed by conventional morphology. Cell proliferation was assessed in the oesophageal mucosa by Ki-67 immunohistochemistry and cyclooxygenase 2 (COX-2) protein by Western blotting. Dietary ZD plus DCA treatment induced mild hyperkeratosis and hyperplasia, increased cell proliferation index and COX-2 protein expression in the oesophagus, and intranuclear inclusion, karyocytomegaly and microvesicular fatty change in the liver. Cigarette smoke increased COX-2 protein expression in oesophageal mucosa and irregular enlargement of alveolus and alveolar ductal air spaces, while ethanol enhanced liver damage induced by ZD plus DCA diet. These findings indicate that dietary ZD plus DCA treatment during 20 weeks induces a pattern of chemical oesophageal injury but not Barrett's-like lesions.

  16. [Vitamin deficiencies in breastfed children due to maternal dietary deficiency].

    PubMed

    Kollée, L A A

    2006-03-04

    Dietary deficiencies of vitamin B12 and vitamin D during pregnancy and lactation may result in health problems in exclusively breastfed infants. Vitamin-B12 deficiency in these infants results in irritability, anorexia and failure to thrive during the first 4-8 months of life. Severe and permanent neurodevelopmental disturbances may occur. The most at risk for vitamin-B12 deficiency are breast-fed infants ofveganist and vegetarian mothers. Mothers who cover their skin prevent exposure to the sun and may consequently be at risk for vitamin-D deficiency, as well as putting their offspring at risk. In prenatal and perinatal care, it is important to take the maternal dietary history in order to be able to prevent or treat these disorders. Guidelines for obstetrical and neonatal care should include the topic of vitamin deficiency.

  17. DIETARY FOLATE DEFICIENCY ENHANCES INDUCTION OF MICRONUCLEI BY ARSENIC IN MICE

    EPA Science Inventory

    Folate deficiency increases background levels of DNA damage and can enhance the genotoxicity of chemical agents. Arsenic, a known human carcinogen present in drinking water supplies around the world, induces chromosomal and DNA damage. The effect of dietary folate deficiency on...

  18. Dietary choline deficiency and excess induced intestinal inflammation and alteration of intestinal tight junction protein transcription potentially by modulating NF-κB, STAT and p38 MAPK signaling molecules in juvenile Jian carp.

    PubMed

    Wu, Pei; Jiang, Wei-Dan; Jiang, Jun; Zhao, Juan; Liu, Yang; Zhang, Yong-An; Zhou, Xiao-Qiu; Feng, Lin

    2016-11-01

    This study investigated the effects of choline on intestinal mucosal immune and the possible mechanisms in fish by feeding juvenile Jian carp (Cyprinus carpio var. Jian) with graded levels of dietary choline (165-1820 mg/kg diet) for 65 days. The results firstly showed that choline deficiency induced inflammatory infiltration in the proximal intestine (PI), mid intestine (MI) and distal intestine (DI) of fish. Meanwhile, compared with the optimal choline group, choline deficiency decreased the activities of lysozyme and acid phosphatase, contents of complement 3 and IgM in the intestine, downregulated the mRNA levels of antimicrobial peptides (liver-expressed antimicrobial peptide (LEAP) 2A and defensin-3 in the PI and MI, LEAP-2B and hepcidin in the PI, MI and DI), anti-inflammatory cytokines (interleukin (IL) 10 and transforming growth factor β2 in the PI, MI and DI), and signaling molecule IκB in the PI, MI and DI; while upregulated the mRNA levels of pro-inflammatory cytokines (IL-6a and tumor necrosis factor α in the MI and DI, interferon γ2b in the PI and MI, IL-1β and IL-6b in the PI, MI and DI), and signaling molecules (Toll-like receptor 4 in the MI, myeloid differentiation primary response 88 in the PI and MI, Janus kinase 3 and tyrosine kinase 2 in the MI and DI, nuclear factor kappa B (NF-κB), signal transducers and activators of transcription (STAT) 4 and STAT5 in the PI, MI and DI) of juvenile Jian carp, further indicating that choline deficiency caused inflammation and immunity depression in the intestine of fish. But choline deficiency decreased the PI IL-6a mRNA level, and increased the DI LEAP-2A and defensin-3 mRNA levels with unknown reasons. Furthermore, dietary choline deficiency downregulated mRNA levels of tight junction (TJ) proteins (claudin 3c in the PI and MI, claudin 7, claudin 11 and occludin in the PI, MI and DI) and signaling molecule mitogen-activated protein kinases p38 in the PI, MI and DI of juvenile Jian carp, whereas

  19. Helicobacter pylori infection and low dietary iron alter behavior, induce iron deficiency anemia, and modulate hippocampal gene expression in female C57BL/6 mice.

    PubMed

    Burns, Monika; Amaya, Aldo; Bodi, Caroline; Ge, Zhongming; Bakthavatchalu, Vasudevan; Ennis, Kathleen; Wang, Timothy C; Georgieff, Michael; Fox, James G

    2017-01-01

    Helicobacter pylori (H.pylori), a bacterial pathogen, is a causative agent of gastritis and peptic ulcer disease and is a strong risk factor for development of gastric cancer. Environmental conditions, such as poor dietary iron resulting in iron deficiency anemia (IDA), enhance H.pylori virulence and increases risk for gastric cancer. IDA affects billions of people worldwide, and there is considerable overlap between regions of high IDA and high H.pylori prevalence. The primary aims of our study were to evaluate the effect of H.pylori infection on behavior, iron metabolism, red blood cell indices, and behavioral outcomes following comorbid H. pylori infection and dietary iron deficiency in a mouse model. C57BL/6 female mice (n = 40) were used; half were placed on a moderately iron deficient (ID) diet immediately post-weaning, and the other half were maintained on an iron replete (IR) diet. Half were dosed with H.pylori SS1 at 5 weeks of age, and the remaining mice were sham-dosed. There were 4 study groups: a control group (-Hp, IR diet) as well as 3 experimental groups (-Hp, ID diet; +Hp, IR diet; +Hp,ID diet). All mice were tested in an open field apparatus at 8 weeks postinfection. Independent of dietary iron status, H.pylori -infected mice performed fewer exploratory behaviors in the open field chamber than uninfected mice (p<0.001). Hippocampal gene expression of myelination markers and dopamine receptor 1 was significantly downregulated in mice on an ID diet (both p<0.05), independent of infection status. At 12 months postinfection, hematocrit (Hct) and hemoglobin (Hgb) concentration were significantly lower in +Hp, ID diet mice compared to all other study groups. H.pylori infection caused IDA in mice maintained on a marginal iron diet. The mouse model developed in this study is a useful model to study the neurologic, behavioral, and hematologic impact of the common human co-morbidity of H. pylori infection and IDA.

  20. Helicobacter pylori infection and low dietary iron alter behavior, induce iron deficiency anemia, and modulate hippocampal gene expression in female C57BL/6 mice

    PubMed Central

    Burns, Monika; Amaya, Aldo; Bodi, Caroline; Ge, Zhongming; Bakthavatchalu, Vasudevan; Ennis, Kathleen; Wang, Timothy C.; Georgieff, Michael

    2017-01-01

    Helicobacter pylori (H.pylori), a bacterial pathogen, is a causative agent of gastritis and peptic ulcer disease and is a strong risk factor for development of gastric cancer. Environmental conditions, such as poor dietary iron resulting in iron deficiency anemia (IDA), enhance H.pylori virulence and increases risk for gastric cancer. IDA affects billions of people worldwide, and there is considerable overlap between regions of high IDA and high H.pylori prevalence. The primary aims of our study were to evaluate the effect of H.pylori infection on behavior, iron metabolism, red blood cell indices, and behavioral outcomes following comorbid H. pylori infection and dietary iron deficiency in a mouse model. C57BL/6 female mice (n = 40) were used; half were placed on a moderately iron deficient (ID) diet immediately post-weaning, and the other half were maintained on an iron replete (IR) diet. Half were dosed with H.pylori SS1 at 5 weeks of age, and the remaining mice were sham-dosed. There were 4 study groups: a control group (-Hp, IR diet) as well as 3 experimental groups (-Hp, ID diet; +Hp, IR diet; +Hp,ID diet). All mice were tested in an open field apparatus at 8 weeks postinfection. Independent of dietary iron status, H.pylori -infected mice performed fewer exploratory behaviors in the open field chamber than uninfected mice (p<0.001). Hippocampal gene expression of myelination markers and dopamine receptor 1 was significantly downregulated in mice on an ID diet (both p<0.05), independent of infection status. At 12 months postinfection, hematocrit (Hct) and hemoglobin (Hgb) concentration were significantly lower in +Hp, ID diet mice compared to all other study groups. H.pylori infection caused IDA in mice maintained on a marginal iron diet. The mouse model developed in this study is a useful model to study the neurologic, behavioral, and hematologic impact of the common human co-morbidity of H. pylori infection and IDA. PMID:28355210

  1. Iron induced nickel deficiency

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It is increasingly apparent that economic loss due to nickel (Ni) deficiency likely occurs in horticultural and agronomic crops. While most soils contain sufficient Ni to meet crop requirements, situations of Ni deficiency can arise due to antagonistic interactions with other metals. This study asse...

  2. Spontaneous liver fibrosis induced by long term dietary vitamin D deficiency in adult mice is related to chronic inflammation and enhanced apoptosis.

    PubMed

    Zhu, Longdong; Kong, Ming; Han, Yuan-Ping; Bai, Li; Zhang, Xiaohui; Chen, Yu; Zheng, Sujun; Yuan, Hong; Duan, Zhongping

    2015-05-01

    Epidemiological studies have revealed an association between vitamin D deficiency and various chronic liver diseases. However, it is not known whether lack of vitamin D can induce spontaneous liver fibrosis in an animal model. To study this, mice were fed either a control diet or a vitamin D deficient diet (VDD diet). For the positive control, liver fibrosis was induced with carbon tetrachloride. Here we show, for the first time, that liver fibrosis spontaneously developed in mice fed the VDD diet. Long-term administration of a VDD diet resulted in necro-inflammation and liver fibrosis. Inflammatory mediators including tumor necrosis factor-α, interleulin-1, interleukin-6, Toll-like-receptor 4, and monocyte chemotactic protein-1 were up-regulated in the livers of the mice fed the VDD diet. Conversely, the expression of Th2/M2 markers such as IL-10, IL-13, arginase 1, and heme oxygenase-1 were down-regulated in the livers of mice fed the VDD diet. Transforming growth factor-β1 and matrix metalloproteinase 13, which are important for fibrosis, were induced in the livers of mice fed the VDD diet. Moreover, the VDD diet triggered apoptosis in the parenchymal cells, in agreement with the increased levels of Fas and FasL, and decreased Bcl2 and Bclx. Thus, long-term vitamin D deficiency can provoke chronic inflammation that can induce liver apoptosis, which consequently activates hepatic stellate cells to initiate liver fibrosis.

  3. Dietary restriction causing iodine-deficient goitre.

    PubMed

    Cheetham, Tim; Plumb, Emma; Callaghan, James; Jackson, Michael; Michaelis, Louise

    2015-08-01

    Iodine-deficient goitre was common in some parts of the UK prior to the introduction of salt iodisation. Many contemporary salt preparations do not contain much iodine, and there are renewed concerns about the iodine status of the population. We present a boy with severe allergy who developed goitre and significant thyroid dysfunction in association with an iodine-deficient 'food-restricted' diet. The case highlights the importance of a comprehensive nutritional assessment in all children on multiple food restrictions.

  4. The disorders induced by iodine deficiency.

    PubMed

    Delange, F

    1994-01-01

    This paper reviews present knowledge on the etiology, pathophysiology, complications, prevention, and therapy of the disorders induced by iodine deficiency. The recommended dietary allowances of iodine are 100 micrograms/day for adults and adolescents, 60-100 micrograms/day for children aged 1 to 10 years, and 35-40 micrograms/day in infants aged less than 1 year. When the physiological requirements of iodine are not met in a given population, a series of functional and developmental abnormalities occur including thyroid function abnormalities and, when iodine deficiency is severe, endemic goiter and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death, and infant mortality. These complications, which constitute a hindrance to the development of the affected populations, are grouped under the general heading of iodine deficiency disorders (IDD). At least one billion people are at risk of IDD. Iodine deficiency, therefore, constitutes one of the most common preventable causes of mental deficiency in the world today. Most of the affected populations live in mountainous areas in preindustrialized countries, but 50 to 100 million people are still at risk in Europe. The most important target groups to the effects of iodine deficiency from a public health point of view are pregnant mothers, fetuses, neonates, and young infants because the main complication of IDD, i.e., brain damage resulting in irreversible mental retardation, is the consequence of thyroid failure occurring during pregnancy, fetal, and early postnatal life. The main cause of endemic goiter and cretinism is an insufficient dietary supply of iodine. The additional role of naturally occurring goitrogens has been documented in the case of certain foods (milk, cassava, millet, nuts) and bacterial and chemical water pollutants. The mechanism by which the thyroid gland adapts to an insufficient iodine supply is to increase the trapping of iodide as well as the subsequent

  5. The interaction of type of dietary carbohydrates with copper deficiency.

    PubMed

    Fields, M; Ferretti, R J; Smith, J C; Reiser, S

    1984-02-01

    The present study was designed to determine if the more severe copper deficiency in rats fed sucrose and fructose, as compared to starch, is due to a specific effect of the fructose or to a nonspecific effect of any simple carbohydrate. Seventy weanling male rats were fed, for 9 wk, copper-deficient diets or copper-supplemented diets containing either 62% starch, fructose, or glucose. Decreased hematocrit, serum copper, and ceruloplasmin concentrations but increased heart and liver weights, total liver lipid, and hepatic iron concentrations were found in all copper-deficient rats regardless of the dietary carbohydrate. Feeding rats the high glucose diet decreased plasma albumin and liver glycogen but increased blood urea nitrogen when compared to rats fed starch. However, rats fed fructose generally exhibited a more severe copper deficiency as compared to rats fed either starch or glucose. The severity was characterized by lower (p less than 0.05) body weight, liver glycogen, hematocrit, serum copper, and albumin. Conversely, liver and heart weights, blood urea nitrogen, and plasma glutamic oxaloacetic transaminase were higher (p less than 0.05). Plasma cholesterol was increased by copper deficiency only in rats fed fructose or glucose. During the study, 17 of the 40 rats fed copper-deficient diets died; 66% of those fed fructose, 26% fed glucose, and 30% fed starch. These results suggest that the fructose moiety of sucrose is responsible for the increased severity of copper deficiency in rats fed sucrose as compared to starch.

  6. Long-Term Dietary Folate Deficiency Accelerates Progressive Hearing Loss on CBA/Ca Mice

    PubMed Central

    Martínez-Vega, Raquel; Murillo-Cuesta, Silvia; Partearroyo, Teresa; Varela-Moreiras, Gregorio; Varela-Nieto, Isabel; Pajares, María A.

    2016-01-01

    Dietary folic acid deficiency induced early hearing loss in C57BL/6J mice after 2-months, corroborates the epidemiological association previously described between vitamin deficiency and this sensory impairment. However, this strain is prone to early hearing loss, and hence we decided to analyze whether the effects exerted by folate deprivation follow the same pattern in a mouse strain such as CBA/Ca, which is resistant to hearing impairment. Here, we show results of a long-term study on hearing carried out on CBA/Ca mice subjected to dietary folate deprivation. Systemic changes included decreased serum folate levels, hyperhomocysteinemia and signs of anemia in the group fed with folate-deficient (FD) diet. Initial signs of hearing loss were detected in this strain after 8-months of vitamin deficiency, and correlated with histological damage in the cochleae. In conclusion, the data presented reinforce the importance of adequate folic acid levels for the auditory system and suggest that the impact of dietary deficiencies may depend on the genetic background. PMID:27630560

  7. Influence of Secondary Hyperparathyroidism Induced by Low Dietary Calcium, Vitamin D Deficiency, and Renal Failure on Circulating Rat PTH Molecular Forms.

    PubMed

    D'Amour, Pierre; Rousseau, Louise; Hornyak, Stephen; Yang, Zan; Cantor, Tom

    2011-01-01

    Rats(r) with secondary hyperparathyroidism were studied to define the relationship between vitamin D metabolites and rPTH levels measured by 3 different rat ELISAs. Controls and renal failure (RF) rats were on a normal diet, while 2 groups on a low-calcium (-Ca) or a vitamin D-deficient (-D) diet. RF was induced surgically. Mild RF rats had normal calcium and 25(OH)D but reduced 1,25(OH)(2)D levels (P < .001) with a 2.5-fold increased in rPTH (P < .001). Severe RF rats and those on a -Ca or -D diet had reduced calcium (P < .01) and 25(OH)D levels (P < .05), with rPTH increased by 2 (-Ca diet; P < .05), 4 (-D diet; P < .001), and 20-folds (RF; P < .001) while 1,25(OH)(2)D was high (-Ca diet: P < .001) or low (-D diet, RF: P < .001). 25(OH)D and 1,25(OH)(2)D were positively and negatively related on the -Ca and -D diets, respectively. rPTH molecular forms behaved as expected in RF and on -Ca diet, but not on -D diet with more C-rPTH fragments when less were expected. This may be related to the short-time course of this study compared to prior studies.

  8. Role of zinc in regulating the testicular function. Part 3. Histopathological changes induced by dietary zinc deficiency in testes of male albino rats.

    PubMed

    Hafiez, A A; el-Kirdassy, Z H; el-Malkh, N M; el-Zayat, E M

    1990-01-01

    Zinc deficiency affects the testicular tissues adversely. The testes of zinc-deficient rats showed variable degrees of degeneration compared to both control and zinc-supplemented ones. Initially, there was an early pronounced spermatic arrest followed by a series of degeneration of the cellular layers constituting the seminiferous tubules in the zinc-deficient rats. Degenerative changes were additionally demonstrated in the interstitial tissue cells of the zinc-deficient rats. These histopathological observations in testes of zinc-deficient rats run in parallel provide an additional support to our previous publications in which we recorded a significant reduction in both serum and testicular levels of testosterone in the same group of animals, since spermatogenesis in rodents appeared to depend primarily on testosterone level.

  9. Testicular apoptosis after dietary zinc deficiency: ultrastructural and TUNEL studies.

    PubMed

    Kumari, Deepa; Nair, Neena; Bedwal, Ranveer Singh

    2011-10-01

    The present study was conducted in Wistar rats to determine whether prepubertal dietary zinc deficiency causes apoptotic changes in testes. Prepubertal male Wistar rats (40-50 gm) were divided into 3 groups: zinc control (ZC), pairfed (PF), and zinc deficient (ZD). Control and pairfed groups were given a 100 ppm zinc diet while the deficient groups received 1 ppm zinc diet for 2 and 4 weeks (w), respectively. Ultrastructural studies revealed several apoptotic features such as wavy basement membrane, displaced nuclei, chromatin condensation, plasma membrane blebbing, nuclear membrane dissolution, loss of inter-Sertoli cell junctional complexes, and intercellular bridges and deformed mitochondria. A variable spectrum of sperm defects had also been visualized e.g., acrosomal deformities such as decapitation and a ring of condensed chromatin around the nuclear periphery, deformed sperm heads with a condensed nucleus, tail-elements with superfluous cytoplasm, and damage to the mitochondrial sheath and aggregation of spermatozoa within the membrane. This was further supported by TUNEL studies. Apoptotic index, epididymal sperm concentration, motility, and fertility index also revealed a significant (P < 0.05) decrease in zinc deficient groups (2 and 4 w) when compared with their respective control and pairfed groups. All the above findings are indicative that changes observed in the testes after dietary zinc deficiency are due to the onset of apoptosis. Increased apoptotic degeneration in testes may cause irreversible changes in the germ cells associated with decreased epididymal sperm concentration, motility, and fertility index which contributes to the low efficiency of spermatogenesis thereby indicating a possible role of zinc in fertility.

  10. Selenium and selenoprotein deficiencies induce widespread pyogranuloma formation in mice, while high levels of dietary selenium decrease liver tumor size driven by TGFa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Changes in dietary selenium and selenoprotein status may influence both anti- and pro-cancer pathways, making the outcome of interventions different from one study to another. To characterize such outcomes in a defined setting, we undertook a controlled hepatocarcinogenesis study involving varying l...

  11. Dietary selenium deficiency as well as excess supplementation induces multiple defects in mouse epididymal spermatozoa: understanding the role of selenium in male fertility.

    PubMed

    Shalini, Sonia; Bansal, M P

    2008-08-01

    Selenium (Se) is essential for male fertility. The present study was carried out to observe the defects associated with Se deficiency as well as excess Se supplementation by analyzing the sperm ultrastructure and chromatin organization. Different Se status mice were generated viz. Se deficient (group I), Se adequate (group II) and Se excess (group III) by feeding the respective diets for a period of 4 (group Ia, IIa and IIIa) and 8 weeks (group Ib, IIb and IIIb). Reduction in sperm concentration, motility and percentage fertility was observed in Se deficient and Se excess groups. Electron microscopy revealed mitochondrial swelling and gaps between adjacent mitochondria in mice fed Se-deficient diet for 4 weeks. At 8 weeks, several abnormalities such as loose contact of the mitochondrial helix with the plasma membrane, loss of mitochondria, retention of cytoplasmic droplet, fracturing of outer dense fibres and presence of both the midpiece and the principal piece cross-sections in a common plasma membrane were observed. In Se excess group, the predominant defect was the frequent presence of equidistant, cross-sectioned midpieces of the tail embedded in a common cytoplasm. These defects are indicative of loss of sperm motility. Spermatozoa from Se-deficient mice had incompletely condensed chromatin and indicated an increase in occurrence of DNA strand breaks. The animals fed Se excess diet also indicated increase in DNA breaks but this was significantly less than the deficient diet fed groups. Our study reveals the defects associated with Se deficiency that result in loss of reproductive ability and also reflects its possible harmful effects on spermatozoa after prolonged consumption at supranutritional level.

  12. Effect of dietary selenium deficiency on the in vitro fertilizing ability of mice spermatozoa.

    PubMed

    Sánchez-Gutiérrez, M; García-Montalvo, E A; Izquierdo-Vega, J A; Del Razo, L M

    2008-08-01

    Selenium is an essential micronutrient for mammals, being integral part of antioxidant system. The aim of the study was to evaluate the effect of selenium deficiency on in vitro fertilization (IVF) capacity of spermatozoa and on oxidative stress in these cells. Male C57BL/6N mice were maintained on selenium-deficient or selenium-sufficient diets (0.02 or 0.2 ppm of selenium as selenomethionine, respectively) for 4 months. Liver glutathione peroxidase activity measurements were used to confirm selenium deficiency. Sperm quality and IVF capability among both groups were evaluated. To assess oxidative damage, lipid peroxidation as malondialdehyde production was determined in spermatozoa as well as the testes. Ultrastructural analyses of spermatozoa nuclei using transmission electron microscopy were also performed. The percentage of eggs fertilized with sperm from selenium-deficient mice was significantly decreased by approximately 67%. This reduced fertilization capacity was accompanied by increased levels of lipid peroxidation in both the testes and sperm, indicating that selenium deficiency induced oxidative stress. Consistent with this finding, spermatozoa from selenium-deficient animals exhibited altered chromatin condensation. Deficiency in dietary selenium decreases the reproductive potential of male mice and is associated with oxidative damage in spermatozoa.

  13. Iron-induced nickel deficiency in pecan

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Economic loss due to nickel (Ni) deficiency can occur in horticultural and agronomic crops. This study assesses impact of excessive iron (Fe) on expression of Ni deficiency in pecan [Carya illinoinensis (Wangenh.) K. Koch]. Field and greenhouse experiments found Ni deficiency to be inducible by ei...

  14. Dietary taurine deficiency and dilated cardiomyopathy in the fox.

    PubMed

    Moise, N S; Pacioretty, L M; Kallfelz, F A; Stipanuk, M H; King, J M; Gilmour, R F

    1991-02-01

    Taurine deficiency has been implicated as a potential cause of dilated cardiomyopathy. However, the relationship between taurine and myocardial function is presently unclear. The purpose of this study was to determine whether dilated cardiomyopathy in the fox is associated with dietary taurine deficiency. A total of 68 foxes from farms with a history of death caused by dilated cardiomyopathy and 14 foxes from a farm with no history of dilated cardiomyopathy were studied. Dilated cardiomyopathy was diagnosed by echocardiography in 48% of the foxes from one farm with a positive history and in none of the foxes from the control farm. Foxes less than 9 months of age were more commonly affected than older foxes (p = 0.03). Plasma taurine concentrations were significantly less (p less than 0.01) in foxes that had dilated cardiomyopathy (26.8 +/- 16.4 nmol/ml) than in the control foxes (99.3 +/- 60.2 nmol/ml). A significantly higher (p less than 0.01) incidence of dilated cardiomyopathy was present in foxes with a history of a sibling or offspring that died of dilated cardiomyopathy than in foxes without a family history of cardiac death. In one fox with dilated cardiomyopathy that was tested, the myocardial taurine concentration was lower (1.7 mumol/gm wet weight) than that of control foxes (7.3 +/- 1.6 mumol/gm wet weight). Hepatic cysteinesulfinic acid decarboxylase activity was significantly less (p less than 0.001) in foxes with dilated cardiomyopathy (0.97 +/- 0.2 nmol/mm.mg protein) than in control foxes (2.11 +/- 0.07 nmol CO2/mm.mg protein).(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Dietary factors and luteal phase deficiency in healthy eumenorrheic women

    PubMed Central

    Andrews, Mary A.; Schliep, Karen C.; Wactawski-Wende, Jean; Stanford, Joseph B.; Zarek, Shvetha M.; Radin, Rose G.; Sjaarda, Lindsey A.; Perkins, Neil J.; Kalwerisky, Robyn A.; Hammoud, Ahmad O.; Mumford, Sunni L.

    2015-01-01

    STUDY QUESTION Are prospectively assessed dietary factors, including overall diet quality, macronutrients and micronutrients, associated with luteal phase deficiency (LPD) in healthy reproductive aged women with regular menstrual cycles? SUMMARY ANSWER Mediterranean Diet Score (MDS), fiber and isoflavone intake were positively associated with LPD while selenium was negatively associated with LPD after adjusting for age, percentage body fat and total energy intake. WHAT IS KNOWN ALREADY LPD may increase the risk of infertility and early miscarriage. Prior research has shown positive associations between LPD and low energy availability, either through high dietary restraint alone or in conjunction with high energy expenditure via exercise, but few studies with adequate sample sizes have been conducted investigating dietary factors and LPD among healthy, eumenorrheic women. STUDY DESIGN, SIZE, DURATION The BioCycle Study (2005–2007) prospectively enrolled 259 women from Western New York state, USA, and followed them for one (n = 9) or two (n = 250) menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS Women aged 18–44 years, with self-reported BMI between 18 and 35 kg/m2 and cycle lengths between 21 and 35 days, were included in the study. Participants completed baseline questionnaires, four 24-h dietary recalls per cycle and daily diaries capturing vigorous exercise, perceived stress and sleep; they also provided up to eight fasting serum samples during clinic visits timed to specific phases of the menstrual cycle using a fertility monitor. Cycles were included for this analysis if the peak serum luteal progesterone was >1 ng/ml and a urine or serum LH surge was detected. Associations between prospectively assessed diet quality, macronutrients and micronutrients and LPD (defined as luteal duration <10 days) were evaluated using generalized linear models adjusting for age, percentage body fat and total energy intake. MAIN RESULTS AND THE ROLE OF CHANCE LPD

  16. Deficient and excess dietary selenium levels affect growth performance, blood cells apoptosis and liver HSP70 expression in juvenile yellow catfish Pelteobagrus fulvidraco.

    PubMed

    Hu, Jun-Ru; Huang, Yan-Hua; Wang, Guo-Xia; Wu, Ying-Xia; Xian, Jian-An; Wang, An-Li; Cao, Jun-Ming

    2016-02-01

    We investigated the effects of deficient and excess dietary selenium (Se) on growth, blood cells apoptosis and liver heat shock protein 70 (HSP70) expression in juvenile yellow catfish (Pelteobagrus fulvidraco). After 8 weeks, yellow catfish (initial weight: 2.12 ± 0.01 g) fed isonitrogenous and isolipid diets containing <0.05 (deficient dietary Se) or 6.5 (excess dietary Se) mg Se/kg displayed a significantly lower weight gain ratio (WGR) than those fed a diet containing 0.23 (normal dietary Se) mg Se/kg. As dietary Se levels increased, liver Se concentration, glutathione peroxidase activity and the hepatosomatic index increased significantly. Plasma glucose concentration was highest in the normal treatment compared with the excess dietary Se treatment. Both deficient and excess dietary Se lead to increased reactive oxygen species (ROS) production and apoptosis ratio in blood cells, whereas only excess dietary Se increased their cytoplasmic free-Ca(2+) (CF-Ca(2+)) concentration. Excess dietary Se also resulted in the highest level of HSP70 expression, thereby possibly providing a protective mechanism against oxidative stress. These results indicate that both deficient and excess dietary Se restrained the growth of juvenile yellow catfish and caused oxidative stress. The overproduction of ROS may act as a signal molecule mediate apoptosis when dietary Se deficiency. Both ROS and CF-Ca(2+) were recorded when dietary Se excess, suggesting that Ca(2+) may be activated by Se and play a major role during Se-induced oxidative stress and cell apoptosis.

  17. Maternal dietary choline deficiency alters angiogenesis in fetal mouse hippocampus

    PubMed Central

    Mehedint, Mihai G.; Craciunescu, Corneliu N.; Zeisel, Steven H.

    2010-01-01

    We examined whether maternal dietary choline modulates angiogenesis in fetal brain. Pregnant C57BL/6 mice were fed either a choline-deficient (CD), control (CT), or choline-supplemented diet (CS) from days 12 to 17 (E12-17) of pregnancy and then fetal brains were studied. In CD fetal hippocampus, proliferation of endothelial cells (EC) was decreased by 32% (p < 0.01 vs. CT or CS) while differentiated EC clusters (expressing factor VIII related antigen (RA)) increased by 25% (p < 0.01 vs. CT or CS). These changes were associated with > 25% decrease in the number of blood vessels in CD fetal hippocampus (p < 0.01 vs. CT and CS), with no change in total cross-sectional area of these blood vessels. Expression of genes for the angiogenic signals derived from both endothelial and neuronal progenitor cells (NPC) was increased in CD fetal hippocampus VEGF C (Vegfc), 2.0-fold, p < 0.01 vs. CT and angiopoietin 2 (Angpt2), 2.1-fold, (p < 0.01 vs. CT)). Similar increased expression was observed in NPC isolated from E14 fetal mouse brains and exposed to low (5 μM), CT (70 μM), or high choline (280 μM) media for 72 h (low choline caused a 9.7-fold increase in relative gene expression of Vegfc (p < 0.001 vs. CT and high) and a 3.4-fold increase in expression of Angpt2, (p < 0.05 vs. CT and high). ANGPT2 protein was increased 42.2% (p < 0.01). Cytosine-phosphate-guanine dinucleotide islands in the proximity of the promoter areas of Vegfc and Angpt2 were hypomethylated in low choline NPC compared to CT NPC (p < 0.01). We conclude that maternal dietary choline intake alters angiogenesis in the developing fetal hippocampus. PMID:20624989

  18. The severity of copper deficiency in rats is determined by the type of dietary carbohydrate.

    PubMed

    Fields, M; Ferretti, R J; Reiser, S; Smith, J C

    1984-04-01

    The purpose of this investigation was to study the interaction between copper and dietary carbohydrates on clinical and enzymatic indices associated with copper deficiency. Copper deficiency was produced in rats by feeding diets adequate in all nutrients including selenium and chromium, but marginal in copper (1.2 micrograms/g diet) containing 62% of either starch, fructose, or glucose. During the fifth week, the fructose of the copper-deficient diet (20 rats) was replaced by either starch (10 rats) or by glucose (10 rats). The experiment was terminated after 11 weeks. Copper deficiency in rats fed fructose significantly lowered body weight and hematocrit, but increased liver weight, blood urea nitrogen, ammonia, cholesterol, and triglycerides when compared to rats fed starch or glucose. The copper metalloenzyme, superoxide dismutase, the selenoenzyme, glutathione peroxidase, and hepatic ATP were decreased in the copper-deficient rats fed fructose as compared to copper-deficient rats fed starch or glucose. These results indicate that fructose may be the dietary component which has a deleterious effect on copper and selenium status. Changing the type of dietary carbohydrate in copper-deficient rats from fructose to either starch or glucose ameliorated the severity of the deficiency. The protective effects were more pronounced with starch than with glucose.

  19. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity.

    PubMed

    An, Lin; Hu, Xiao-Wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-02-22

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity.

  20. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity

    PubMed Central

    An, Lin; Hu, Xiao-wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-01-01

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity. PMID:28225086

  1. Dietary calcium and zinc deficiency risks are decreasing but remain prevalent

    PubMed Central

    Kumssa, Diriba B.; Joy, Edward J. M.; Ander, E. Louise; Watts, Michael J.; Young, Scott D.; Walker, Sue; Broadley, Martin R.

    2015-01-01

    Globally, more than 800 million people are undernourished while >2 billion people have one or more chronic micronutrient deficiencies (MNDs). More than 6% of global mortality and morbidity burdens are associated with undernourishment and MNDs. Here we show that, in 2011, 3.5 and 1.1 billion people were at risk of calcium (Ca) and zinc (Zn) deficiency respectively due to inadequate dietary supply. The global mean dietary supply of Ca and Zn in 2011 was 684 ± 211 and 16 ± 3 mg capita−1 d−1 (±SD) respectively. Between 1992 and 2011, global risk of deficiency of Ca and Zn decreased from 76 to 51%, and 22 to 16%, respectively. Approximately 90% of those at risk of Ca and Zn deficiency in 2011 were in Africa and Asia. To our knowledge, these are the first global estimates of dietary Ca deficiency risks based on food supply. We conclude that continuing to reduce Ca and Zn deficiency risks through dietary diversification and food and agricultural interventions including fortification, crop breeding and use of micronutrient fertilisers will remain a significant challenge. PMID:26098577

  2. Dietary calcium and zinc deficiency risks are decreasing but remain prevalent

    NASA Astrophysics Data System (ADS)

    Kumssa, Diriba B.; Joy, Edward J. M.; Ander, E. Louise; Watts, Michael J.; Young, Scott D.; Walker, Sue; Broadley, Martin R.

    2015-06-01

    Globally, more than 800 million people are undernourished while >2 billion people have one or more chronic micronutrient deficiencies (MNDs). More than 6% of global mortality and morbidity burdens are associated with undernourishment and MNDs. Here we show that, in 2011, 3.5 and 1.1 billion people were at risk of calcium (Ca) and zinc (Zn) deficiency respectively due to inadequate dietary supply. The global mean dietary supply of Ca and Zn in 2011 was 684 ± 211 and 16 ± 3 mg capita-1 d-1 (±SD) respectively. Between 1992 and 2011, global risk of deficiency of Ca and Zn decreased from 76 to 51%, and 22 to 16%, respectively. Approximately 90% of those at risk of Ca and Zn deficiency in 2011 were in Africa and Asia. To our knowledge, these are the first global estimates of dietary Ca deficiency risks based on food supply. We conclude that continuing to reduce Ca and Zn deficiency risks through dietary diversification and food and agricultural interventions including fortification, crop breeding and use of micronutrient fertilisers will remain a significant challenge.

  3. Dietary deficiencies of unsaturated fatty acids and starch cause atopic dermatitis-like pruritus in hairless mice.

    PubMed

    Fujii, Masanori; Shimazaki, Yuki; Muto, Yoshiko; Kohno, Shigekatsu; Ohya, Susumu; Nabe, Takeshi

    2015-02-01

    Hairless mice fed with a special diet (named HR-AD) show atopic dermatitis (AD)-like pruritic skin inflammation that is almost completely resolved with the supplementation of an unsaturated fatty acid (UFA), the linoleic acid (LA). This suggests that the dietary deficiency of LA is the key cause of this dermatitis. However, because there is no appropriate control diet for HR-AD, the involvement of other dietary ingredients cannot be ruled out. Furthermore, it has not yet been tested whether only UFA deficiency can cause such AD-like pruritus. In this study, using semi-purified custom diets, we attempted to reproduce this syndrome. Four-week-old hairless mice were maintained on a widely used standard diet American Institute of Nutrition-76A (AIN-76A), its modifications, or HR-AD. Several modifications of fat and carbohydrate components revealed that dietary deficiency of both UFAs and cornstarch was required to induce severe skin barrier dysfunction as typically occurred in HR-AD-fed mice. An UFA- and cornstarch-deficient diet caused severe AD-like pruritus comparable to HR-AD, despite weak Th2 immune responses and absence of immunoglobulin E production. On the other hand, a diet lacking UFAs but containing cornstarch significantly alleviated the development of pruritic dermatitis. Furthermore, the supplementation of wheat starch similarly improved skin barrier function. In conclusion, this study showed that a lack of certain starches might also be the cause of diet-induced AD. Our findings could help to reproduce the diet-induced AD itch model and also provide evidence that certain starches can have protective and ameliorative effects on AD-like pruritus.

  4. Eats roots and leaves. Can edible horticultural crops address dietary calcium, magnesium and potassium deficiencies?

    PubMed

    Broadley, Martin R; White, Philip J

    2010-11-01

    Human individuals require at least 20 inorganic elements ('minerals') for normal functioning. However, much of the world's population is probably deficient in one or more essential minerals and at increased risk of physiological disorders. Addressing these 'hidden hungers' is a challenge for the nutrition and agriculture sectors. Mineral deficiencies among populations are typically identified from dietary surveys because (1) minerals are acquired primarily from dietary sources and (2) (bio)assays of mineral status can be unreliable. While dietary surveys are likely to under-report energy intakes, surveys show that 9% of all UK and US adults consume Ca and Mg, and 14% of adults consume K, at quantities below the UK lower reference nutrient intake, and are therefore at risk of deficiency. Low dietary Ca, Mg and K intakes can be caused by energy-malnourishment and by cultural and economic factors driving dietary conservatism. For example, cereal grains routinely displace vegetables and fruits in the diet. Cereal grains have low concentrations of several minerals, notably Ca, as a consequence of their physiology. Low grain mineral concentrations are compounded when cereal crops are grown in soils of low mineral phytoavailability and when grain is processed. In this paper, the impact of increased vegetable consumption and horticultural biofortification, i.e. enhancing crop mineral content through breeding and agronomy, on intakes of the major minerals Ca, Mg and K is assessed. Despite low energy intake from horticultural crops generally, increased vegetable consumption and biofortification would significantly improve dietary intakes of Ca, Mg and K.

  5. FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED GENOTOXICITY IN MICE

    EPA Science Inventory

    Folate deficiency increases background levels of DNA damage and can enhance the mutagenicity of chemical agents. Duplicate experiments were performed to investigate the effect of dietary folate deficiency on arsenic induction of micronuclei (MN) in peripheral blood cells. Male C5...

  6. Response to Dietary Phosphate Deficiency is Affected by Genetic Background in Growing Pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Concern over the environmental impact of phosphate (P) excretion from pig production has led to reduced dietary P supplementation. To examine how genetics influence P utilization, 94 gilts sired by 2 genetic lines (PIC337 and PIC280) were fed either a P adequate diet (PA) or a 20% P deficient diet ...

  7. EFFECT OF DIETARY FOLATE DEFICIENCY ON ARSENIC GENOTOXICITY IN MICE

    EPA Science Inventory

    Arsenic, a human carcinogen found in drinking water supplies throughout the world, is clastogenic in human and rodent cells. An estimated ten percent of Americans are deficient in folate, a methyl donor necessary for normal nucleotide metabolism, DNA synthesis, and DNA methylatio...

  8. Amelioration of estrogen deficiency-induced obesity by collagen hydrolysate

    PubMed Central

    Chiang, Tsay-I; Chang, I-Chang; Lee, Hsueh-Hui; Hsieh, Kuang hui; Chiu, Yung-Wei; Lai, Te-Jen; Liu, Jer-Yuh; Hsu, Li-Sung; Kao, Shao-Hsuan

    2016-01-01

    Objectives: Menopausal transition with declining estrogen levels significantly affects the physiological properties of women and consequently contributes to a series of medical conditions, including obesity. Obesity is a crucial risk factor associated with cardiovascular diseases, diabetes mellitus, and breast cancer. Increasing dietary protein content improves satiety and energy expenditure. Thus, we hypothesize that supplementing with collagen, a common dietary protein, may alleviate menopause-induced obesity. Methods: We used ovariectomized (OVX) rats to mimic a menopausal human. The body weight of OVX rats significantly increased compared with that of sham-operated rats (P<0.05), but uterus weight was decreased. Adipocyte size in perigonadal adipose tissue also increased (P<0.05). Results: By contrast, OVX rats supplemented with aqueous collagen hydrolysate (2.5 mg/mL) exhibited significant attenuation in body weight gain and adipocyte enlargement (P<0.05), but insignificant change in uterus weight. Further investigation indicated that collagen hydrolysate supplementation insignificantly affected the levels of dorsal fat, serum total cholesterol, and serum triacylglycerol. Levels of serum biochemical factors, calcium, phosphorus, and glucose were also insignificantly altered by collagen hydrolysate supplementation. Conclusion: Collagen hydrolysate supplementation reduced body weight gain and adipocyte enlargement in response to ovariectomy but slightly affected blood lipids, calcium, and glucose in both sham-operated and OVX rats. Collagen hydrolysate supplementation is beneficial in ameliorating estrogen deficiency-induced obesity and its associated risk factors. PMID:27877077

  9. Amelioration of estrogen deficiency-induced obesity by collagen hydrolysate.

    PubMed

    Chiang, Tsay-I; Chang, I-Chang; Lee, Hsueh-Hui; Hsieh, Kuang Hui; Chiu, Yung-Wei; Lai, Te-Jen; Liu, Jer-Yuh; Hsu, Li-Sung; Kao, Shao-Hsuan

    2016-01-01

    Objectives: Menopausal transition with declining estrogen levels significantly affects the physiological properties of women and consequently contributes to a series of medical conditions, including obesity. Obesity is a crucial risk factor associated with cardiovascular diseases, diabetes mellitus, and breast cancer. Increasing dietary protein content improves satiety and energy expenditure. Thus, we hypothesize that supplementing with collagen, a common dietary protein, may alleviate menopause-induced obesity. Methods: We used ovariectomized (OVX) rats to mimic a menopausal human. The body weight of OVX rats significantly increased compared with that of sham-operated rats (P<0.05), but uterus weight was decreased. Adipocyte size in perigonadal adipose tissue also increased (P<0.05). Results: By contrast, OVX rats supplemented with aqueous collagen hydrolysate (2.5 mg/mL) exhibited significant attenuation in body weight gain and adipocyte enlargement (P<0.05), but insignificant change in uterus weight. Further investigation indicated that collagen hydrolysate supplementation insignificantly affected the levels of dorsal fat, serum total cholesterol, and serum triacylglycerol. Levels of serum biochemical factors, calcium, phosphorus, and glucose were also insignificantly altered by collagen hydrolysate supplementation. Conclusion: Collagen hydrolysate supplementation reduced body weight gain and adipocyte enlargement in response to ovariectomy but slightly affected blood lipids, calcium, and glucose in both sham-operated and OVX rats. Collagen hydrolysate supplementation is beneficial in ameliorating estrogen deficiency-induced obesity and its associated risk factors.

  10. Pre-weaning dietary iron deficiency impairs spatial learning and memory in the cognitive holeboard task in piglets

    PubMed Central

    Antonides, Alexandra; Schoonderwoerd, Anne C.; Scholz, Gabi; Berg, Brian M.; Nordquist, Rebecca E.; van der Staay, Franz Josef

    2015-01-01

    Iron deficiency is the most common nutritional deficiency in humans, affecting more than two billion people worldwide. Early-life iron deficiency can lead to irreversible deficits in learning and memory. The pig represents a promising model animal for studying such deficits, because of its similarities to humans during early development. We investigated the effects of pre-weaning dietary iron deficiency in piglets on growth, blood parameters, cognitive performance, and brain histology later in life. Four to six days after birth, 10 male sibling pairs of piglets were taken from 10 different sows. One piglet of each pair was given a 200 mg iron dextran injection and fed a control milk diet for 28 days (88 mg Fe/kg), whereas the other sibling was given a saline injection and fed an iron deficient (ID) milk diet (21 mg Fe/kg). Due to severely retarded growth of two of the ID piglets, only eight ID piglets were tested behaviorally. After dietary treatment, all piglets were fed a balanced commercial pig diet (190–240 mg Fe/kg). Starting at 7.5 weeks of age, piglets were tested in a spatial cognitive holeboard task. In this task, 4 of 16 holes contain a hidden food reward, allowing measurement of working (short-term) memory and reference (long-term) memory (RM) simultaneously. All piglets received 40–60 acquisition trials, followed by a 16-trial reversal phase. ID piglets showed permanently retarded growth and a strong decrease in blood iron parameters during dietary treatment. After treatment, ID piglets' blood iron values restored to normal levels. In the holeboard task, ID piglets showed impaired RM learning during acquisition and reversal. Iron staining at necropsy at 12 weeks of age showed that ID piglets had fewer iron-containing cells in hippocampal regions CA1 and dentate gyrus (DG). The number of iron-containing cells in CA3 correlated positively with the average RM score during acquisition across all animals. Our results support the hypothesis that early

  11. Pre-weaning dietary iron deficiency impairs spatial learning and memory in the cognitive holeboard task in piglets.

    PubMed

    Antonides, Alexandra; Schoonderwoerd, Anne C; Scholz, Gabi; Berg, Brian M; Nordquist, Rebecca E; van der Staay, Franz Josef

    2015-01-01

    Iron deficiency is the most common nutritional deficiency in humans, affecting more than two billion people worldwide. Early-life iron deficiency can lead to irreversible deficits in learning and memory. The pig represents a promising model animal for studying such deficits, because of its similarities to humans during early development. We investigated the effects of pre-weaning dietary iron deficiency in piglets on growth, blood parameters, cognitive performance, and brain histology later in life. Four to six days after birth, 10 male sibling pairs of piglets were taken from 10 different sows. One piglet of each pair was given a 200 mg iron dextran injection and fed a control milk diet for 28 days (88 mg Fe/kg), whereas the other sibling was given a saline injection and fed an iron deficient (ID) milk diet (21 mg Fe/kg). Due to severely retarded growth of two of the ID piglets, only eight ID piglets were tested behaviorally. After dietary treatment, all piglets were fed a balanced commercial pig diet (190-240 mg Fe/kg). Starting at 7.5 weeks of age, piglets were tested in a spatial cognitive holeboard task. In this task, 4 of 16 holes contain a hidden food reward, allowing measurement of working (short-term) memory and reference (long-term) memory (RM) simultaneously. All piglets received 40-60 acquisition trials, followed by a 16-trial reversal phase. ID piglets showed permanently retarded growth and a strong decrease in blood iron parameters during dietary treatment. After treatment, ID piglets' blood iron values restored to normal levels. In the holeboard task, ID piglets showed impaired RM learning during acquisition and reversal. Iron staining at necropsy at 12 weeks of age showed that ID piglets had fewer iron-containing cells in hippocampal regions CA1 and dentate gyrus (DG). The number of iron-containing cells in CA3 correlated positively with the average RM score during acquisition across all animals. Our results support the hypothesis that early

  12. Marginal biotin deficiency can be induced experimentally in humans using a cost-effective outpatient design.

    PubMed

    Stratton, Shawna L; Henrich, Cindy L; Matthews, Nell I; Bogusiewicz, Anna; Dawson, Amanda M; Horvath, Thomas D; Owen, Suzanne N; Boysen, Gunnar; Moran, Jeffery H; Mock, Donald M

    2012-01-01

    To date, marginal, asymptomatic biotin deficiency has been successfully induced experimentally by the use of labor-intensive inpatient designs requiring rigorous dietary control. We sought to determine if marginal biotin deficiency could be induced in humans in a less expensive outpatient design incorporating a self-selected, mixed general diet. We sought to examine the efficacy of three outpatient study designs: two based on oral avidin dosing and one based on a diet high in undenatured egg white for a period of 28 d. In study design 1, participants (n = 4; 3 women) received avidin in capsules with a biotin binding capacity of 7 times the estimated dietary biotin intake of a typical self-selected diet. In study design 2, participants (n = 2; 2 women) received double the amount of avidin capsules (14 times the estimated dietary biotin intake). In study design 3, participants (n = 5; 3 women) consumed egg-white beverages containing avidin with a biotin binding capacity of 7 times the estimated dietary biotin intake. Established indices of biotin status [lymphocyte propionyl-CoA carboxylase activity; urinary excretion of 3-hydroxyisovaleric acid, 3-hydroxyisovaleryl carnitine (3HIA-carnitine), and biotin; and plasma concentration of 3HIA-carnitine] indicated that study designs 1 and 2 were not effective in inducing marginal biotin deficiency, but study design 3 was as effective as previous inpatient study designs that induced deficiency by egg-white beverage. Marginal biotin deficiency can be induced experimentally by using a cost-effective outpatient design by avidin delivery in egg-white beverages. This design should be useful to the broader nutritional research community.

  13. Lack of an effect of dietary fructose on severity of zinc deficiency in rats.

    PubMed

    Smith, J C; Failla, M L; Fields, M; Rose, A; Seidel, K

    1987-08-01

    Because feeding rats diets containing fructose as the carbohydrate source reduces copper and selenium status, we investigated whether the type of dietary carbohydrate also affected indices of zinc status. The experimental design was a 2 X 2 factorial study with the source of dietary carbohydrate (cornstarch or fructose) and the level of dietary zinc (0.7 or 31 micrograms Zn/g) as the variables. The experiment utilized 76 weanling male Sprague-Dawley rats randomly assigned to one of four dietary groups. Animals fed a zinc-deficient fructose diet were allowed to consume the diet ad libitum; all other groups were pair-fed to that group to ensure equivalent nutrient and energy intake. The results of the 29-d study showed that the most sensitive indices of zinc status measured, including growth, survival and the zinc concentrations of plasma, femur and testes, were not affected by the type of dietary carbohydrate. This lack of an effect of fructose on the zinc status of the experimental animals indicates that the ability of fructose to exacerbate copper and selenium deficiencies is specific, rather than representing a generalized effect of this simple sugar on the requirements and/or metabolism of all essential trace elements.

  14. Effect of selenium and vitamin E dietary deficiencies on chick lymphoid organ development (42361)

    SciTech Connect

    Marsh, J.A.; Combs, G.F. Jr.; Whitacre, M.E.; Dietert, R.R.

    1986-09-01

    Diets specifically deficient in selenium (Se) and/or vitamin E or adequate in both nutrients were fed to chicks from the time of hatching. Lymphoid organs (bursa, thymus, and in some instances, spleen) were collected from chicks 7-35 days of age. Growth of the chicks fed these diets was monitored over the experimental period as was lymphoid organ growth. The development of the primary lymphoid organs was further assessed by histological techniques and the organ contents of vitamin E (..cap alpha..-tocopherol) and Se were determined. Specific deficiencies of either Se or vitamin E were found to significantly impair bursal growth as did a combined deficiency. Thymic growth was impaired only by the combined deficiency diet. Severe histopathological changes in the bursa resulted from the combined deficiency and these were detectable by 10-14 days after hatching. These changes were characterized by a gradual degeneration of the epithelium and an accompanying depletion of lymphocytes. Similar changes, although slower to develop and less severe, were observed in the thymus as a result of the combined deficiency. When both serum and tissue levels of vitamin E and Se were monitored, it was observed that these were rapidly and independently depleted by the specific deficiency diets. These data suggest that the primary lymphoid organs are major targets of Se and vitamin E dietary deficiencies and provide a possible mechanism by which immune function may be impaired.

  15. Effect of dietary zinc deficiency on the endogenous phosphorylation and dephosphorylation of rat erythrocyte membrane

    SciTech Connect

    Paterson, P.G.; Allen, O.B.; Bettger, W.J.

    1987-12-01

    The effect of dietary zinc deficiency on patterns of phosphorylation and dephosphorylation of rat erythrocyte membrane proteins and erythrocyte filterability was examined. Weanling male Wistar rats were fed an egg white-based diet containing less than 1.1 mg zinc/kg diet ad libitum for 3 wk. Control rats were either pair-fed or ad libitum-fed the basal diet supplemented with 100 mg zinc/kg diet. Net phosphorylation and dephosphorylation of erythrocyte membrane proteins were carried out by an in vitro assay utilizing (gamma-/sup 32/P)ATP. The membrane proteins were subsequently separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the /sup 32/P content of gel slices was counted by Cerenkov counting. Erythrocyte filterability was measured as the filtration time of suspensions of erythrocytes, both untreated and preincubated with diamide, under constant pressure. Erythrocyte ghosts from zinc-deficient rats demonstrated greater dephosphorylation of protein bands R1 plus R2 and R7 than pair-fed rats and greater net phosphorylation of band R2.2 than pair-fed or ad libitum-fed control rats (P less than 0.05). Erythrocytes from ad libitum-fed control rats showed significantly longer filtration times than those from zinc-deficient or pair-fed control rats. In conclusion, dietary zinc deficiency alters in vitro patterns of erythrocyte membrane protein phosphorylation and dephosphorylation, whereas the depression in food intake associated with the zinc deficiency increases erythrocyte filterability. 71 references.

  16. Effects of dietary vitamin E deficiency on systematic pathological changes and oxidative stress in fish.

    PubMed

    Wang, Kaiyu; Wang, Erlong; Qin, Zhenyang; Zhou, Zhen; Geng, Yi; Chen, Defang

    2016-12-20

    The aim of this study was to investigate the effects of dietary vitamin E deficiency on systematic pathological changes and oxidative stress in fish. A total of 320 healthy common carp (Cyprinus carpio) were randomized into four groups; the control group was fed a basal diet supplemented with 100 IUkg-1 of vitamin E, while the three experimental groups were fed the same basal diet with reduced vitamin E content (0, 25, or 50 IUkg-1). Findings showed that fish in the experimental groups mainly presented with sekoke disease, exophthalmia, leprnorthsis, and ascites. Histopathological and ultrastructural changes comprised nutritional myopathy with muscle fiber denaturation and necrosis, and multi-tissue organ swelling, degeneration, and necrosis. Compared with the control group, RBC count, hemoglobin content, vitamin E concentration, and superoxide dismutase activity were significantly lower in all three experimental groups. However, malondialdehyde content was considerably higher in experimental groups than in the control group. However, there was no difference in glutathione peroxidase activity among groups. In conclusion, dietary vitamin E deficiency (<100 IUkg-1) can cause severe injury and, in particular, oxidative damage in common carp. The oxidative damage might be a main influence caused by vitamin E deficiency in fish. These findings reveal the complete systematic pathological effect of vitamin E deficiency in common carp, which may be applicable to other fish and animals.

  17. Visual loss and optic nerve head swelling in thiamine deficiency without prolonged dietary deficiency

    PubMed Central

    Gratton, Sean M; Lam, Byron L

    2014-01-01

    Visual loss due to optic neuropathy is a rare manifestation of thiamine deficiency. We report a case of a 39-year-old woman with a body mass index (BMI) of 29 kg/m2 who developed visual loss and bilateral optic nerve head swelling after a short, self-limited gastrointestinal illness. She was disoriented and inattentive and had absent ankle jerk reflexes, diminished sensation in both legs below the knees, and marked truncal ataxia. Magnetic resonance imaging (MRI) showed increased T2-signal in the medial thalami and mammillary bodies. The serum thiamine level was 8 nmol/L (normal 8–30). The diagnosis of thiamine deficiency was made, and the patient’s vision and neurologic symptoms improved significantly with intramuscular thiamine treatment. Thiamine deficiency can occur in the absence of an obvious predisposing factor such as alcoholism or low body weight. The clinician must be aware of the factors that govern vitamin availability and maintain a high index of suspicion to make the diagnosis in such cases. PMID:24899800

  18. Influence of dietary iron level and form on biochemical, hematological, and immunological changes in copper deficient rats

    SciTech Connect

    Leu, H.; Gallaher, D.D.; Kramer, T.R.

    1986-03-01

    Weanling male Lewis rats (N = 10/group) were fed ad-libitum for 42 days diets based on AIN standards containing 21% casein, 5% safflower oil, deficient (0.6 ..mu..g/g) or adequate (5.6 ..mu..g/g) levels of Cu, and adequate (50 ..mu..g/g) or high (300 ..mu..g/g) levels of Fe/sup +2/ or Fe/sup +3/. Cu-deficient rats, regardless of Fe level or form, exhibited depressed (p < 0.05) serum Cu, Fe and ceruloplasmin activity, and hemoglobin levels; and elevated (p < 0.05) unsaturated serum Fe binding capacity. Except for high Fe/sup +3/ fed rats, Cu-deficient rats showed decreased hematocrits. Decreased proliferation was exhibited by concanavalin-A (Con-A) stimulated spleen lymphoid cells (SLC) of Cu-deficient rats fed adequate dietary Fe, but not by SLC of Cu-deficient rats fed high dietary Fe. High Fe fed rats exhibited reduced proliferation and increased variability in proliferation by Con-A stimulated SLC, which apparently caused a lack of difference in proliferation by SLC of Cu-deficient and Cu-adequate rats fed high Fe. Thus, high dietary Fe did not correct biochemical and hematological parameters in Cu-deficient rats, but because of lowered proliferation and increased variability of SLC proliferation, high dietary Fe did alleviate suppressed Con-A stimulated SLC proliferation in Cu-deficiency.

  19. Physiological management of dietary deficiency in n-3 fatty acids by spawning Gulf killifish (Fundulus grandis).

    PubMed

    Patterson, Joshua T; Green, Christopher C

    2015-08-01

    Lipid dynamics of spawning fish are critical to the production of viable embryos and larvae. The present study utilized manipulation of dietary fatty acid (FA) profiles to examine the ability of spawning Gulf killifish (Fundulus grandis) to mobilize critical lipid components from somatic reserves or synthesize long-chain polyunsaturated FAs (LC-PUFAs) de novo from shorter-chain C18 precursors. An egg and multi-tissue evaluation of changes in FA concentrations across time after fish were switched from LC-PUFA-rich to LC-PUFA-deficient experimental diets was employed. The two experimental diets contained lipid sources which differed drastically in n-3 C18 FA content but had similar levels of n-6 C18 FAs. Discrete effects of dietary n-3 FAs can be analyzed because n-3 and n-6 represent distinct metabolic families which cannot be exchanged in vivo. Results indicate that a combination of mobilization and de novo synthesis is likely utilized to maintain physiologically required FA levels in critical tissues and embryos. Mobilization was supported by decreases in LC-PUFAs in somatic tissues and decreases in intraperitoneal fat content and liver mass. Evidence for biosynthesis was provided by a higher level of n-3 LC-PUFAs in the liver and ova of fish fed diets containing n-3 C18 precursors versus those fed diets with low levels of precursor FAs. The characteristic physiological plasticity of Gulf killifish is exemplified in the nutritional domain by its management of dietary FA deficiency.

  20. Acute dietary zinc deficiency before conception compromises oocyte epigenetic programming and disrupts embryonic development

    PubMed Central

    Tian, X; Diaz, FJ

    2013-01-01

    Recent findings show that zinc is an important factor necessary for regulating the meiotic cell cycle and ovulation. However, the role of zinc in promoting oocyte quality and developmental potential is not known. Using an in vivo model of acute dietary zinc deficiency, we show that feeding a zinc deficient diet (ZDD) for 3–5 days before ovulation (preconception) dramatically disrupts oocyte chromatin methylation and preimplantation development. There was a dramatic decrease in histone H3K4 trimethylation and global DNA methylation in zinc deficient oocytes. Moreover, there was a 3–20 fold increase in transcript abundance of repetitive elements (Iap, Line1, Sineb1, Sineb2), but a decrease in Gdf9, Zp3 and Figla mRNA. Only 53% and 8% of mature eggs reached the 2-cell stage after IVF in animals receiving a 3 and 5 day ZDD, respectively, while a 5 day ZDD in vivo reduced the proportion of 2-cells to 49%. In vivo fertilized 2-cell embryos cultured in vitro formed fewer (38%) blastocysts compared to control embryos (74%). Likewise, fewer blastocyst and expanded blastocyst were collected from the reproductive tract of zinc deficient animals on day 3.5 of pregnancy. This could be due to a decrease in Igf2 and H19 mRNA in ZDD blastocyst. Supplementation with a methyl donor (SAM) during IVM restored histone H3K4me3 and doubled the IVF success rate from 17% to 43% in oocytes from zinc deficient animals. Thus, the terminal period of oocyte development is extremely sensitive to perturbation in dietary zinc availability. PMID:23348678

  1. Perforin deficiency attenuates collagen-induced arthritis

    PubMed Central

    Bauer, Kristin; Knipper, Annika; Tu-Rapp, Hoang; Koczan, Dirk; Kreutzer, Hans-Jürgen; Nizze, Horst; Mix, Eilhard; Thiesen, Hans-Juergen; Holmdahl, Rikard; Ibrahim, Saleh M

    2005-01-01

    Collagen-induced arthritis (CIA), an approved animal model for rheumatoid arthritis, is thought to be a T cell-dependent disease. There is evidence that CD8+ T cells are a major subset controlling the pathogenesis of CIA. They probably contribute to certain features of disease, namely tissue destruction and synovial hyperplasia. In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8+ T cells, for the pathogenesis of CIA. We generated DBA/1J mice suffering from mutations of the pfp molecule, DBA/1J-pfp-/-, and studied their susceptibility to arthritis. As a result, pfp-deficient mice showed a reduced incidence (DBA/1J-pfp+/+, 64%; DBA/1J-pfp-/-, 54%), a slightly delayed onset (onset of disease: DBA/1J-pfp+/+, 53 ± 3.6; DBA/1J-pfp-/-, 59 ± 4.9 (mean ± SEM), and milder form of the disease (maximum disease score: DBA/1J-pfp+/+, 7.3 ± 1.1; DBA/1J-pfp-/-, 3.4 ± 1.4 (mean ± SEM); P < 0.05). Concomitantly, peripheral T cell proliferation in response to the specific antigen bovine collagen II was increased in pfp-/- mice compared with pfp+/+ mice, arguing for an impaired killing of autoreactive T cells caused by pfp deficiency. Thus, pfp-mediated cytotoxicity is involved in the initiation of tissue damage in arthritis, but pfp-independent cytotoxic death pathways might also contribute to CIA. PMID:15987490

  2. The effect of zinc deficiency on salt taste acuity, preference, and dietary sodium intake in hemodialysis patients.

    PubMed

    Kim, So Mi; Kim, Miyeon; Lee, Eun Kyoung; Kim, Soon Bae; Chang, Jai Won; Kim, Hyun Woo

    2016-07-01

    Introduction High sodium intake is the main cause of fluid overload in hemodialysis (HD) patients, leading to increased cardiovascular mortality. High sodium intake is known to be associated with low salt taste acuity and/or high preference. As the zinc status could influence taste acuity, we analyzed the effect of zinc deficiency on salt taste acuity, preference, and dietary sodium intake in HD patients. Methods A total of 77 HD patients was enrolled in this cross-sectional study. Zinc deficiency was defined as serum zinc level with below 70 µg/mL. The patients were divided into two groups based on serum zinc level. Salt taste acuity and preference were determined by a sensory test using varying concentrations of NaCl solution, and dietary sodium intake was estimated using 3-day dietary recall surveys. Findings The mean salt recognition threshold and salt taste preference were significantly higher in the zinc deficient group than in the non-zinc deficient group. And there was significant positive correlation between salt taste preference and dietary sodium intake in zinc deficient group (r = 0.43, P = 0.002). Although, the dietary sodium intake showed a high tendency with no significance (P = 0.052), interdialytic weight gain was significantly higher in the zinc deficient group than in the non-zinc deficient group (2.68 ± 1.02 kg vs. 3.18 ± 1.02 kg; P = 0.047). Discussion Zinc deficiency may be related to low salt taste acuity and high salt preference, leading to high dietary sodium intake in HD patients.

  3. Optimal management of iron deficiency anemia due to poor dietary intake

    PubMed Central

    Aspuru, Kattalin; Villa, Carlos; Bermejo, Fernando; Herrero, Pilar; López, Santiago García

    2011-01-01

    Iron is necessary for the normal development of multiple vital processes. Iron deficiency (ID) may be caused by several diseases, even by physiological situations that increase requirements for this mineral. One of its possible causes is a poor dietary iron intake, which is infrequent in developed countries, but quite common in developing areas. In these countries, dietary ID is highly prevalent and comprises a real public health problem and a challenge for health authorities. ID, with or without anemia, can cause important symptoms that are not only physical, but can also include a decreased intellectual performance. All this, together with a high prevalence, can even have negative implications for a community’s economic and social development. Treatment consists of iron supplements. Prevention of ID obviously lies in increasing the dietary intake of iron, which can be difficult in developing countries. In these regions, foods with greater iron content are scarce, and attempts are made to compensate this by fortifying staple foods with iron. The effectiveness of this strategy is endorsed by multiple studies. On the other hand, in developed countries, ID with or without anemia is nearly always associated with diseases that trigger a negative balance between iron absorption and loss. Its management will be based on the treatment of underlying diseases, as well as on oral iron supplements, although these latter are limited by their tolerance and low potency, which on occasions may compel a change to intravenous administration. Iron deficiency has a series of peculiarities in pediatric patients, in the elderly, in pregnant women, and in patients with dietary restrictions, such as celiac disease. PMID:22114518

  4. Interactions between excessive manganese exposures and dietary iron-deficiency in neurodegeneration.

    PubMed

    Erikson, Keith M; Syversen, Tore; Aschner, Judy L; Aschner, Michael

    2005-05-01

    For nearly a century, manganese has been recognized as an essential nutrient for proper bone formation, lipid, amino acid and carbohydrate metabolism. While manganese deficiency is characterized by symptoms ranging from stunted growth and poor bone remodeling to ataxia, it is manganese toxicity that is far more devastating from a public health standpoint. Most cases of manganese toxicity are the result of occupational exposure to high levels of the metal, and are characterized by specific neurological symptoms referred to as manganism. While manganism shares many common features with Parkinson's disease, there are distinct differences between the two disorders suggesting that manganism might indirectly affect nigrostriatal dopaminergic function. Recent studies from our laboratory show that dietary iron deficiency is a risk factor for brain manganese accumulation and that the striatum is particularly vulnerable. This review briefly discusses manganese from nutritional and toxicological aspects.

  5. Calcium deficiency cannot induce obesity in rats.

    PubMed

    Paradis, S; Cabanac, M

    2005-06-30

    If intake of a required nutrient--here calcium--affects body weight, the effect must be mediated by a change in the body weight set-point. Thus, the controversial 'anti-obesity' influence of high calcium intake should decrease the body weight set-point. Diets differing in calcium content were assigned to three groups of rats. The effects of the diets on body weight, BMI, fat content, plasma calcium, body weight set-point, food intake, and preference for various calcium solutions were measured after 6 weeks of calcium deprivation or supplementation, and again after a further 6 weeks of recovery on a regular diet. After 6 weeks, the low-calcium diet had induced calcium deficiency but had failed to raise the body weight set-point. Nor had it produced obesity or fat accumulation. After 6 weeks of recovery, body weight and fat content were no higher in calcium-deprived rats than in the control or supplemented rats. In this experiment, low-calcium intake failed to cause obesity and did not raise the body weight set-point. The results indicate that calcium intake probably does not affect body weight.

  6. Copper deficiency potentiates ethanol induced liver damage

    SciTech Connect

    Zidenberg-Cherr, S.; Han, B.; Graham, T.W.; Keen, C.L. )

    1992-02-26

    Copper sufficient (+Cu) and deficient ({minus}Cu) rats were fed liquid diets with EtOH or dextrose at 36% of kcals for 2 mo. Consumption of either the {minus}Cu diet or EtOH resulted in lower liver CuZn superoxide dismutase (CuZnSOD) and glutathione peroxidase (GPx) activities were lowest in EtOH/{minus}Cu rats; being 20% and 50% of control values, respectively. Ethanol resulted in higher MnSOD activity in +Cu and {minus}Cu rats. Low Cu intake as well as EtOH resulted in lower mitochondrial (Mit) TBARS relative to controls. TBARS were lowest in Mit from EtOH/{minus}Cu rats. Microsomal (Micro) TBARS were lower in {minus}Cu and EtOH-fed rats than in controls. The peroxidizability index (PI) was calculated as an index of substrate availability for lipid peroxidation. Ethanol feeding resulted in lower PI's in Mit and Micro than measured in non-EtOH rats. There was a positive correlation between Micro PI's and TBARS. These results show that despite reductions in components of antioxidant defense, compensatory mechanism arise resulting in reduction in peroxidation targets and/or an increase in alternate free radical quenching factors. Histological examination demonstrated increased portal and intralobular connective tissue and cell necrosis in EtOH/{minus}Cu rats, suggesting that Cu may be a critical modulator of EtOH induced tissue damage.

  7. Probucol-Induced α-Tocopherol Deficiency Protects Mice against Malaria Infection

    PubMed Central

    Ishida, Noriko; Kume, Aiko; Hagihara, Yoshihisa; Yoshida, Yasukazu; Suzuki, Hiroshi

    2015-01-01

    The emergence of malaria pathogens having resistance against antimalarials implies the necessity for the development of new drugs. Recently, we have demonstrated a resistance against malaria infection of α-tocopherol transfer protein knockout mice showing undetectable plasma levels of α-tocopherol, a lipid-soluble antioxidant. However, dietary restriction induced α-tocopherol deficiency is difficult to be applied as a clinical antimalarial therapy. Here, we report on a new strategy to potentially treat malaria by using probucol, a drug that can reduce the plasma α-tocopherol concentration. Probucol pre-treatment for 2 weeks and treatment throughout the infection rescued from death of mice infected with Plasmodium yoelii XL-17 or P. berghei ANKA. In addition, survival was extended when the treatment started immediately after parasite inoculation. The ratio of lipid peroxidation products to parent lipids increased in plasma after 2 weeks treatment of probucol. This indicates that the protective effect of probucol might be mediated by the oxidative stressful environment induced by α-tocopherol deficiency. Probucol in combination with dihydroartemisin suppressed the proliferation of P. yoelii XL-17. These results indicated that probucol might be a candidate for a drug against malaria infection by inducing α-tocopherol deficiency without dietary α-tocopherol restriction. PMID:26296197

  8. Probucol-Induced α-Tocopherol Deficiency Protects Mice against Malaria Infection.

    PubMed

    Herbas, Maria Shirely; Shichiri, Mototada; Ishida, Noriko; Kume, Aiko; Hagihara, Yoshihisa; Yoshida, Yasukazu; Suzuki, Hiroshi

    2015-01-01

    The emergence of malaria pathogens having resistance against antimalarials implies the necessity for the development of new drugs. Recently, we have demonstrated a resistance against malaria infection of α-tocopherol transfer protein knockout mice showing undetectable plasma levels of α-tocopherol, a lipid-soluble antioxidant. However, dietary restriction induced α-tocopherol deficiency is difficult to be applied as a clinical antimalarial therapy. Here, we report on a new strategy to potentially treat malaria by using probucol, a drug that can reduce the plasma α-tocopherol concentration. Probucol pre-treatment for 2 weeks and treatment throughout the infection rescued from death of mice infected with Plasmodium yoelii XL-17 or P. berghei ANKA. In addition, survival was extended when the treatment started immediately after parasite inoculation. The ratio of lipid peroxidation products to parent lipids increased in plasma after 2 weeks treatment of probucol. This indicates that the protective effect of probucol might be mediated by the oxidative stressful environment induced by α-tocopherol deficiency. Probucol in combination with dihydroartemisin suppressed the proliferation of P. yoelii XL-17. These results indicated that probucol might be a candidate for a drug against malaria infection by inducing α-tocopherol deficiency without dietary α-tocopherol restriction.

  9. Dietary Nitrite Restores NO Homeostasis and is Cardioprotective in eNOS Deficient Mice

    PubMed Central

    Bryan, Nathan S.; Calvert, John W.; Gundewar, Susheel; Lefer, David J.

    2008-01-01

    Endothelial production of nitric oxide (NO) is critical for vascular homeostasis. Nitrite and nitrate are formed endogenously by the step wise oxidation of NO and have for years been regarded as inactive degradation products. As a result both anions are routinely used as surrogate markers of NO production with nitrite as a more sensitive marker. However, both nitrite and nitrate are derived from dietary sources. We sought to determine how exogenous nitrite affects steady state concentrations of NO metabolites thought to originate from NOS derived NO as well as blood pressure and myocardial ischemia-reperfusion (I/R) injury. Mice deficient in endothelial nitric oxide synthase (eNOS−/−) demonstrated decreased blood and tissue nitrite, nitrate and nitroso which were further reduced by low nitrite (NOx) diet for 1 week. Nitrite supplementation (50mg/L) in the drinking water for 1 week restored NO homeostasis in eNOS−/− mice and protected against I/R injury. Nitrite failed to alter heart rate or mean arterial blood pressure at the protective dose. These data demonstrate the significant influence of dietary nitrite intake on the maintenance of steady-state NO levels. Dietary nitrite and nitrate may serve as essentials nutrient for optimal cardiovascular health and may provide a novel prevention/treatment modality for disease associated with NO insufficiency. PMID:18501719

  10. Blood donation, being Asian, and a history of iron deficiency are stronger predictors of iron deficiency than dietary patterns in premenopausal women.

    PubMed

    Beck, Kathryn L; Conlon, Cathryn A; Kruger, Rozanne; Heath, Anne-Louise M; Matthys, Christophe; Coad, Jane; Jones, Beatrix; Stonehouse, Welma

    2014-01-01

    This study investigated dietary patterns and nondietary determinants of suboptimal iron status (serum ferritin < 20 μg/L) in 375 premenopausal women. Using multiple logistic regression analysis, determinants were blood donation in the past year [OR: 6.00 (95% CI: 2.81, 12.82); P < 0.001], being Asian [OR: 4.84 (95% CI: 2.29, 10.20); P < 0.001], previous iron deficiency [OR: 2.19 (95% CI: 1.16, 4.13); P = 0.016], a "milk and yoghurt" dietary pattern [one SD higher score, OR: 1.44 (95% CI: 1.08, 1.93); P = 0.012], and longer duration of menstruation [days, OR: 1.38 (95% CI: 1.12, 1.68); P = 0.002]. A one SD change in the factor score above the mean for a "meat and vegetable" dietary pattern reduced the odds of suboptimal iron status by 79.0% [OR: 0.21 (95% CI: 0.08, 0.50); P = 0.001] in women with children. Blood donation, Asian ethnicity, and previous iron deficiency were the strongest predictors, substantially increasing the odds of suboptimal iron status. Following a "milk and yoghurt" dietary pattern and a longer duration of menstruation moderately increased the odds of suboptimal iron status, while a "meat and vegetable" dietary pattern reduced the odds of suboptimal iron status in women with children.

  11. Blood Donation, Being Asian, and a History of Iron Deficiency Are Stronger Predictors of Iron Deficiency than Dietary Patterns in Premenopausal Women

    PubMed Central

    Beck, Kathryn L.; Conlon, Cathryn A.; Heath, Anne-Louise M.; Coad, Jane; Stonehouse, Welma

    2014-01-01

    This study investigated dietary patterns and nondietary determinants of suboptimal iron status (serum ferritin < 20 μg/L) in 375 premenopausal women. Using multiple logistic regression analysis, determinants were blood donation in the past year [OR: 6.00 (95% CI: 2.81, 12.82); P < 0.001], being Asian [OR: 4.84 (95% CI: 2.29, 10.20); P < 0.001], previous iron deficiency [OR: 2.19 (95% CI: 1.16, 4.13); P = 0.016], a “milk and yoghurt” dietary pattern [one SD higher score, OR: 1.44 (95% CI: 1.08, 1.93); P = 0.012], and longer duration of menstruation [days, OR: 1.38 (95% CI: 1.12, 1.68); P = 0.002]. A one SD change in the factor score above the mean for a “meat and vegetable” dietary pattern reduced the odds of suboptimal iron status by 79.0% [OR: 0.21 (95% CI: 0.08, 0.50); P = 0.001] in women with children. Blood donation, Asian ethnicity, and previous iron deficiency were the strongest predictors, substantially increasing the odds of suboptimal iron status. Following a “milk and yoghurt” dietary pattern and a longer duration of menstruation moderately increased the odds of suboptimal iron status, while a “meat and vegetable” dietary pattern reduced the odds of suboptimal iron status in women with children. PMID:25006582

  12. Three successful pregnancies through dietary management of fructose-1,6-bisphosphatase deficiency.

    PubMed

    Krishnamurthy, V; Eschrich, K; Boney, A; Sullivan, J; McDonald, M; Kishnani, P S; Koeberl, D D

    2007-10-01

    Fructose-1,6-bisphosphatase (FBPase) deficiency (OMIM 229700) has been characterized as the cause of life-threatening hypoglycaemia and lactic acidaemia following prolonged fasting. The patient, an adult African-American woman, presented during the second trimester of her first pregnancy with recurrent episodes of lactic acidaemia and hypoglycaemia. She had recently been admitted to a nearby intensive care unit after presentation with profound hypoglycaemia and lactic acidosis, and was found to be pregnant. The history was remarkable for approximately 30 hospitalizations for hypoglycaemia and acidosis. She had previously undergone liver biopsy at another centre and was diagnosed with a 'glycogen storage disease', although no enzyme testing had been done for confirmation. Based on clinical symptoms, a diagnosis of FBPase deficiency was accomplished through gene sequencing, which revealed homozygosity for a panethnic, common mutation, 960/961insG in exon 7. The availability of mutation testing facilitated the confirmation of FBPase deficiency in this patient, obviating liver biopsy for enzyme activity confirmation. The patient underwent three successful pregnancies by strict compliance with dietary management, including nocturnal uncooked cornstarch to manage hypoglycaemia. The pregnancies were complicated by mild gestational diabetes, increased cornstarch requirements, and hypoglycaemia at the time of discharge from the hospital. The three infants had normal birth weights and experienced no complications during the neonatal period. The patient subsequently developed sensorineural hearing loss and early-onset cognitive impairment, despite compliance with the monitoring and treatment of hypoglycaemia. The experience with multiple pregnancies in this FBPase-deficient patient provides insight into the management of hypoglycaemia in inherited disorders of gluconeogenesis.

  13. Levodopa-induced dyskinesias in tyrosine hydroxylase deficiency.

    PubMed

    Pons, Roser; Syrengelas, Dimitris; Youroukos, Sotiris; Orfanou, Irene; Dinopoulos, Arqirios; Cormand, Bru; Ormazabal, Aida; Garzía-Cazorla, Angels; Serrano, Mercedes; Artuch, Rafael

    2013-07-01

    The objective of this study was to characterize levodopa (l-dopa)-induced dyskinesias in patients with tyrosine hydroxylase deficiency. Clinical observation was carried out on 6 patients who were diagnosed with tyrosine hydroxylase deficiency and were treated with escalating doses of l-dopa. All 6 patients showed l-dopa-induced dyskinesias of variable intensity early in the course of treatment and regardless of the age of initiation. l-Dopa-induced dyskinesias were precipitated by increases in the dose of l-dopa and also by febrile illnesses and stress. They caused dysfunction and distress in 2 patients. The dyskinesias were improved by decreasing the l-dopa dose or by slowing its titration upward. Increasing the dose frequency was helpful in 2 patients, and introducing amantadine was helpful in another 2 patients. l-Dopa-induced dyskinesias are a common phenomenon in tyrosine hydroxylase deficiency. The current observations show that l-dopa-induced dyskinesias are frequent in a dopamine-deficient state in the absence of nigrostriatal degeneration. Although l-dopa-induced dyskinesias in tyrosine hydroxylase deficiency are phenomenologically similar to those that occur in Parkinson's disease, they are different in a number of other respects, suggesting intrinsic differences in the pathophysiologic basis of l-dopa-induced dyskinesias in the 2 conditions. © 2013 Movement Disorder Society.

  14. Vitamin A deficiency decreases and high dietary vitamin A increases disease severity in the mouse model of asthma

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Th1/ Th2 paradigm has become an important issue in the pathogenesis of asthma, characterized by normal Th-1 and elevated Th-2 cytokine expression, resulting in a Th2 predominance. Vitamin A deficiency (VAD) produces a significant Th1 bias, while high-level dietary vitamin A supplementation promo...

  15. Effect of dietary zinc deficiency on the accumulation of cadmium and metallothionein in selected tissues of the rat

    SciTech Connect

    Waalkes, M.P.

    1986-01-01

    The effect of continuous dietary zinc deficiency on the metabolism of the toxic heavy metal cadmium has not been widely studied. This investigation was designed to assess the effects of subadequate dietary zinc intake on the accumulation of dietary cadmium and on metallothionein (MT) and zinc concentrations in target organs of cadmium toxicity. Adult male Wistar rats (180-200 g) were allowed, ad libitum, diets either adequate (60 ppm) or deficient (7 ppm) in zinc for a total of 9 wk. The zinc-deficient diet resulted in an approximately 40% reduction in plasma zinc (assessed at 3, 6, and 9 wk) in the absence of overt signs of zinc deficiency (i.e., reduced weight gain, alopecia, etc.). Separate groups of rats were also maintained on zinc-defined diets for a total of 9 wk, but cadmium was added to the diet (0, 12.5, 25, 50, 100, and 200 ppm) a the end of wk 3 and maintained at that level throughout the remaining 6 wk of the study, when the rats were killed. The feeding of the zinc-deficient diet markedly enhanced the accumulation of cadmium in the liver, kidney, and testes. Hepatic, renal, and testicular zinc concentrations were not affected by suboptimal zinc intake alone. However, marked reductions in renal and testicular zinc concentrations were caused by zinc deficiency in concert with cadmium exposure. MT levels, when related to tissue cadmium concentrations, were elevated to a significantly lesser extent in the kidneys of zinc-deficient animals. These results indicate that marginal zinc deficiency markedly increases cadmium accumulation in various organs and reduces zinc content and MT induction in some organs.

  16. Impact of Dietary Intake on Bone Turnover in Patients with Phenylalanine Hydroxylase Deficiency.

    PubMed

    Coakley, Kathryn E; Felner, Eric I; Tangpricha, Vin; Wilson, Peter W F; Singh, Rani H

    2017-01-28

    Phenylalanine hydroxylase (PAH) deficiency is a genetic disorder characterized by deficiency of the PAH enzyme. Patients follow a phenylalanine-restricted diet low in intact protein, and must consume synthetic medical food (MF) to supply phenylalanine-free protein. We assessed relationships between dietary intake and nutrient source (food or MF) on bone mineral density (BMD) and bone turnover markers (BTM) in PAH deficiency. Blood from 44 fasted females 11-52 years of age was analyzed for plasma phenylalanine, serum BTM [CTx (resorption), P1NP (formation)], vitamin D, and parathyroid hormone (PTH). BTM ratios were calculated to assess resorption relative to formation (CTx/P1NP). Dual energy X-ray absorptiometry measured total BMD and age-matched Z-scores. Three-day food records were analyzed for total nutrient intake, nutrients by source (food, MF), and compliance with MF prescription. Spearman's partial coefficients (adjusted for age, BMI, energy intake, blood phenylalanine) assessed correlations. All had normal BMD for age (Z-score >-2). Sixty-four percent had high resorption and normal formation indicating uncoupled bone turnover. CTx/P1NP was positively associated with food phenylalanine (r (2) = 0.39; p-value = 0.017), energy (r (2) = 0.41; p-value = 0.011) and zinc (r (2) = 0.41; p-value = 0.014). CTx/P1NP was negatively associated with MF fat (r (2) = -0.44; p-value = 0.008), MF compliance (r (2) = -0.34; p-value = 0.056), and positively with food sodium (r (2) = 0.43; p-value = 0.014). CTx/P1NP decreased significantly with age (p-value = 0.002) and higher PTH (p-value = 0.0002). Phenylalanine was not correlated with any bone indicator. Females with PAH deficiency had normal BMD but elevated BTM, particularly resorption. More favorable ratios were associated with nutrients from MF and compliance. Younger females had less favorable BTM ratios. Promoting micronutrient intake through compliance with MF may impact bone metabolism in

  17. Synergistic Interaction of Dietary Cholesterol and Dietary Fat in Inducing Experimental Steatohepatitis

    PubMed Central

    Savard, Christopher; Tartaglione, Erica V.; Kuver, Rahul; Haigh, W. Geoffrey; Farrell, Geoffrey C.; Subramanian, Savitha; Chait, Alan; Yeh, Matthew M.; Quinn, LeBris S.; Ioannou, George N.

    2017-01-01

    The majority of patients with nonalcoholic fatty liver disease (NAFLD) have “simple steatosis,” which is defined by hepatic steatosis in the absence of substantial inflammation or fibrosis and is considered to be benign. However, 10%–30% of patients with NAFLD progress to fibrosing nonalcoholic steatohepatitis (NASH), which is characterized by varying degrees of hepatic inflammation and fibrosis, in addition to hepatic steatosis, and can lead to cirrhosis. The cause(s) of progression to fibrosing steatohepatitis are unclear. We aimed to test the relative contributions of dietary fat and dietary cholesterol and their interaction on the development of NASH. We assigned C57BL/6J mice to four diets for 30 weeks: control (4% fat and 0% cholesterol); high cholesterol (HC; 4% fat and 1% cholesterol); high fat (HF; 15% fat and 0% cholesterol); and high fat, high cholesterol (HFHC; 15% fat and 1% cholesterol). The HF and HC diets led to increased hepatic fat deposition with little inflammation and no fibrosis (i.e., simple hepatic steatosis). However, the HFHC diet led to significantly more profound hepatic steatosis, substantial inflammation, and perisinusoidal fibrosis (i.e., steatohepatitis), associated with adipose tissue inflammation and a reduction in plasma adiponectin levels. In addition, the HFHC diet led to other features of human NASH, including hypercholesterolemia and obesity. Hepatic and metabolic effects induced by dietary fat and cholesterol together were more than twice as great as the sum of the separate effects of each dietary component alone, demonstrating significant positive interaction. Conclusion Dietary fat and dietary cholesterol interact synergistically to induce the metabolic and hepatic features of NASH, whereas neither factor alone is sufficient to cause NASH in mice. PMID:22508243

  18. Obesity development in neuron-specific lipoprotein lipase deficient mice is not responsive to increased dietary fat content or change in fat composition.

    PubMed

    Wang, Hong; Taussig, Matthew D; DiPatrizio, Nicholas V; Bruce, Kimberley; Piomelli, Daniele; Eckel, Robert H

    2016-07-01

    We have previously reported that mice with neuron-specific LPL deficiency (NEXLPL-/-) become obese by 16weeks of age on chow. Moreover, these mice had reduced uptake of triglyceride (TG)-rich lipoprotein-derived fatty acids and lower levels of n-3 long chain polyunsaturated fatty acids (n-3 PUFAs) in the hypothalamus. Here, we asked whether increased dietary fat content or altered dietary composition could modulate obesity development in NEXLPL-/- mice. Male NEXLPL-/- mice and littermate controls (WT) were randomly assigned one of three synthetic diets; a high carbohydrate diet (HC, 10% fat), a high-fat diet (HF, 45% fat), or a HC diet supplemented with n-3 PUFAs (HCn-3, 10% fat, Lovaza, GSK®). After 42weeks of HC feeding, body weight and fat mass were increased in the NEXLPL-/- mice compared to WT. WT mice fed a HF diet displayed typical diet-induced obesity, but weight gain was only marginal in HF-fed NEXLPL-/- mice, with no significant difference in body composition. Dietary n-3 PUFA supplementation did not prevent obesity in NEXLPL-/- mice, but was associated with differential modifications in hypothalamic gene expression and PUFA concentration compared to WT mice. Our findings suggest that neuronal LPL is involved in the regulation of body weight and composition in response to either the change in quantity (HF feeding) or quality (n-3 PUFA-enriched) of dietary fat. The precise role of LPL in lipid sensing in the brain requires further investigation.

  19. Influence of dietary phosphorus deficiency with or without addition of fumaric acid to a diet in pigs on bone parameters.

    PubMed

    Liesegang, A; Ursprung, R; Gasser, J; Sassi, M-L; Risteli, J; Riond, J-L; Wanner, M

    2002-02-01

    The purpose of this study was to examine if substantial bone loss occurs in weaned pigs by feeding a phosphorus-deficient diet with or without fumaric acid. Eighteen weaned pigs were used. The animals were assigned to three groups: group C (control; 0.65% P on DM basis), group LP (low phosphorus; 0.37% P on DM basis) and group LPF (low phosphorus plus fumaric acid; 0.35% P on DM basis plus 2% fumaric acid). These three diets were fed to the groups for a period of four weeks after a two-week adaptation period. Blood samples were collected once a week. Carboxyterminal telopeptide of type I collagen (ICTP) in serum was used as a bone resorption marker. Osteocalcin (OC) and bone-specific alkaline phosphatase (bAP) were used as bone formation markers. Bone mineral density (BMD) and content (BMC) were determined by peripheral quantitative computer tomography. BAP activities significantly increased (24%) in group LPF, and at the last sampling day group LPF had significantly increased activities in comparison to group C. In contrast, ICTP concentrations significantly increased with time in group LP and LPF, and at the last sampling day group LPF had significantly increased activities in comparison to group C. BMD and BMC in femur and tibia significantly decreased in group LP and LPF. The results show that P-deficient diets induce a bone loss. Fumaric acid did not influence the degree of bone loss. With a better understanding of its effect on bone, dietary phosphorus requirements in pigs could be more precisely defined.

  20. Dietary sodium protects fish against copper-induced olfactory impairment.

    PubMed

    Azizishirazi, Ali; Dew, William A; Bougas, Berenice; Bernatchez, Louis; Pyle, Greg G

    2015-04-01

    Exposure to low concentrations of copper impairs olfaction in fish. To determine the transcriptional changes in the olfactory epithelium induced by copper exposure, wild yellow perch (Perca flavescens) were exposed to 20 μg/L of copper for 3 and 24h. A novel yellow perch microarray with 1000 candidate genes was used to measure differential gene transcription in the olfactory epithelium. While three hours of exposure to copper changed the transcription of only one gene, the transcriptions of 70 genes were changed after 24h of exposure to copper. Real-time PCR was utilized to determine the effect of exposure duration on two specific genes of interest, two sub-units of Na/K-ATPase. At 24 and 48 h, Na/K-ATPase transcription was down-regulated by copper at olfactory rosettes. As copper-induced impairment of Na/K-ATPase activity in gills can be ameliorated by increased dietary sodium, rainbow trout (Oncorhynchus mykiss) were used to determine if elevated dietary sodium was also protective against copper-induced olfactory impairment. Measurement of the olfactory response of rainbow trout using electro-olfactography demonstrated that sodium was protective of copper-induced olfactory dysfunction. This work demonstrates that the transcriptions of both subunits of Na/K-ATPase in the olfactory epithelium of fish are affected by Cu exposure, and that dietary Na protects against Cu-induced olfactory dysfunction.

  1. Testis damage induced by zinc deficiency in rats.

    PubMed

    Merker, H J; Günther, T

    1997-04-01

    Male Wistar rats were fed a Zn-deficient diet (1.2 mg/kg of Zn) for 28 days. Testes were then studied by light and electron microscopy. Zn deficiency induced necroses of precursors of germ cells leading to tubular atrophy and affected differentiation of spermatids. This was expressed by the occurrence of 2-4 axoneme-dense fibre-mitochondria complexes in one spermatid. Moreover, outer dense fibres, which normally contain 90% of sperm Zn, were "uncoiled" and flattened. The multiplication of the axoneme-dense fibre-mitochondria complexes induced by Zn deficiency might have been produced by an increase of Fe in spermatids and an increased formation of oxygen free radicals.

  2. Suppression of muscle protein turnover and amino acid degradation by dietary protein deficiency

    NASA Technical Reports Server (NTRS)

    Tawa, N. E. Jr; Goldberg, A. L.

    1992-01-01

    To define the adaptations that conserve amino acids and muscle protein when dietary protein intake is inadequate, rats (60-70 g final wt) were fed a normal or protein-deficient (PD) diet (18 or 1% lactalbumin), and their muscles were studied in vitro. After 7 days on the PD diet, both protein degradation and synthesis fell 30-40% in skeletal muscles and atria. This fall in proteolysis did not result from reduced amino acid supply to the muscle and preceded any clear decrease in plasma amino acids. Oxidation of branched-chain amino acids, glutamine and alanine synthesis, and uptake of alpha-aminoisobutyrate also fell by 30-50% in muscles and adipose tissue of PD rats. After 1 day on the PD diet, muscle protein synthesis and amino acid uptake decreased by 25-40%, and after 3 days proteolysis and leucine oxidation fell 30-45%. Upon refeeding with the normal diet, protein synthesis also rose more rapidly (+30% by 1 day) than proteolysis, which increased significantly after 3 days (+60%). These different time courses suggest distinct endocrine signals for these responses. The high rate of protein synthesis and low rate of proteolysis during the first 3 days of refeeding a normal diet to PD rats contributes to the rapid weight gain ("catch-up growth") of such animals.

  3. Dietary methyl donor deficiency during pregnancy in rats shapes learning and anxiety in offspring.

    PubMed

    Konycheva, Galina; Dziadek, Marie A; Ferguson, Lynnette R; Krägeloh, Christian U; Coolen, Marcel W; Davison, Michael; Breier, Bernhard H

    2011-10-01

    Two important lines of research have enhanced our understanding of the molecular role of nutrition in influencing behavior. First, exposure to an adverse environment during early life can influence the long-term behavior of the offspring. Second, regulation of the nervous system development and functioning appears to involve epigenetic mechanisms that require a continuous supply of methyl group donors in food. We hypothesized that a maternal diet during pregnancy deficient in methyl donors (MDD) may lead to altered behavior in offspring through permanent changes in hippocampal DNA methylation. We used a rat model of prenatal dietary MDD to test this hypothesis in female offspring as they aged. Prenatal MDD reduced birth weight, litter size, and newborn viability. Aged female offspring of MDD mothers showed increased anxiety and increased learning ability in comparison with control diet group offspring. To explore the role of MDD on epigenetic mechanisms in the brain of adult offspring, we studied expression and methylation of 4 selected genes coding for glucocorticoid receptor, hydroxysteroid dehydrogenase 11 type 2, neuronatin, and reelin proteins in the hippocampus. No major group differences in methylation or expression of the studied genes were detected, except for a significant down-regulation of the reelin gene in the MDD female offspring. The prenatal MDD diet caused intrauterine growth restriction, associated with long-term effects on the behavior of the offspring. However, the observed behavioral differences between the MDD and control diet offspring cannot be explained by epigenetic regulation of the specific genes investigated in this study.

  4. Bovine monocyte-derived macrophage function in induced copper deficiency.

    PubMed

    Cerone, S; Sansinanea, A; Streitenberger, S; García, C; Auza, N

    2000-03-01

    The effect of molybdenum-induced copper deficiency on monocyte-derived macrophage function was examined. Five female calves were given molybdenum (30 ppm) and sulphate (225 ppm) to induce experimental secondary copper deficiency. Oxidant production by bovine macrophages was measured after stimulation with phorbol myristate acetate (PMA) and opsonized zymosan (OpZ). Lipoperoxidative effects inside of macrophage, superoxide dismutase activity, superoxide anion and hydrogen peroxide formation were determined. Copper deficiency was confirmed from decreased serum copper levels, and animals with values less than 5.9 micromol/l were considered deficient. The content of intracellular copper decreased about 40% in deficient cells compared with the controls. The respiratory burst activity determined by nitroblue tetrazolium reduction was significantly impaired with both stimulants used. Superoxide anion formation was less affected than hydrogen peroxide generation. In addition, increased lipid peroxidation was observed. It could be concluded that the effect of these changes may impair the monocyte-derived macrophage function in the immune system.

  5. Iron deficiency is uncommon among lactating women in urban Nepal, despite a high risk of inadequate dietary iron intake.

    PubMed

    Henjum, Sigrun; Manger, Mari; Skeie, Eli; Ulak, Manjeswori; Thorne-Lyman, Andrew L; Chandyo, Ram; Shrestha, Prakash S; Locks, Lindsey; Ulvik, Rune J; Fawzi, Wafaie W; Strand, Tor A

    2014-07-14

    The main objective of the present study was to examine the association between dietary Fe intake and dietary predictors of Fe status and Hb concentration among lactating women in Bhaktapur, Nepal. We included 500 randomly selected lactating women in a cross-sectional survey. Dietary information was obtained through three interactive 24 h recall interviews including personal recipes. Concentrations of Hb and plasma ferritin and soluble transferrin receptors were measured. The daily median Fe intake from food was 17·5 mg, and 70% of the women were found to be at the risk of inadequate dietary Fe intake. Approximately 90% of the women had taken Fe supplements in pregnancy. The prevalence of anaemia was 20% (Hb levels < 123 g/l) and that of Fe deficiency was 5% (plasma ferritin levels < 15 μg/l). In multiple regression analyses, there was a weak positive association between dietary Fe intake and body Fe (β 0·03, 95% CI 0·014, 0·045). Among the women with children aged < 6 months, but not those with older infants, intake of Fe supplements in pregnancy for at least 6 months was positively associated with body Fe (P for interaction < 0·01). Due to a relatively high dietary intake of non-haem Fe combined with low bioavailability, a high proportion of the women in the present study were at the risk of inadequate intake of Fe. The low prevalence of anaemia and Fe deficiency may be explained by the majority of the women consuming Fe supplements in pregnancy.

  6. The effect of dietary phosphorus deficiency on the immune responses of European whitefish (Coregonus lavaretus L.).

    PubMed

    Jokinen, E I; Vielma, J; Aaltonen, T M; Koskela, J

    2003-08-01

    Low phosphorous (P) feeds in aquaculture are recommended to reduce eutrophication of water systems. However, the feed should be adequate for normal growth and intact immune defence. Influence of low dietary P supply on non-specific and specific immune defence of European whitefish (Coregonus lavaretus) was studied in two trials. For Trial 1, a semi-purified, low-P diet was formulated and supplied with 0, 2.5, 5.0, 7.5, or 10.0 g P kg(-1)to obtain a P gradient of 4.4-14.9 g kg(-1)diet. Diets were fed to four replicate groups of fingerling whitefish for 42 days in a flow-through, freshwater system maintained at 15 degrees C. Fish fed with the P-unsupplemented diet had significantly lower plasma immunoglobulin M (IgM) levels than fish fed with the P-fortified diets (means 2.53 vs. 3.19 mg ml(-1); P=0.047). Plasma lysozyme activity did not differ between fish fed with the P-unsupplemented diet and fish fed with the P-fortified diets (means 21.8 vs. 25.5 U ml(-1); P=0.107). For Trial 2, fish were acclimated for 49 days by feeding the lowest or highest dietary P contents, and thereafter immunised with a single intraperitoneal injection of a novel antigen, bovine gamma globulin (BGG). A clear antibody response against BGG was elicited but the antibody levels did not differ between fish fed low-P or high-P contents. Similar to Trial 1, plasma IgM was lower in fish fed low-P diets, and low-P diet did not influence plasma lysozyme activity. In both trials the growth of fish, having received low-P diet, was significantly lowered. It is concluded that P deficiency has only minor effects on the immune parameters in whitefish, and the practical aquafeed with P contents sufficient for normal growth does not compromise immune functions of this species.

  7. Herbal and Dietary Supplement-Induced Liver Injury.

    PubMed

    de Boer, Ynto S; Sherker, Averell H

    2017-02-01

    The increase in the use of herbal and dietary supplements (HDSs) over the last decades has been accompanied by an increase in the reports of HDS-associated hepatotoxicity. The spectrum of HDS-induced liver injury is diverse and the outcome may vary from transient liver test increases to fulminant hepatic failure resulting in death or requiring liver transplant. There are no validated standardized tools to establish the diagnosis, but some HDS products have a typical clinical signature that may help to identify HDS-induced liver injury.

  8. Response to dietary phosphorus deficiency is affected by genetic background in growing pigs.

    PubMed

    Alexander, L S; Qu, A; Cutler, S A; Mahajan, A; Lonergan, S M; Rothschild, M F; Weber, T E; Kerr, B J; Stahl, C H

    2008-10-01

    Concern over the environmental effect of P excretion from pig production has led to reduced dietary P supplementation. To examine how genetics influence P utilization, 94 gilts sired by 2 genetic lines (PIC337 and PIC280) were housed individually and fed either a P-adequate diet (PA) or a 20% P-deficient diet (PD) for 14 wk. Initially and monthly, blood samples were collected and BW recorded after an overnight fast. Growth performance and plasma indicators of P status were determined monthly. At the end of the trial, carcass traits, meat quality, bone strength, and ash percentage were determined. Pigs fed the PD diet had decreased (P < 0.05) plasma P concentrations and poorer G:F (P < 0.05) over the length of the trial. After 4 wk on trial, pigs fed the PD diet had increased (P < 0.05) plasma 1,25(OH)(2)D(3) and decreased (P < 0.05) plasma parathyroid hormone compared with those fed the PA diet. At the end of the trial, pigs fed the PD diet had decreased (P < 0.05) BW, HCW, and percentage fat-free lean and tended to have decreased LM area (P = 0.06) and marbling (P = 0.09) and greater (P = 0.12) 10th-rib backfat than pigs fed the PA diet. Additionally, animals fed the PD diet had weaker bones and also decreased (P < 0.05) ash percentage and increased (P < 0.05) concentrations of 1alpha-hydroxylase and parathyroid hormone receptor mRNA in kidney tissue. Regardless of dietary treatment, PIC337-sired pigs consumed more feed and gained more BW than their PIC280-sired counterparts (P < 0.05) during the study. The PIC337-sired pigs also had greater (P < 0.05) HCW, larger (P < 0.01) LM area, and tended to have (P = 0.07) greater dressing percentage. Meat from the PIC337-sired pigs also tended to have greater (P = 0.12) concentrations of lactate but decreased (P = 0.07) concentrations of total glucose units 24 h postslaughter. Although plasma 1,25(OH)(2)D(3) concentrations were elevated (P < 0.05) in all the animals fed the PD diet, this elevation due to P deficiency

  9. Calnexin deficiency and endoplasmic reticulum stress-induced apoptosis.

    PubMed

    Zuppini, Anna; Groenendyk, Jody; Cormack, Lori A; Shore, Gordon; Opas, Michal; Bleackley, R Chris; Michalak, Marek

    2002-02-26

    In this study, we used calnexin-deficient cells to investigate the role of this protein in ER stress-induced apoptosis. We found that calnexin-deficient cells are relatively resistant to ER stress-induced apoptosis. However, caspase 3 and 8 cleavage and cytochrome c release were unchanged in these cells, indicating that ER to mitochondria "communication" during apoptotic stimulation is not affected in the absence of calnexin. The Bcl-2:Bax ratio was also not significantly changed in calnexin-deficient cells regardless of whether the ER stress was induced with thapsigargin or not. Ca(2+) homeostasis and ER morphology were unaffected by the lack of calnexin, but ER stress-induced Bap31 cleavage was significantly inhibited. Immunoprecipitation experiments revealed that Bap31 forms complexes with calnexin, which may play a role in apoptosis. The results suggest that calnexin may not play a role in the initiation of the ER stress but that the protein has an effect on later apoptotic events via its influence on Bap31 function.

  10. Cardiac Electrophysiological Alterations in Heart/Muscle-Specific Manganese-Superoxide Dismutase-Deficient Mice: Prevention by a Dietary Antioxidant Polyphenol

    PubMed Central

    Matsumoto, Akio; Tagashira, Motoyuki; Kanda, Tomomasa; Nakaya, Haruaki

    2014-01-01

    Cardiac electrophysiological alterations induced by chronic exposure to reactive oxygen species and protective effects of dietary antioxidant have not been thoroughly examined. We recorded surface electrocardiograms (ECG) and evaluated cellular electrophysiological abnormalities in enzymatically-dissociated left ventricular (LV) myocytes in heart/muscle-specific manganese-superoxide dismutase-deficient (H/M-Sod2−/−) mice, which exhibit dilated cardiomyopathy due to increased oxidative stress. We also investigated the influences of intake of apple polyphenols (AP) containing mainly procyanidins with potent antioxidant activity. The QRS and QT intervals of ECG recorded in H/M-Sod2−/− mice were prolonged. The effective refractory period in the LV myocardium of H/M-Sod2−/− mice was prolonged, and susceptibility to ventricular tachycardia or fibrillation induced by rapid ventricular pacing was increased. Action potential duration in H/M-Sod2−/− LV myocytes was prolonged, and automaticity was enhanced. The density of the inwardly rectifier K+ current (IK1) was decreased in the LV cells of H/M-Sod2−/− mice. The AP intake partially improved these electrophysiological alterations and extended the lifespan in H/M-Sod2−/− mice. Thus, chronic exposure of the heart to oxidative stress produces a variety of electrophysiological abnormalities, increased susceptibility to ventricular arrhythmias, and action potential changes associated with the reduced density of IK1. Dietary intake of antioxidant nutrients may prevent oxidative stress-induced electrophysiological disturbances. PMID:24772433

  11. Formate Dehydrogenase, an Enzyme of Anaerobic Metabolism, Is Induced by Iron Deficiency in Barley Roots1

    PubMed Central

    Suzuki, Kazuya; Itai, Reiko; Suzuki, Koichiro; Nakanishi, Hiromi; Nishizawa, Naoko-Kishi; Yoshimura, Etsuro; Mori, Satoshi

    1998-01-01

    To identify the proteins induced by Fe deficiency, we have compared the proteins of Fe-sufficient and Fe-deficient barley (Hordeum vulgare L.) roots by two-dimensional polyacrylamide gel electrophoresis. Peptide sequence analysis of induced proteins revealed that formate dehydrogenase (FDH), adenine phosphoribosyltransferase, and the Ids3 gene product (for Fe deficiency-specific) increased in Fe-deficient roots. FDH enzyme activity was detected in Fe-deficient roots but not in Fe-sufficient roots. A cDNA encoding FDH (Fdh) was cloned and sequenced. Fdh expression was induced by Fe deficiency. Fdh was also expressed under anaerobic stress and its expression was more rapid than that induced by Fe deficiency. Thus, the expression of Fdh observed in Fe-deficient barley roots appeared to be a secondary effect caused by oxygen deficiency in Fe-deficient plants. PMID:9489019

  12. Flavonoids, the emerging dietary supplement against cisplatin-induced nephrotoxicity.

    PubMed

    Athira, K V; Madhana, Rajaram Mohanrao; Lahkar, Mangala

    2016-03-25

    The letter illustrates the emerging potential of flavonoids as dietary supplement to ameliorate cisplatin-induced nephrotoxicity and refers to the recent article on ''Anti-apoptotic and anti-inflammatory effects of naringin on cisplatin-induced renal injury in the rat'' by Chtourou et al. They demonstrated that supplementation of naringin, a flavanone glycoside, found in grape and citrus fruit species, can attenuate cisplatin-induced renal dysfunction via restoration of redox balance and suppression of inflammation, NF-κB activation and apoptosis. The chemotherapeutic efficacy of cisplatin has always compelled the researchers to find solution to ameliorate its side effects. In recent years, numerous candidates have been evaluated for their protective potential against cisplatin-induced nephrotoxicity and flavonoids have come up with promising results. The future prospects might be promising with a proper refinement and collective integration of the preclinical and clinical research in the field of flavonoid supplementation to cisplatin therapy.

  13. CHOP deficiency inhibits methylglyoxal-induced endothelial dysfunction.

    PubMed

    Choi, Yoon Young; Kim, Suji; Han, Jung-Hwa; Nam, Dae-Hwan; Park, Kwon Moo; Kim, Seong Yong; Woo, Chang-Hoon

    2016-11-18

    Epidemiological studies suggested that diabetic patients are susceptible to develop cardiovascular complications along with having endothelial dysfunction. It has been suggested that methylglyoxal (MGO), a glycolytic metabolite, has more detrimental effects on endothelial dysfunction rather than glucose itself. Here, we investigated the molecular mechanism by which MGO induces endothelial dysfunction via the regulation of ER stress. Biochemical data showed that 4-PBA significantly inhibited MGO-induced protein cleavages of PARP-1 and caspase-3. In addition, it was found that high glucose-induced endothelial apoptosis was enhanced in the presence of GLO1 inhibitor, suggesting the role of endogenous MGO in high glucose-induced endothelial dysfunction. MGO-induced endothelial apoptosis was significantly diminished by the depletion of CHOP with si-RNA against human CHOP, but not by SP600125, a specific inhibitor of JNK. The physiological relevance of this signaling pathway was demonstrated in CHOP deficiency mouse model, in which instillation of osmotic pump containing MGO led to aortic endothelial dysfunction. Notably, the aortic endothelial dysfunction response to MGO infusion was significantly improved in CHOP deficiency mice compared to littermate control. Taken together, these findings indicate that MGO specifically induces endothelial dysfunction in a CHOP-dependent manner, suggesting the therapeutic potential of CHOP inhibition in diabetic cardiovascular complications.

  14. Oxidative stress induces mitochondrial fragmentation in frataxin-deficient cells

    SciTech Connect

    Lefevre, Sophie; Sliwa, Dominika; Rustin, Pierre; Camadro, Jean-Michel; Santos, Renata

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer Yeast frataxin-deficiency leads to increased proportion of fragmented mitochondria. Black-Right-Pointing-Pointer Oxidative stress induces complete mitochondrial fragmentation in {Delta}yfh1 cells. Black-Right-Pointing-Pointer Oxidative stress increases mitochondrial fragmentation in patient fibroblasts. Black-Right-Pointing-Pointer Inhibition of mitochondrial fission in {Delta}yfh1 induces oxidative stress resistance. -- Abstract: Friedreich ataxia (FA) is the most common recessive neurodegenerative disease. It is caused by deficiency in mitochondrial frataxin, which participates in iron-sulfur cluster assembly. Yeast cells lacking frataxin ({Delta}yfh1 mutant) showed an increased proportion of fragmented mitochondria compared to wild-type. In addition, oxidative stress induced complete fragmentation of mitochondria in {Delta}yfh1 cells. Genetically controlled inhibition of mitochondrial fission in these cells led to increased resistance to oxidative stress. Here we present evidence that in yeast frataxin-deficiency interferes with mitochondrial dynamics, which might therefore be relevant for the pathophysiology of FA.

  15. Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease.

    PubMed

    Tallino, Savannah; Duffy, Megan; Ralle, Martina; Cortés, María Paz; Latorre, Mauricio; Burkhead, Jason L

    2015-10-01

    Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes nonalcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decreases liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w) or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high-sucrose or low-Cu diet had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase and fatty acid synthase gene transcription (fold change > 2, P < 0.02). Low dietary Cu decreased hepatic and serum Cu (P ≤ 0.05), promoted lipid peroxidation and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis.

  16. Severe but Not Moderate Vitamin B12 Deficiency Impairs Lipid Profile, Induces Adiposity, and Leads to Adverse Gestational Outcome in Female C57BL/6 Mice.

    PubMed

    Ghosh, Shampa; Sinha, Jitendra Kumar; Putcha, Uday Kumar; Raghunath, Manchala

    2016-01-01

    Vitamin B12 deficiency is widely prevalent in women of childbearing age, especially in developing countries. In the present study, through dietary restriction, we have established mouse models of severe and moderate vitamin B12 deficiencies to elucidate the impact on body composition, biochemical parameters, and reproductive performance. Female weanling C57BL/6 mice were fed for 4 weeks: (a) control AIN-76A diet, (b) vitamin B12-restricted AIN-76A diet with pectin as dietary fiber (severe deficiency group, as pectin inhibits vitamin B12 absorption), or (c) vitamin B12-restricted AIN-76A diet with cellulose as dietary fiber (moderate deficiency group as cellulose does not interfere with vitamin B12 absorption). After confirming deficiency, the mice were mated with male colony mice and maintained on their respective diets throughout pregnancy, lactation, and thereafter till 12 weeks. Severe vitamin B12 deficiency increased body fat% significantly, induced adiposity and altered lipid profile. Pregnant dams of both the deficient groups developed anemia. Severe vitamin B12 deficiency decreased the percentage of conception and litter size, pups were small-for-gestational-age and had significantly lower body weight at birth as well as weaning. Most of the offspring born to severely deficient dams died within 24 h of birth. Stress markers and adipocytokines were elevated in severe deficiency with concomitant decrease in antioxidant defense. The results show that severe but not moderate vitamin B12 restriction had profound impact on the physiology of C57BL/6 mice. Oxidative and corticosteroid stress, inflammation and poor antioxidant defense seem to be the probable underlying mechanisms mediating the deleterious effects.

  17. Severe but Not Moderate Vitamin B12 Deficiency Impairs Lipid Profile, Induces Adiposity, and Leads to Adverse Gestational Outcome in Female C57BL/6 Mice

    PubMed Central

    Ghosh, Shampa; Sinha, Jitendra Kumar; Putcha, Uday Kumar; Raghunath, Manchala

    2016-01-01

    Vitamin B12 deficiency is widely prevalent in women of childbearing age, especially in developing countries. In the present study, through dietary restriction, we have established mouse models of severe and moderate vitamin B12 deficiencies to elucidate the impact on body composition, biochemical parameters, and reproductive performance. Female weanling C57BL/6 mice were fed for 4 weeks: (a) control AIN-76A diet, (b) vitamin B12-restricted AIN-76A diet with pectin as dietary fiber (severe deficiency group, as pectin inhibits vitamin B12 absorption), or (c) vitamin B12-restricted AIN-76A diet with cellulose as dietary fiber (moderate deficiency group as cellulose does not interfere with vitamin B12 absorption). After confirming deficiency, the mice were mated with male colony mice and maintained on their respective diets throughout pregnancy, lactation, and thereafter till 12 weeks. Severe vitamin B12 deficiency increased body fat% significantly, induced adiposity and altered lipid profile. Pregnant dams of both the deficient groups developed anemia. Severe vitamin B12 deficiency decreased the percentage of conception and litter size, pups were small-for-gestational-age and had significantly lower body weight at birth as well as weaning. Most of the offspring born to severely deficient dams died within 24 h of birth. Stress markers and adipocytokines were elevated in severe deficiency with concomitant decrease in antioxidant defense. The results show that severe but not moderate vitamin B12 restriction had profound impact on the physiology of C57BL/6 mice. Oxidative and corticosteroid stress, inflammation and poor antioxidant defense seem to be the probable underlying mechanisms mediating the deleterious effects. PMID:26835453

  18. Physiogenomic analysis of weight loss induced by dietary carbohydrate restriction

    PubMed Central

    Ruaño, Gualberto; Windemuth, Andreas; Kocherla, Mohan; Holford, Theodore; Fernandez, Maria Luz; Forsythe, Cassandra E; Wood, Richard J; Kraemer, William J; Volek, Jeff S

    2006-01-01

    Background Diets that restrict carbohydrate (CHO) have proven to be a successful dietary treatment of obesity for many people, but the degree of weight loss varies across individuals. The extent to which genetic factors associate with the magnitude of weight loss induced by CHO restriction is unknown. We examined associations among polymorphisms in candidate genes and weight loss in order to understand the physiological factors influencing body weight responses to CHO restriction. Methods We screened for genetic associations with weight loss in 86 healthy adults who were instructed to restrict CHO to a level that induced a small level of ketosis (CHO ~10% of total energy). A total of 27 single nucleotide polymorphisms (SNPs) were selected from 15 candidate genes involved in fat digestion/metabolism, intracellular glucose metabolism, lipoprotein remodeling, and appetite regulation. Multiple linear regression was used to rank the SNPs according to probability of association, and the most significant associations were analyzed in greater detail. Results Mean weight loss was 6.4 kg. SNPs in the gastric lipase (LIPF), hepatic glycogen synthase (GYS2), cholesteryl ester transfer protein (CETP) and galanin (GAL) genes were significantly associated with weight loss. Conclusion A strong association between weight loss induced by dietary CHO restriction and variability in genes regulating fat digestion, hepatic glucose metabolism, intravascular lipoprotein remodeling, and appetite were detected. These discoveries could provide clues to important physiologic adaptations underlying the body mass response to CHO restriction. PMID:16700901

  19. Dietary coenzyme Q10 does not protect against cigarette smoke-augmented atherosclerosis in apoE-deficient mice.

    PubMed

    Gairola, C Gary; Howatt, Deborah A; Daugherty, Alan

    2010-06-01

    Dietary coenzyme Q10 reduces spontaneous atherosclerosis in the apoE-deficient mouse model of experimental atherosclerosis. We have shown previously that exposure to sidestream cigarette smoke (SSCS) enhances atherosclerotic lesion formation in apoE-deficient mice. The aim of the present study was to determine if CoQ10 protected against SSCS-mediated atherosclerosis. Female apoE-deficient mice were fed a saturated fat-enriched diet (SFD) alone, or supplemented with 1% wt/wt coenzyme Q10 (SFD-Q10). Mice in each diet group were exposed to SSCS for 4hrs/day, 5days/week in a whole-body exposure chamber maintained at 35+/-4mg smoke particulates/m(3). Mice kept in filtered ambient air served as controls. Mice were euthanized after either 6 or 15weeks of SSCS exposure and following measurements were performed: i) lung 7-ethoxyresorufin-O-deethylase (EROD) activity; ii) plasma cholesterol and CoQ10 concentrations; iii) aortic intimal area covered by atherosclerotic lesions; and, iv) pathological characterization of lesions. Lung EROD activity increased in SSCS mice of both diet groups, confirming SSCS exposure. Plasma concentrations of CoQ10 in SFD-Q10-fed mice were increased markedly in comparison to SFD-fed mice. Plasma cholesterol concentrations and distributions of cholesterol in lipoprotein fractions were unaffected by SSCS exposure. Dietary supplementation with CoQ10 significantly reduced atherosclerotic lesions in control mice. As reported previously, exposure to SSCS increased the size of lesions in apoE-/- mice at both time points. However, dietary supplementation with CoQ10 had no effect on atherosclerotic lesions augmented by SSCS exposure. The results suggest a role of oxidative processes in smoke-augmented atherosclerosis that are different than those mitigated by CoQ10.

  20. Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice

    PubMed Central

    Reis, Felipe C. G.; Branquinho, Jéssica L. O.; Brandão, Bruna B.; Guerra, Beatriz A.; Silva, Ismael D.; Frontini, Andrea; Thomou, Thomas; Sartini, Loris; Cinti, Saverio; Kahn, C. Ronald; Festuccia, William T.; Kowaltowski, Alicia J.; Mori, Marcelo A.

    2016-01-01

    Aging increases the risk of type 2 diabetes, and this can be prevented by dietary restriction (DR). We have previously shown that DR inhibits the downregulation of miRNAs and their processing enzymes - mainly Dicer - that occurs with aging in mouse white adipose tissue (WAT). Here we used fat-specific Dicer knockout mice (AdicerKO) to understand the contributions of adipose tissue Dicer to the metabolic effects of aging and DR. Metabolomic data uncovered a clear distinction between the serum metabolite profiles of Lox control and AdicerKO mice, with a notable elevation of branched-chain amino acids (BCAA) in AdicerKO. These profiles were associated with reduced oxidative metabolism and increased lactate in WAT of AdicerKO mice and were accompanied by structural and functional changes in mitochondria, particularly under DR. AdicerKO mice displayed increased mTORC1 activation in WAT and skeletal muscle, where Dicer expression is not affected. This was accompanied by accelerated age-associated insulin resistance and premature mortality. Moreover, DR-induced insulin sensitivity was abrogated in AdicerKO mice. This was reverted by rapamycin injection, demonstrating that insulin resistance in AdicerKO mice is caused by mTORC1 hyperactivation. Our study evidences a DR-modulated role for WAT Dicer in controlling metabolism and insulin resistance. PMID:27241713

  1. High dose zinc supplementation induces hippocampal zinc deficiency and memory impairment with inhibition of BDNF signaling.

    PubMed

    Yang, Yang; Jing, Xiao-Peng; Zhang, Shou-Peng; Gu, Run-Xia; Tang, Fang-Xu; Wang, Xiu-Lian; Xiong, Yan; Qiu, Mei; Sun, Xu-Ying; Ke, Dan; Wang, Jian-Zhi; Liu, Rong

    2013-01-01

    Zinc ions highly concentrate in hippocampus and play a key role in modulating spatial learning and memory. At a time when dietary fortification and supplementation of zinc have increased the zinc consuming level especially in the youth, the toxicity of zinc overdose on brain function was underestimated. In the present study, weaning ICR mice were given water supplemented with 15 ppm Zn (low dose), 60 ppm Zn (high dose) or normal lab water for 3 months, the behavior and brain zinc homeostasis were tested. Mice fed high dose of zinc showed hippocampus-dependent memory impairment. Unexpectedly, zinc deficiency, but not zinc overload was observed in hippocampus, especially in the mossy fiber-CA3 pyramid synapse. The expression levels of learning and memory related receptors and synaptic proteins such as NMDA-NR2A, NR2B, AMPA-GluR1, PSD-93 and PSD-95 were significantly decreased in hippocampus, with significant loss of dendritic spines. In keeping with these findings, high dose intake of zinc resulted in decreased hippocampal BDNF level and TrkB neurotrophic signaling. At last, increasing the brain zinc level directly by brain zinc injection induced BDNF expression, which was reversed by zinc chelating in vivo. These results indicate that zinc plays an important role in hippocampus-dependent learning and memory and BDNF expression, high dose supplementation of zinc induces specific zinc deficiency in hippocampus, which further impair learning and memory due to decreased availability of synaptic zinc and BDNF deficit.

  2. Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice.

    PubMed

    Zhang, Jingyao; Song, Sidong; Pang, Qing; Zhang, Ruiyao; Zhou, Lei; Liu, Sushun; Meng, Fandi; Wu, Qifei; Liu, Chang

    2015-01-29

    Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH₂-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.

  3. Dietary phosphorus overload aggravates the phenotype of the dystrophin-deficient mdx mouse.

    PubMed

    Wada, Eiji; Yoshida, Mizuko; Kojima, Yoriko; Nonaka, Ikuya; Ohashi, Kazuya; Nagata, Yosuke; Shiozuka, Masataka; Date, Munehiro; Higashi, Tetsuo; Nishino, Ichizo; Matsuda, Ryoichi

    2014-11-01

    Duchenne muscular dystrophy is a lethal X-linked disease with no effective treatment. Progressive muscle degeneration, increased macrophage infiltration, and ectopic calcification are characteristic features of the mdx mouse, a murine model of Duchenne muscular dystrophy. Because dietary phosphorus/phosphate consumption is increasing and adverse effects of phosphate overloading have been reported in several disease conditions, we examined the effects of dietary phosphorus intake in mdx mice phenotypes. On weaning, control and mdx mice were fed diets containing 0.7, 1.0, or 2.0 g phosphorus per 100 g until they were 90 days old. Dystrophic phenotypes were evaluated in cryosections of quadriceps and tibialis anterior muscles, and maximal forces and voluntary activity were measured. Ectopic calcification was analyzed by electron microscopy to determine the cells initially responsible for calcium deposition in skeletal muscle. Dietary phosphorus overload dramatically exacerbated the dystrophic phenotypes of mdx mice by increasing inflammation associated with infiltration of M1 macrophages. In contrast, minimal muscle necrosis and inflammation were observed in exercised mdx mice fed a low-phosphorus diet, suggesting potential beneficial therapeutic effects of lowering dietary phosphorus intake on disease progression. To our knowledge, this is the first report showing that dietary phosphorus intake directly affects muscle pathological characteristics of mdx mice. Dietary phosphorus overloading promoted dystrophic disease progression in mdx mice, whereas restricting dietary phosphorus intake improved muscle pathological characteristics and function.

  4. Contact Lens-induced Limbal Stem Cell Deficiency.

    PubMed

    Rossen, Jennifer; Amram, Alec; Milani, Behrad; Park, Dongwook; Harthan, Jennifer; Joslin, Charlotte; McMahon, Timothy; Djalilian, Ali

    2016-10-01

    Limbal stem cell deficiency (LSCD) is a pathologic condition caused by the dysfunction and/or destruction of stem cell precursors of the corneal epithelium, typified clinically by corneal conjunctivalization. The purpose of this review is to critically discuss a less well-known cause of limbal stem cell disease: contact lens (CL) wear. A literature search was conducted to include original articles containing patients with CL-induced LSCD. This review describes epidemiology, diagnostic strategies, pathogenesis, differential diagnosis, and treatment modalities for this condition.

  5. Serum lipids in rats as related to modifications in dietary fat, fiber, and sodium with magnesium deficiency

    SciTech Connect

    Howe, C.A.; Kubena, K.S. )

    1991-03-11

    Recommendations to modify dietary intake to attenuate risk of cardiovascular disease have been released by numerous governmental and health organizations. Since magnesium is associated with lipid metabolism and normal cardiovascular function, this study was designed to determine the effect of modifications in dietary fat, fiber, and sodium with magnesium deficiency on serum lipids and tissue minerals. The control (C) diet was based upon the AIN-76 diet formulation; the American (A) diet included average fat, fiber, and sodium levels in the US; and the recommended (R) diet was lower in fat and sodium and higher in fiber. Diets contained either 1,000 or 150 (L) mg Mg/kg diet. Male weanling Sprague-Dawley rats were fed one of the diets (C, CL, A, Al, R, RL) for six weeks. Levels of tissue Mg, Ca, Zn, and P were determined. Neither initial nor final body weights varied between groups. Serum levels of triglyceride were higher in the C and Cl groups than in the others. Serum cholesterol was lower in the R and Rl groups than in the Cl and A groups. Animals which were fed the diet modified with regard to fat, fiber, and sodium had lower serum cholesterol levels than did those fed the American diet. Magnesium deficiency was not consistently related to serum lipid levels.

  6. Paradoxical zinc toxicity and oxidative stress in the mammary gland during marginal dietary zinc deficiency

    PubMed Central

    Bostanci, Zeynep; Mack, Ronald P.; Lee, Sooyeon; Soybel, David I.; Kelleher, Shannon L.

    2014-01-01

    Zinc (Zn) regulates numerous cellular functions. Zn deficiency is common in females; ~80% of women and 40% of adolescent girls consume inadequate Zn. Zn deficiency enhances oxidative stress, inflammation and DNA damage. Oxidative stress and inflammation is associated with breast disease. We hypothesized that Zn deficiency increases oxidative stress in the mammary gland, altering the microenvironment and architecture. Zn accumulated in the mammary glands of Zn deficient mice and this was associated with macrophage infiltration, enhanced oxidative stress and over-expression of estrogen receptor α. Ductal and stromal hypercellularity was associated with aberrant collagen deposition and disorganized e-cadherin. Importantly, these microenvironmental alterations were associated with substantial impairments in ductal expansion and mammary gland development. This is the first study to show that marginal Zn deficiency creates a toxic microenvironment in the mammary gland impairing breast development. These changes are consistent with hallmarks of potential increased risk for breast disease and cancer. PMID:25088245

  7. Susceptibility to cerulein-induced pancreatitis in inducible nitric oxide synthase-deficient mice.

    PubMed

    Qui, B; Mei, Q B; Ma, J J; Korsten, M A

    2001-07-01

    Production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been proposed as a pathogenic factor in acute pancreatitis, but its role has still not been fully examined. The present study explored the role of iNOS in cerulein-induced acute pancreatitis using iNOS-deficient mice. Twelve- to 14-week-old male mice (C57B1/6 and iNOS-deficient) were administered cerulein by intraperitoneal (i.p.) injection at hourly intervals for 7 hours and killed 24 hours later after the first dose. Pancreatic wet weight, pancreatic myeloperoxidase (MPO) activity, and levels of plasma nitrite and serum amylase were measured. In another experiment isosorbide dinitrate (an NO donor) was given by oral gavage every 6 hours for 24 hours beginning simultaneously with cerulein injections in iNOS-deficient mice. Cerulein administration dose-dependently increased pancreatic wet weight, myeloperoxidase activity, and levels of nitrite and amylase in C57B1/6 mice. These parameters (except nitrite levels) were significantly intensified in iNOS-deficient mice. At the dose employed, cerulein failed to increase nitrite levels in iNOS-deficient mice. The susceptibility to cerulein toxicity in iNOS-deficient mice was abolished by NO donor treatment. NO release from an iNOS source appears to play a protective role in cerulein-induced pancreatitis. At least in part, NO may prevent neutrophil accumulation after cerulein administration.

  8. NAD(P)H: Quinone Oxidoreductase 1 Deficiency Conjoint with Marginal Vitamin C Deficiency Causes Cigarette Smoke Induced Myelodysplastic Syndromes

    PubMed Central

    Das, Archita; Dey, Neekkan; Ghosh, Arunava; Das, Tanusree; Chatterjee, Indu B.

    2011-01-01

    Background The etiology of myelodysplastic syndromes (MDS) is largely unknown. Exposure to cigarette smoke (CS) is reported to be associated with MDS risk. There is inconsistent evidence that deficiency of NAD(P)H-quinone: oxidoreductase 1 (NQO1) increases the risk of MDS. Earlier we had shown that CS induces toxicity only in marginal vitamin C-deficient guinea pigs but not in vitamin C-sufficient ones. We therefore considered that NQO1 deficiency along with marginal vitamin C deficiency might produce MDS in CS-exposed guinea pigs. Methodology and Principal Findings Here we show that CS exposure for 21 days produces MDS in guinea pigs having deficiency of NQO1 (fed 3 mg dicoumarol/day) conjoint with marginal vitamin C deficiency (fed 0.5 mg vitamin C/day). As evidenced by morphology, histology and cytogenetics, MDS produced in the guinea pigs falls in the category of refractory cytopenia with unilineage dysplasia (RCUD): refractory anemia; refractory thrombocytopenia that is associated with ring sideroblasts, micromegakaryocytes, myeloid hyperplasia and aneuploidy. MDS is accompanied by increased CD34(+) cells and oxidative stress as shown by the formation of protein carbonyls and 8-oxodeoxyguanosine. Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein. MDS produced in the guinea pigs are irreversible. MDS and all the aforesaid pathophysiological events do not occur in vitamin C-sufficient guinea pigs. However, after the onset of MDS vitamin C becomes ineffective. Conclusions and Significance CS exposure causes MDS in guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. The syndromes are not produced in singular deficiency of NQO1 or marginal vitamin C deficiency. Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS. PMID:21655231

  9. Dietary Selenium Deficiency Partially Rescues Type 2 Diabetes–Like Phenotypes of Glutathione Peroxidase-1–Overexpressing Male Mice123

    PubMed Central

    Yan, Xi; Pepper, Matthew P.; Vatamaniuk, Marko Z.; Roneker, Carol A.; Li, Li; Lei, Xin Gen

    2012-01-01

    This study was conducted to determine whether dietary Se deficiency precluded overproduction of glutathione peroxidase-1 (GPX1) activity in mice overexpressing (OE) this gene and thus rescued their type 2 diabetes–like phenotypes. A total of 20 male OE and wild-type (WT) mice were fed an Se-deficient (<0.02 mg/kg) diet or an Se-supplemented (0.3 mg/kg as sodium selenite) diet from 1 to 5 mo of age. Dietary Se deficiency eliminated or attenuated (P < 0.05) genotype differences in concentrations of blood glucose, plasma insulin, and/or hepatic lipids, insulin sensitivity, and glucose-stimulated insulin secretion at the end of the study. Dietary Se deficiency decreased (P < 0.05) OE islet mRNA levels of 2 key transcriptional activators (Beta2 and Foxa2) and removed genotype differences in islet mRNA levels of 7 genes (Beta2, Cfos, Foxa2, Pregluc, Ins1, p53, and Sur1) related to insulin synthesis and secretion. Compared with those of the Se-adequate OE mice, the Se-deficient OE mice had lower (P < 0.05) hepatic mRNA levels of 2 key rate-limiting enzymes for lipogenesis (Acc1) and glycolysis (Gk1), along with lower (P < 0.05) activities of hepatic glucokinase and muscle phosphoenolpyruvate carboxykinase. Dietary Se deficiency also decreased (P < 0.05) blood glucose and hepatic lipid concentrations in the WT mice. In conclusion, dietary Se deficiency precluded the overproduction of GPX1 in full-fed OE mice and partially rescued their metabolic syndromes. This alleviation resulted from modulating the expression and/or function of proinsulin genes, lipogenesis rate-limiting enzyme genes, and key glycolysis and gluconeogenesis enzymes in islets, liver, and muscle. PMID:23014491

  10. Therapeutic paracetamol treatment in older persons induces dietary and metabolic modifications related to sulfur amino acids.

    PubMed

    Pujos-Guillot, Estelle; Pickering, Gisèle; Lyan, Bernard; Ducheix, Gilles; Brandolini-Bunlon, Marion; Glomot, Françoise; Dardevet, Dominique; Dubray, Claude; Papet, Isabelle

    2012-02-01

    Sulfur amino acids are determinant for the detoxification of paracetamol (N-acetyl-p-aminophenol) through sulfate and glutathione conjugations. Long-term paracetamol treatment is common in the elderly, despite a potential cysteine/glutathione deficiency. Detoxification could occur at the expense of anti-oxidative defenses and whole body protein stores in elderly. We tested how older persons satisfy the extra demand in sulfur amino acids induced by long-term paracetamol treatment, focusing on metabolic and nutritional aspects. Effects of 3 g/day paracetamol for 14 days on fasting blood glutathione, plasma amino acids and sulfate, urinary paracetamol metabolites, and urinary metabolomic were studied in independently living older persons (five women, five men, mean (±SEM) age 74 ± 1 years). Dietary intakes were recorded before and at the end of the treatment and ingested sulfur amino acids were evaluated. Fasting blood glutathione, plasma amino acids, and sulfate were unchanged. Urinary nitrogen excretion supported a preservation of whole body proteins, but large-scale urinary metabolomic analysis revealed an oxidation of some sulfur-containing compounds. Dietary protein intake was 13% higher at the end than before paracetamol treatment. Final sulfur amino acid intake reached 37 mg/kg/day. The increase in sulfur amino acid intake corresponded to half of the sulfur excreted in urinary paracetamol conjugates. In conclusion, older persons accommodated to long-term paracetamol treatment by increasing dietary protein intake without any mobilization of body proteins, but with decreased anti-oxidative defenses. The extra demand in sulfur amino acids led to a consumption far above the corresponding population-safe recommendation.

  11. Metallothionein deficiency aggravates depleted uranium-induced nephrotoxicity

    SciTech Connect

    Hao, Yuhui; Huang, Jiawei; Gu, Ying; Liu, Cong; Li, Hong; Liu, Jing; Ren, Jiong; Yang, Zhangyou; Peng, Shuangqing; Wang, Weidong; Li, Rong

    2015-09-15

    Depleted uranium (DU) has been widely used in both civilian and military activities, and the kidney is the main target organ of DU during acute high-dose exposures. In this study, the nephrotoxicity caused by DU in metallothionein-1/2-null mice (MT −/−) and corresponding wild-type (MT +/+) mice was investigated to determine any associations with MT. Each MT −/− or MT +/+ mouse was pretreated with a single dose of DU (10 mg/kg, intraperitoneal injection) or an equivalent volume of saline. After 4 days of DU administration, kidney changes were assessed. After DU exposure, serum creatinine and serum urea nitrogen in MT −/− mice significantly increased than in MT +/+ mice, with more severe kidney pathological damage. Moreover, catalase and superoxide dismutase (SOD) decreased, and generation of reactive oxygen species and malondialdehyde increased in MT −/− mice. The apoptosis rate in MT −/− mice significantly increased, with a significant increase in both Bax and caspase 3 and a decrease in Bcl-2. Furthermore, sodium-glucose cotransporter (SGLT) and sodium-phosphate cotransporter (NaPi-II) were significantly reduced after DU exposure, and the change of SGLT was more evident in MT −/− mice. Finally, exogenous MT was used to evaluate the correlation between kidney changes induced by DU and MT doses in MT −/− mice. The results showed that, the pathological damage and cell apoptosis decreased, and SOD and SGLT levels increased with increasing dose of MT. In conclusion, MT deficiency aggravated DU-induced nephrotoxicity, and the molecular mechanisms appeared to be related to the increased oxidative stress and apoptosis, and decreased SGLT expression. - Highlights: • MT −/− and MT +/+ mice were used to evaluate nephrotoxicity of DU. • Renal damage was more evident in the MT −/− mice after exposure to DU. • Exogenous MT also protects against DU-induced nephrotoxicity. • MT deficiency induced more ROS and apoptosis after exposure to

  12. Ornithine transcarbamylase deficiency combined with type 1 diabetes mellitus - a challenge in clinical and dietary management.

    PubMed

    Grünert, Sarah C; Villavicencio-Lorini, Pablo; Wermuth, Bendicht; Lehnert, Willy; Sass, Jörn Oliver; Schwab, K Otfried

    2013-07-05

    Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle defect. The clinical presentation in female manifesting carriers varies both in onset and severity. We report on a female with insulin dependent diabetes mellitus and recurrent episodes of hyperammonemia. Since OTC activity measured in a liver biopsy sample was within normal limits, OTC deficiency was initially excluded from the differential diagnoses of hyperammonemia. Due to moderately elevated homocitrulline excretion, hyperornithinemia-hyperammonemia-homocitrullinuria-syndrome was suggested, but further assays in fibroblasts showed normal ornithine utilization. Later, when mutation analysis of the OTC gene became available, a known pathogenic missense mutation (c.533C>T) in exon 5 leading to an exchange of threonine-178 by methionine (p.Thr178Met) was detected. Skewed X-inactivation was demonstrated in leukocyte DNA. In the further clinical course the girl developed marked obesity. By initiating physical activities twice a week, therapeutic control of both diabetes and OTC deficiency improved, but obesity persisted. In conclusion, our case confirms that normal hepatic OTC enzyme activity measured in a single liver biopsy sample does not exclude a clinical relevant mosaic of OTC deficiency because of skewed X-inactivation. Mutation analysis of the OTC gene in whole blood may be a simple way to establish the diagnosis of OTC deficiency. The joint occurrence of OTC deficiency and diabetes in a patient has not been reported before.

  13. Rice Bran Dietary Supplementation Improves Neurological Symptoms and Loss of Purkinje Cells in Vitamin E-Deficient Mice

    PubMed Central

    Takahashi, Toru; Nakaso, Kazuhiro; Horikoshi, Yosuke; Hanaki, Takehiko; Yamakawa, Miho; Nakasone, Masato; Kitagawa, Yoshinori; Koike, Taisuke; Matsura, Tatsuya

    2016-01-01

    Background Vitamin E (VE, α-tocopherol) is a fat-soluble vitamin and is well known as an antioxidant. A deficiency in VE induces oxidative stress in the brain and causes motor and memory dysfunction. The consumption of a VE-rich diet has been given much attention in recent years, in regards to anti-aging and the prevention of age-related neuronal disorders. Methods A VE-deficient mouse model was prepared by feeding the animals a diet lacking VE. In addition, to evaluate the effect of VE-containing rice bran (RB) on VE deficiency, a diet including RB was also provided. VE levels in the brain tissue, as well as in the RB, were measured using an HPLC system. Behavioral tests, including rotarod, wheel running activity, Y-maze, and elevated plus maze were performed. To clarify the effect of VE deficiency and RB, we investigated the induction of heme oxygenase-1 (HO-1). Histological studies were performed using HE staining and immunohistochemical studies were performed using antibodies against glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1). Results VE in the mouse brain under a VE-deficient diet was decreased, and recovered α-tocopherol levels were observed in the brain of mice fed an RB diet. Motor behavioral scores were decreased in VE-deficient conditions, while the supplementation of RB improved motor function. HO-1, a marker of oxidative stress, was upregulated in the mouse brain under VE deficiency, however, RB supplementation inhibited the increase of HO-1. Histological analyses showed neuronal degeneration of Purkinje cells and decreased GFAP-immunoreactivity of Bergmann glia in the cerebellum. In addition, activated astrocytes and microglia were observed in mice fed the VE-deficient diet. Mice fed the RB diet showed improvement in these histological abnormalities. Conclusion A VE-deficient diet induced motor dysfunction in mice due to the degeneration of Purkinje cells in the cerebellum. Oral supplementation of RB

  14. Ferric Carboxymaltose-Mediated Attenuation of Doxorubicin-Induced Cardiotoxicity in an Iron Deficiency Rat Model

    PubMed Central

    Toblli, Jorge Eduardo; Rivas, Carlos; Cao, Gabriel; Giani, Jorge Fernando; Dominici, Fernando Pablo

    2014-01-01

    Since anthracycline-induced cardiotoxicity (AIC), a complication of anthracycline-based chemotherapies, is thought to involve iron, concerns exist about using iron for anaemia treatment in anthracycline-receiving cancer patients. This study evaluated how intravenous ferric carboxymaltose (FCM) modulates the influence of iron deficiency anaemia (IDA) and doxorubicin (3–5 mg per kg body weight [BW]) on oxidative/nitrosative stress, inflammation, and cardiorenal function in spontaneously hypertensive stroke-prone (SHR-SP) rats. FCM was given as repeated small or single total dose (15 mg iron per kg BW), either concurrent with or three days after doxorubicin. IDA (after dietary iron restriction) induced cardiac and renal oxidative stress (markers included malondialdehyde, catalase, Cu,Zn-superoxide dismutase, and glutathione peroxidase), nitrosative stress (inducible nitric oxide synthase and nitrotyrosine), inflammation (tumour necrosis factor-alpha and interleukin-6), and functional/morphological abnormalities (left ventricle end-diastolic and end-systolic diameter, fractional shortening, density of cardiomyocytes and capillaries, caveolin-1 expression, creatinine clearance, and urine neutrophil gelatinase-associated lipocalin) that were aggravated by doxorubicin. Notably, iron treatment with FCM did not exacerbate but attenuated the cardiorenal effects of IDA and doxorubicin independent of the iron dosing regimen. The results of this model suggest that intravenous FCM can be used concomitantly with an anthracycline-based chemotherapy without increasing signs of AIC. PMID:24876963

  15. Further studies on the effects of dietary copper deficiency on rat pancreas

    SciTech Connect

    Mylroie, A.A.; Boseman, A.; Kyle, J.

    1988-01-01

    The present study was designed to obtain further information on the effect of Cu deficiency on the pancreas and on pancreatic SOD activity. In a series of experiments, groups of male weanling Sprague Dawley rats were fed either a Cu sufficient Cu or Cu deficient purified AIN-'76 diet. Cu levels were determined in blood and selected organs by atomic absorption spectrophotometry. Serum ceruloplasmin, hemoglobin and hematocrit values were determined. Aliquots of homogenized pancreas were assayed for CuSOD, MnSOD and other pancreatic enzyme activities. Although the experimental conditions appeared to be identical to those used in previous experiments, the results were different. In the experiments reported here, even though pancreatic weights decreased by week 7 relative to controls, there was no evidence of pancreatic atrophy. There was no significant decrease in CuSOD, but an unexpected increase in MnSOD activity by week 9 in rats fed Cu-deficient diet. An examination of all data indicates that the difference in results between previous experiments and those reported here was due to the varying degree of Cu deficiency produced: Cu deficiency was less pronounced in the present study.

  16. Increased folate uptake prevents dietary development of folate deficiency in the rat brain

    SciTech Connect

    McMartin, K.E.; Collins, T.D.; Eisenga, B.H.; Bhandari, S.D. )

    1990-02-26

    Folic acid and folate deficiency have been implicated in disorders of the central nervous system. In a study of the mechanism for the effects of chronic ethanol on folate homeostasis, the uptake of {sup 3}H-folic acid by the rat brain has been studied. Male Sprague-Dawley rats were fed sulfonamide-supplemented folate-sufficient and folate-deficient liquid diets containing either ethanol or isoenergic carbohydrate as a control. After 16 weeks, severe folate depletion occurred in tissues (liver, kidney, spleen, lung intestine, testes), but not in the brain. Tissue retention of {sup 3}H-folic acid was increased four-fold in the brain of folate-deficient rats. A smaller increase in uptake was observed in the other tissues, except for the liver, in which the retention of {sup 3}H-folic acid was slightly decreased. Chronic ethanol feeding decreased hepatic folate uptake, but not that by the increase the uptake of folate from the plasma of folate-deficient rats, thereby inhibiting the development of brain folate deficiency.

  17. Dissecting iron deficiency-induced proton extrusion in Arabidopsis roots.

    PubMed

    Santi, Simonetta; Schmidt, Wolfgang

    2009-01-01

    Here, we have analysed the H(+)-ATPase-mediated extrusion of protons across the plasma membrane (PM) of rhizodermic cells, a process that is inducible by iron (Fe) deficiency and thought to serve in the mobilization of sparingly soluble Fe sources. The induction and function of Fe-responsive PM H(+)-ATPases in Arabidopsis roots was investigated by gene expression analysis and by using mutants defective in the expression or function of one of the isogenes. In addition, the expression of the most responsive isogenes was investigated in natural Arabidopsis accessions that have been selected for their in vivo proton extrusion activity. Our data suggest that the rhizosphere acidification in response to Fe deficiency is chiefly mediated by AHA2, while AHA1 functions as a housekeeping isoform. The aha7 knock-out mutant plants showed a reduced frequency of root hairs, suggesting an involvement of AHA7 in the differentiation of rhizodermic cells. Acidification capacity varied among Arabidopsis accessions and was associated with a high induction of AHA2 and IRT1, a high relative growth rate and a shoot-root ratio that was unaffected by the external Fe supply. An effective regulation of the Fe-responsive genes and a stable shoot-root ratio may represent important characteristics for the Fe uptake efficiency.

  18. Paradoxical glucose-induced hyperkalemia. Combined aldosterone-insulin deficiency.

    PubMed

    Goldfarb, S; Strunk, B; Singer, I; Goldberg, M

    1975-11-01

    Severe hyperkalemia associated with spontaneous hyperglycemia as well as with the intravenous infusions of glucose occurred in an insulin-requiring diabetic patient in the absence of potassium administration, the use of diuretics which inhibit urinary potassium excretion or acidemia. Metabolic balance studies revealed, in addition to diabets, the presence of isolated aldosterone deficiency of the hyporeninemic type. Intravenous glucose infusions (0.5 g/kg body weight) produced significant hyperkalemia but desoxycortisone acetate (DOCA) therapy (10 mg/day) prevented the glucose-induced hyperkalemia. In this patient, the serum potassium concentration increases after the intravenous infusions of glucose because there is insufficient aldosterone and insulin to reverse the transfer of potassium to the extracellular fluid which normally occurs after hypertonic infusions of glucose. Although DOCA replacement modifies the distribution of potassium in the extracellular fluid and blunts the hyperkalemic effect of intravenous infusions of glucose, a rise in the insulin level is required for the usual hypokalemic response to intravenously administered glucose. These studies illustrate the risk of raising blood glucose levels in patients with combined aldosterone and insulin deficiency and the tendency towards hyperkalemia in diabetic patients under certain clinical conditions.

  19. Echocardiographic evidence for myocardial failure induced by taurine deficiency in domestic cats.

    PubMed Central

    Novotny, M J; Hogan, P M; Flannigan, G

    1994-01-01

    Dietary taurine-deficiency is a cause of dilated cardiomyopathy (DCM) in cats. While the incidence of clinical cases of feline DCM has markedly decreased since the association between DCM and taurine-deficiency was first recognized, not all cats maintained on taurine-deficient diets develop DCM. The objective was to temporally evaluate left ventricular (LV) function using M-mode echocardiography in 23 cats maintained on a taurine-deficient diet; 20 time-matched, taurine-supplemented cats served as controls. The duration of feeding trials ranged from 6-15 months. No diminution of myocardial function was recorded in a small number of taurine-deficient cats whereas cardiac performance in some taurine-deficient cats diminished to levels characteristic of DCM. Of the taurine-deficient cats, 17 (74%) experienced a greater than 25% reduction in fractional shortening and 21 (91%) had a greater than 25% increase in LV end-systolic short-axis diameter. On average, LV end-systolic short-axis diameter increased by 70% and fractional shortening decreased by 37% in taurine-deficient cats. Mean velocity of circumferential fiber shortening was similarly reduced in taurine-deficient cats. The greatest rate of change in M-mode echocardiographic variables occurred during the first four months on the taurine-deficient diet. Dietary taurine deficiency leads to a spectrum of changes in myocardial function in domestic cats. While DCM is observed in some cats, decreased systolic pump function and increased LV end-systolic short-axis diameter are more consistent findings. PMID:8143255

  20. TRIBROMOMETHANE EXPOSURE AND DIETARY FOLATE DEFICIENCY IN THE FORMATION OF ABERRANT CRYPT FOCI IN THE COLONS OF F344/N RATS

    EPA Science Inventory

    TRIBROMOMETHANE EXPOSURE AND DIETARY FOLATE DEFICIENCY IN THE FORMATION OF ABERRANT CRYPT FOCI IN THE COLONS OF F344/N RATS

    David R. Geter', Tanya M. Moore', Michael H. George', Steve R. Kilburn', Gloria Huggins-Clark', James W. Allen', and Anthony B. DeAngelo' 'National H...

  1. Dietary zinc deficiency affects blood linoleic acid: dihomo-gamma-linolenic acid (LA:DGLA) ratio; a reactive physiological marker of zinc status in vivo (Gallus gallus)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dietary Zinc (Zn) deficiency affects approximately 30% of the world’s population. Zinc is a vital micronutrient and is important for the body’s ability to function. To date, accurate biological markers of the Zn subject’s status are still needed. The aim of this study was to evaluate the chicken mod...

  2. Dietary thyroxine induces molt in chickens (Gallus gallus domesticus).

    PubMed

    Bass, P D; Hooge, D M; Koutsos, E A

    2007-03-01

    Thyroxine increases during a molt in wild and captive birds, and thyroidectomy prevents induction of molt. This trial examined the effect of dietary thyroxine on molt induction molt in chickens (laying hens, 59 weeks of age). In a completely randomized design (n=15 hens/replication; 6 replications/treatment), hens were randomly assigned to either a traditional molting program consisting of feed withdrawal (FWD), or to diets containing 40 mg thyroxine/kg diet (HT), 20 mg thyroxine/kg diet (LT), or 40 mg thyroxine from thyroactive iodinated casein/kg diet (TIC). The molting treatment lasted 7-13 d, until egg production reached 0%. After molt induction, birds had ad libitum access to the same diet, until egg production was re-initiated and maximized ( approximately 56 d). All treatments induced molt, based upon cessation of egg laying and regression of ovary and oviduct. Birds on FWD treatment lost more body weight during the molting period, but gained more after molt compared to thyroxine treatments (P<0.01 for each), although all body weights were similar when egg production was maximized. Data demonstrate that oral thyroxine, in purified or non-purified form, induces a molt and may enhance animal well-being by reducing the need for FWD.

  3. Dimethylthiourea inhibits heart weight and hematocrit changes caused by dietary copper deficiency

    SciTech Connect

    Saari, J.T. )

    1991-03-11

    Feeding antioxidants to rats in a copper (Cu)-deficient diet can partially inhibit the cardiac enlargement and anemia caused by Cu deficiency. This study was done to determine whether an antioxidant which bypassed the gastrointestinal tract was also protective and whether an agent more potent than previously used was more effective in this inhibition. Male, weanling rats were fed diets deficient or sufficient in Cu for 4 wks. Dimethylthiourea (DMTU) or saline was injected (ip) 4 times a week; minimum amount of DMTU retained during the experiment was estimated to be 250 mg/kg. Unlike other antioxidants, DMTU completely prevented the increase in heart wt/body wt ratio; like the other agents, it only partially inhibited the anemia of Cu deficiency. DMTU did not affect plasma or liver Cu content of CuD rats; however, heart copper of CuD rats was significantly increased by DMTU. The effects of DMTU on heart size and hematocrit (Hct) may be attributed to its antioxidant function, but the possibility of altered mineral status must also be considered.

  4. Increased adiposity induced by high dietary butter oil increases vertebrae trabecular structural indices in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity has been associated with both improved and impaired bone health, and other dietary factors apparently affect the nature of the association. An experiment was performed to determine whether increased adiposity induced by high dietary butter oil impairs bone structure and whether that effect ...

  5. EFFECTS OF DIETARY FOLATE ON ARSENIC-INDUCED GENE EXPRESSION IN MICE

    EPA Science Inventory

    Effects of Dietary Folate on Arsenic-induced Gene Expression in Mice

    Arsenic, a drinking water contaminant, is a known carcinogen. Human exposure to inorganic arsenic has been linked to tumors of skin, bladder, lung, and to a lesser extent, kidney and liver. Dietary fola...

  6. Differential effects of dietary Oenothera, Zizyphus mistol, and corn oils, and essential fatty acid deficiency on the progression of a murine mammary gland adenocarcinoma.

    PubMed

    Muñoz, S E; Piegari, M; Guzmán, C A; Eynard, A R

    1999-03-01

    The modulating effect of dietary enrichment in mistol seed oil (MO) containing 25% of alpha-linolenic acid (ALA), evening primrose oil (EPO) enriched in gamma-linolenic acid (GLA) and corn oil (CO) as sources of omega-6 and omega-9 fatty acids on the growth parameters of one transplantable mammary tumor were compared. Mice fed on different lipid formulae were inoculated with a mammary gland adenocarcinoma and different growth development tumor parameters were recorded. Results showed that corn oil feeding slowed down most of the tumor growth parameters, as did the EPO diet. MO also showed antitumor activity. Olein feeding, which induces an essential fatty acid deficiency (EFAD), increased the incidence and the multiplicity of metastases when compared with the controls. It may be concluded that a diet enriched in omega-6 fatty acids did not behave as a tumor promoter in this mammary gland tumor model. The antitumor activities of EPO and MO are corroborated in present experiments, suggesting that both oils may be of value in nutritional approaches of mammary gland tumor therapies. In addition, present data add further experimental proof about the proposed protumorigenic proneness induced by the EFAD state.

  7. Pre- and postnatal dietary protein deficiency influences anxiety, memory and social behaviour in the African striped mouse Rhabdomys dilectus chakae.

    PubMed

    Pillay, Neville; Rimbach, Rebecca; Rymer, Tasmin

    2016-07-01

    Dietary protein deficiency influences the behavioural phenotypes of mammals. We studied whether protein deficiency during gestation and/or post-weaning heightened anxiety, reduced memory recall and influenced competitive ability in the African striped mouse Rhabdomys dilectus chakae. Mice were subjected to five protein diet treatments, which they received continuously, or were raised on one diet to weaning and switched to an alternate diet post-weaning (Day 16): 1) HP-HP: high protein (24%); first letter pair indicates maternal diet and the second pair indicates offspring diet post-weaning; 2) BP-BP: baseline protein (19%); 3) LP-LP: low protein (10%); 4) HP-LP: switched from high to low protein diet; and 5) LP-HP: switched from low protein to high protein diet. From Day 70, when mice were sexually mature, 20 individuals (10 males, 10 females) per treatment were subjected to three successive experiments, in which we tested their anxiety responses in: 1) an open field arena (time spent in the centre of the open field); 2) novel object recognition (time spent exploring a novel object); and 3) social interactions (excluding BP-BP) in age-matched same-sex dyadic encounters (aggressive, amicable and avoidance behaviours). LP-LP and LP-HP treatment mice spent the least amount of time in the centre of the open field, did not demonstrate object preference compared to the other treatments, and were the most aggressive in dyadic encounters. Our study shows that the systemic effects of protein-deficient diets during early life shapes the behavioural phenotype in R. d. chakae, possibly through early organisation of neuro-biological pathways or competition among littermates.

  8. Interleukin-17A deficiency ameliorates streptozotocin-induced diabetes.

    PubMed

    Tong, Zan; Liu, Weihuang; Yan, Huichao; Dong, Chen

    2015-10-01

    Interleukin-17 (IL-17) is a cytokine with critical functions in multiple autoimmune diseases. However, its roles in type I diabetes and the underlying mechanisms remain to be fully elucidated. In the current study, we investigated the impact of IL-17 deficiency on streptozotocin (STZ) -induced diabetes. Il-17(-/-) mice exhibited attenuated hyperglycaemia and insulitis after STZ treatment compared with control mice. The Il-17(-/-) mice had fewer CD8(+) cells infiltrating the pancreas than wild-type controls after STZ injection. Wild-type mice showed increased percentage and number of splenic CD8(+) cells and decreased Gr1(+)  CD11b(+) myeloid-derived suppressor cells (MDSC) after STZ treatment, but Il-17(-/-) mice maintained the percentages and numbers of splenic CD8(+) cells and MDSC, suggesting that IL-17 is implicated in STZ-induced cellular immune responses in the spleen. We further purified the MDSC from spleens of STZ-treated mice. Il-17(-/-) MDSC showed increased ability to suppress CD8(+) cell proliferation in vitro compared with wild-type MDSC. Transfer of MDSC to diabetic mice showed that MDSC from Il-17(-/-) mice could ameliorate hyperglycaemia. Moreover, recipients with MDSC from Il-17(-/-) mice had a decreased percentage of CD8(+) cell in the spleen compared with recipients with MDSC from wild-type mice. These data suggest that IL-17 is required in splenic MDSC function after STZ delivery. In summary, our study has revealed a pathogenic role of IL-17 in an STZ-induced diabetes model with important implications for our understanding of IL-17 function in autoimmune diseases.

  9. Dietary vitamin D supplementation does not reduce the incidence or severity of asbestos-induced mesothelioma in a mouse model.

    PubMed

    Robinson, Cleo; Woo, Samantha; Nowak, Anna K; Lake, Richard A

    2014-01-01

    Epidemiological studies suggest that vitamin and mineral intake is associated with cancer incidence. A prevention strategy based on diet or dietary supplementation could have enormous benefit, both directly, by preventing disease, and indirectly by alleviating fear in millions of people worldwide who have been exposed to asbestos. We have previously shown that dietary supplementation with the antioxidants vitamins A, E, and selenium does not affect overall survival nor the time to progression of asbestos-induced mesothelioma in MexTAg mice. Here we have extended our analysis to vitamin D. We compared survival of asbestos-exposed MexTAg mice provided with diets that were deficient or supplemented with 4500 IU/kg vitamin D (cholecalciferol). Survival of supplemented mice was significantly shorter than mice given a standard AIN93 diet containing 1000 IU/kg cholecalciferol (median survival was 29 and 32.5 weeks respectively). However, mice deficient in vitamin D had the same rate of mesothelioma development as control mice. Neither the latency time from asbestos exposure to diagnosis nor disease progression after diagnosis were significantly different between mice on these diets. We conclude that vitamin D is unlikely to moderate the incidence of disease in asbestos-exposed populations or to ameliorate the pathology in patients with established mesothelioma.

  10. Differential regulation of the renal sodium-phosphate cotransporters NaPi-IIa, NaPi-IIc, and PiT-2 in dietary potassium deficiency.

    PubMed

    Breusegem, Sophia Y; Takahashi, Hideaki; Giral-Arnal, Hector; Wang, Xiaoxin; Jiang, Tao; Verlander, Jill W; Wilson, Paul; Miyazaki-Anzai, Shinobu; Sutherland, Eileen; Caldas, Yupanqui; Blaine, Judith T; Segawa, Hiroko; Miyamoto, Ken-ichi; Barry, Nicholas P; Levi, Moshe

    2009-08-01

    Dietary potassium (K) deficiency is accompanied by phosphaturia and decreased renal brush border membrane (BBM) vesicle sodium (Na)-dependent phosphate (P(i)) transport activity. Our laboratory previously showed that K deficiency in rats leads to increased abundance in the proximal tubule BBM of the apical Na-P(i) cotransporter NaPi-IIa, but that the activity, diffusion, and clustering of NaPi-IIa could be modulated by the altered lipid composition of the K-deficient BBM (Zajicek HK, Wang H, Puttaparthi K, Halaihel N, Markovich D, Shayman J, Beliveau R, Wilson P, Rogers T, Levi M. Kidney Int 60: 694-704, 2001; Inoue M, Digman MA, Cheng M, Breusegem SY, Halaihel N, Sorribas V, Mantulin WW, Gratton E, Barry NP, Levi M. J Biol Chem 279: 49160-49171, 2004). Here we investigated the role of the renal Na-P(i) cotransporters NaPi-IIc and PiT-2 in K deficiency. Using Western blotting, immunofluorescence, and quantitative real-time PCR, we found that, in rats and in mice, K deficiency is associated with a dramatic decrease in the NaPi-IIc protein abundance in proximal tubular BBM and in NaPi-IIc mRNA. In addition, we documented the presence of a third Na-coupled P(i) transporter in the renal BBM, PiT-2, whose abundance is also decreased by dietary K deficiency in rats and in mice. Finally, electron microscopy showed subcellular redistribution of NaPi-IIc in K deficiency: in control rats, NaPi-IIc immunolabel was primarily in BBM microvilli, whereas, in K-deficient rats, NaPi-IIc BBM label was reduced, and immunolabel was prevalent in cytoplasmic vesicles. In summary, our results demonstrate that decreases in BBM abundance of the phosphate transporter NaPi-IIc and also PiT-2 might contribute to the phosphaturia of dietary K deficiency, and that the three renal BBM phosphate transporters characterized so far can be differentially regulated by dietary perturbations.

  11. RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma

    PubMed Central

    Arikkatt, Jaisy; Ullah, Md Ashik; Short, Kirsty Renfree; Zhang, Vivan; Gan, Wan Jun; Loh, Zhixuan; Werder, Rhiannon B; Simpson, Jennifer; Sly, Peter D; Mazzone, Stuart B; Spann, Kirsten M; Ferreira, Manuel AR; Upham, John W; Sukkar, Maria B; Phipps, Simon

    2017-01-01

    Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target. DOI: http://dx.doi.org/10.7554/eLife.21199.001 PMID:28099113

  12. Nitrous oxide–induced vitamin B12 deficiency

    PubMed Central

    Simonsen, Cameron; Seago, Susan

    2017-01-01

    Nitrous oxide is a gas that is odorless, colorless, and has a sweet taste at room temperature. Nitrous oxide has several uses, including in surgery and dentistry (referred to as “laughing gas”), in automotive racing, and in aerosol spray propellants. The aerosol spray propellants that typically use nitrous oxide are whipped cream canisters and cooking sprays. Unfortunately, these over-the-counter household items are a source of nitrous oxide that can be used for recreational use. The most popular is the use of industrial-grade canisters having the slang term “whippets.” The nitrous oxide can be extracted by pushing the nozzle down slightly to the side and catching the released gas with a balloon. The contents of the balloon can then be directly inhaled, giving an instant feeling of euphoria. This is not a benign means to achieve a euphoric state but can cause severe nitrous oxide–induced B12 deficiency, which is presented in this case report.

  13. Glucocorticoid-Induced Osteoporosis in Children with 21-Hydroxylase Deficiency

    PubMed Central

    Ventura, Annamaria; Brunetti, Giacomina; Colucci, Silvia; Oranger, Angela; Ladisa, Filomena; Cavallo, Luciano; Grano, Maria; Faienza, Maria Felicia

    2013-01-01

    21-Hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH), resulting from deletions or mutations of the P450 21-hydroxylase gene (CYP21A2). Children with 21-OHD need chronic glucocorticoid (cGC) therapy, both to replace congenital deficit in cortisol synthesis and to reduce androgen secretion by adrenal cortex. GC-induced osteoporosis (GIO) is the most common form of secondary osteoporosis that results in an early, transient increase in bone resorption accompanied by a decrease in bone formation, maintained for the duration of GC therapy. Despite the conflicting results in the literature about the bone status on GC-treated patients with 21-OHD, many reports consider these subjects to be at risk for osteoporosis and fractures. In bone cells, at the molecular level, GCs regulate various functions including osteoblastogenesis, osteoclastogenesis, and the apoptosis of osteoblasts and osteocytes. In this paper, we focus on the physiology and biosynthesis of endogenous steroid hormones as well as on the effects of GCs on bone cells, highlighting the pathogenetic mechanism of GIO in children with 21-OHD. PMID:23484098

  14. Persistent optically induced magnetism in oxygen-deficient strontium titanate.

    PubMed

    Rice, W D; Ambwani, P; Bombeck, M; Thompson, J D; Haugstad, G; Leighton, C; Crooker, S A

    2014-05-01

    Strontium titanate (SrTiO3) is a foundational material in the emerging field of complex oxide electronics. Although its bulk electronic and optical properties are rich and have been studied for decades, SrTiO3 has recently become a renewed focus of materials research catalysed in part by the discovery of superconductivity and magnetism at interfaces between SrTiO3 and other non-magnetic oxides. Here we illustrate a new aspect to the phenomenology of magnetism in SrTiO3 by reporting the observation of an optically induced and persistent magnetization in slightly oxygen-deficient bulk SrTiO3-δ crystals using magnetic circular dichroism (MCD) spectroscopy and SQUID magnetometry. This zero-field magnetization appears below ~18 K, persists for hours below 10 K, and is tunable by means of the polarization and wavelength of sub-bandgap (400-500 nm) light. These effects occur only in crystals containing oxygen vacancies, revealing a detailed interplay between magnetism, lattice defects, and light in an archetypal complex oxide material.

  15. Modelling primaquine-induced haemolysis in G6PD deficiency

    PubMed Central

    Watson, James; Taylor, Walter RJ; Menard, Didier; Kheng, Sim; White, Nicholas J

    2017-01-01

    Primaquine is the only drug available to prevent relapse in vivax malaria. The main adverse effect of primaquine is erythrocyte age and dose-dependent acute haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd). As testing for G6PDd is often unavailable, this limits the use of primaquine for radical cure. A compartmental model of the dynamics of red blood cell production and destruction was designed to characterise primaquine-induced haemolysis using a holistic Bayesian analysis of all published data and was used to predict a safer alternative to the currently recommended once weekly 0.75 mg/kg regimen for G6PDd. The model suggests that a step-wise increase in daily administered primaquine dose would be relatively safe in G6PDd. If this is confirmed, then were this regimen to be recommended for radical cure patients would not require testing for G6PDd in areas where G6PDd Viangchan or milder variants are prevalent. DOI: http://dx.doi.org/10.7554/eLife.23061.001 PMID:28155819

  16. Glucocorticoid-induced osteoporosis in children with 21-hydroxylase deficiency.

    PubMed

    Ventura, Annamaria; Brunetti, Giacomina; Colucci, Silvia; Oranger, Angela; Ladisa, Filomena; Cavallo, Luciano; Grano, Maria; Faienza, Maria Felicia

    2013-01-01

    21-Hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH), resulting from deletions or mutations of the P450 21-hydroxylase gene (CYP21A2). Children with 21-OHD need chronic glucocorticoid (cGC) therapy, both to replace congenital deficit in cortisol synthesis and to reduce androgen secretion by adrenal cortex. GC-induced osteoporosis (GIO) is the most common form of secondary osteoporosis that results in an early, transient increase in bone resorption accompanied by a decrease in bone formation, maintained for the duration of GC therapy. Despite the conflicting results in the literature about the bone status on GC-treated patients with 21-OHD, many reports consider these subjects to be at risk for osteoporosis and fractures. In bone cells, at the molecular level, GCs regulate various functions including osteoblastogenesis, osteoclastogenesis, and the apoptosis of osteoblasts and osteocytes. In this paper, we focus on the physiology and biosynthesis of endogenous steroid hormones as well as on the effects of GCs on bone cells, highlighting the pathogenetic mechanism of GIO in children with 21-OHD.

  17. Thiamine deficiency induces anorexia by inhibiting hypothalamic AMPK.

    PubMed

    Liu, M; Alimov, A P; Wang, H; Frank, J A; Katz, W; Xu, M; Ke, Z-J; Luo, J

    2014-05-16

    Obesity and eating disorders are prevailing health concerns worldwide. It is important to understand the regulation of food intake and energy metabolism. Thiamine (vitamin B1) is an essential nutrient. Thiamine deficiency (TD) can cause a number of disorders in humans, such as Beriberi and Wernicke-Korsakoff syndrome. We demonstrated here that TD caused anorexia in C57BL/6 mice. After feeding a TD diet for 16days, the mice displayed a significant decrease in food intake and an increase in resting energy expenditure (REE), which resulted in a severe weight loss. At the 22nd day, the food intake was reduced by 69% and 74% for male and female mice, respectively in TD group. The REE increased by ninefolds in TD group. The loss of body weight (17-24%) was similar between male and female animals and mainly resulted from the reduction of fat mass (49% decrease). Re-supplementation of thiamine (benfotiamine) restored animal's appetite, leading to a total recovery of body weight. The hypothalamic adenosine monophosphate-activated protein kinase (AMPK) is a critical regulator of food intake. TD inhibited the phosphorylation of AMPK in the arcuate nucleus (ARN) and paraventricular nucleus (PVN) of the hypothalamus without affecting its expression. TD-induced inhibition of AMPK phosphorylation was reversed once thiamine was re-supplemented. In contrast, TD increased AMPK phosphorylation in the skeletal muscle and upregulated the uncoupling protein (UCP)-1 in brown adipose tissues which was consistent with increased basal energy expenditure. Re-administration of thiamine stabilized AMPK phosphorylation in the skeletal muscle as well as energy expenditure. Taken together, TD may induce anorexia by inhibiting hypothalamic AMPK activity. With a simultaneous increase in energy expenditure, TD caused an overall body weight loss. The results suggest that the status of thiamine levels in the body may affect food intake and body weight.

  18. Helicobacter cinaedi Induced Typhlocolitis in Rag-2-Deficient Mice

    PubMed Central

    Shen, Zeli; Feng, Yan; Rickman, Barry; Fox, James G.

    2015-01-01

    Background Helicobacter cinaedi, an enterohepatic helicobacter species (EHS), is an important human pathogen and is associated with a wide range of diseases, especially in immunocompromised patients. It has been convincingly demonstrated that innate immune response to certain pathogenic enteric bacteria is sufficient to initiate colitis and colon carcinogenesis in recombinase-activating gene (Rag)-2-deficient mice model. To better understand the mechanisms of human IBD and its association with development of colon cancer, we investigated whether H. cinaedi could induce pathological changes noted with murine enterohepatic helicobacter infections in the Rag2−/− mouse model. Materials and Methods Sixty 129SvEv Rag2−/− mice mouse were experimentally or sham infected orally with H. cinaedi strain CCUG 18818. Gastrointestinal pathology and immune responses in infected and control mice were analyzed at 3, 6 and 9 months postinfection (MPI). H. cinaedi colonized the cecum, colon, and stomach in infected mice. Results H. cinaedi induced typhlocolitis in Rag2−/− mice by 3 MPI and intestinal lesions became more severe by 9 MPI. H. cinaedi was also associated with the elevation of proinflammatory cytokines, interferon-γ, tumor-necrosis factor-α, IL-1β, IL-10; iNOS mRNA levels were also upregulated in the cecum of infected mice. However, changes in IL-4, IL-6, Cox-2, and c-myc mRNA expressions were not detected. Conclusions Our results indicated that the Rag2−/− mouse model will be useful to continue investigating the pathogenicity of H. cinaedi, and to study the association of host immune responses in IBD caused by EHS. PMID:25381744

  19. MPK3/MPK6 are involved in iron deficiency-induced ethylene production in Arabidopsis.

    PubMed

    Ye, Lingxiao; Li, Lin; Wang, Lu; Wang, Shoudong; Li, Sen; Du, Juan; Zhang, Shuqun; Shou, Huixia

    2015-01-01

    Iron (Fe) is an essential micronutrient that participates in various biological processes important for plant growth. Ethylene production induced by Fe deficiency plays important roles in plant tolerance to stress induced by Fe deficiency. However, the activation and regulatory mechanisms of 1-Aminocyclopropane-1-carboxylic acid synthase (ACS) genes in this response are not clear. In this study, we demonstrated that Fe deficiency increased the abundance of ACS2, ACS6, ACS7, and ACS11 transcripts in both leaves and roots as well as the abundance of ACS8 transcripts in leaves and ACS9 transcripts in roots. Furthermore, we investigated the role of mitogen-activated protein kinase 3 and 6 (MPK3/MPK6)-regulated ACS2/6 activation in Fe deficiency-induced ethylene production. Our results showed that MPK3/MPK6 transcript abundance and MPK3/MPK6 phosphorylation are elevated under conditions of Fe deficiency. Furthermore, mpk3 and mpk6 mutants show a lesser induction of ethylene production under Fe deficiency and a greater sensitivity to Fe deficiency. Finally, in mpk3, mpk6, and acs2 mutants under conditions of Fe deficiency, induction of transcript expression of the Fe-deficiency response genes FRO2, IRT1, and FIT is partially compromised. Taken together, our results suggest that the MPK3/MPK6 and ACS2 are part of the Fe starvation-induced ethylene production signaling pathway.

  20. Effect of dietary antioxidant supplementation (Cuminum cyminum) on bacterial susceptibility of diabetes-induced rats.

    PubMed

    Moubarz, Gehan; Embaby, Mohamed A; Doleib, Nada M; Taha, Mona M

    2016-01-01

    Diabetic patients are at risk of acquiring infections. Chronic low-grade inflammation is an important factor in the pathogenesis of diabetic complication. Diabetes causes generation of reactive oxygen species that increases oxidative stress, which may play a role in the development of complications as immune-deficiency and bacterial infection. The study aimed to investigate the role of a natural antioxidant, cumin, in the improvement of immune functions in diabetes. Diabetes was achieved by interperitoneal injection of streptozotocin (STZ). Bacterial infection was induced by application of Staphylococcus aureus suspension to a wound in the back of rats. The antioxidant was administered for 6 weeks. Results revealed a decrease in blood glucose levels in diabetic rats (p < 0.001), in addition to improving immune functions by decreasing total IgE approaching to the normal control level. Also, inflammatory cytokine (IL-6, IL-1β and TNF) levels, as well as total blood count decreased in diabetic rats as compared to the control group. Thus, cumin may serve as anti-diabetic treatment and may help in attenuating diabetic complications by improving immune functions. Therefore, a medical dietary antioxidant supplementation is important to improve the immune functions in diabetes.

  1. Effect of dietary antioxidant supplementation (Cuminum cyminum) on bacterial susceptibility of diabetes-induced rats

    PubMed Central

    Embaby, Mohamed A.; Doleib, Nada M.; Taha, Mona M.

    2016-01-01

    Diabetic patients are at risk of acquiring infections. Chronic low-grade inflammation is an important factor in the pathogenesis of diabetic complication. Diabetes causes generation of reactive oxygen species that increases oxidative stress, which may play a role in the development of complications as immune-deficiency and bacterial infection. The study aimed to investigate the role of a natural antioxidant, cumin, in the improvement of immune functions in diabetes. Diabetes was achieved by interperitoneal injection of streptozotocin (STZ). Bacterial infection was induced by application of Staphylococcus aureus suspension to a wound in the back of rats. The antioxidant was administered for 6 weeks. Results revealed a decrease in blood glucose levels in diabetic rats (p < 0.001), in addition to improving immune functions by decreasing total IgE approaching to the normal control level. Also, inflammatory cytokine (IL-6, IL-1β and TNF) levels, as well as total blood count decreased in diabetic rats as compared to the control group. Thus, cumin may serve as anti-diabetic treatment and may help in attenuating diabetic complications by improving immune functions. Therefore, a medical dietary antioxidant supplementation is important to improve the immune functions in diabetes. PMID:27536197

  2. Dietary Salt Exacerbates Isoproterenol-induced Cardiomyopathy in Rats

    EPA Science Inventory

    Spontaneously Hypertensive Heart Failure rats (SHHFs) take far longer to develop compensated heart failure and congestive decompensation than common surgical models of heart failure. Isoproterenol (ISO) infusion can accelerate cardiomyopathy in young SHHFs, while dietary salt loa...

  3. Effects of dietary boron and phytase supplementation on growth performance and mineral profile of broiler chickens fed on diets adequate or deficient in calcium and phosphorus.

    PubMed

    Çinar, M; Küçükyilmaz, K; Bozkurt, M; Çatli, A U; Bintaş, E; Akşit, H; Konak, R; Yamaner, Ç; Seyrek, K

    2015-01-01

    1. Two experiments were designed to determine the effect of dietary boron (B) in broiler chickens. In Experiment 1, a 2 × 4 factorial arrangement of treatments was used to investigate the effect of dietary calcium (Ca) and available phosphorus (aP) (adequate or deficient) and supplemental B (0, 20, 40, and 60 mg/kg diet). In Experiment 2, B, at 20 mg/kg, and phytase (PHY) (500 FTU/kg diet) were incorporated into a basal diet deficient in Ca and aP, either alone or in combination. 2. The parameters that were measured were growth performance indices, serum biochemical activity as well as ash and mineral (i.e. Ca, P, Mg, Fe, Cu and Zn) content of tibia, breast muscle and liver. 3. Results indicated that both supplemental B and dietary Ca and aP had marginal effects on performance indices of chickens grown for 42 d. 4. There were positive correlations (linear effect) between B concentrations of serum, bone, breast muscle and liver and the amount of B consumed. 5. Serum T3 and T4 activities increased linearly with higher B supplementation. 6. Increasing supplemental B had significant implications on breast muscle and liver mineral composition. Lowering dietary Ca and aP level increased Cu content in liver and both Fe and Zn retention in breast muscle. Tibia ash content and mineral composition did not respond to dietary modifications with either Ca-aP or B. 7. The results also suggested that dietary contents of Ca and aP do not affect the response to B regarding tissue mineral profile. Dietary combination with B and PHY did not create a synergism with regard to growth performance and bioavailability of the minerals.

  4. Complex carbohydrates in the dietary management of patients with glycogenosis caused by glucose-6-phosphatase deficiency.

    PubMed

    Smit, G P; Ververs, M T; Belderok, B; Van Rijn, M; Berger, R; Fernandes, J

    1988-07-01

    Carbohydrates with digestion characteristics between those of lente uncooked starches and rapidly digestible oligosaccharides were administered in a dose of 1.5 g/kg body weight to five patients with glycogenosis from glucose-6-phosphatase deficiency. Postprandial duration of normoglycemia and concentrations of blood insulin and lactate were determined. Uncooked barley groats in water, or incorporated in a meal turned out to behave as lente carbohydrates. Uncooked couscous in water, couscous incorporated in a meal, and partially cooked macaroni given as a meal behaved as semilente carbohydrates as compared with uncooked cornstarch and glucose. The in vitro determination of the digestibility index along with the in vivo tolerance test enables us to choose and incorporate semilente carbohydrates in the day-time treatment of patients.

  5. Seminal quality and sperm production in beef bulls with chronic dietary vitamin A deficiency and subsequent re-alimentation.

    PubMed

    Rode, L M; Coulter, G H; Kastelic, J P; Bailey, D R

    1995-05-01

    Sixteen Hereford bulls (16 mo of age, 462 kg average body weight) were used in each of 2 yr to evaluate the effects of hypovitaminosis A on seminal quality and sperm production. Bulls were fed a high-concentrate diet with (+VIT) or without (-VIT) supplemental Vitamin A until the apparent onset of hypovitaminosis A (28 and 32 wk in Year 1 and 2, respectively). Half of the bulls on each treatment were then slaughtered and those remaining were re-alimented with Vitamin A. Plasma retinol concentration in -VIT bulls reached a nadir at approximately 25 wk. In Year 1, the proportion of progressively motile spermatozoa was lower in -VIT bulls after 17 wk but returned to that of the +VIT group after re-alimentation. The proportion of spermatozoa with primary morphological defects appeared to be greater in -VIT bulls compared to +VIT bulls by 26 and 24 wk in Year 1 and 2, respectively. The incidence of these defects declined in -VIT bulls upon re-alimentation, and approached the incidence observed in +VIT bulls by 8 to 12 wk of re-alimentation. Hypovitaminosis A decreased paired testes weight, daily sperm production, and epididymal sperm reserves but did not affect daily gain. Prolonged dietary Vitamin A deficiency impaired semen quality and sperm production in the absence of other clinical symptoms. However, under practical feeding conditions, diets that result in long-term, marginal Vitamin A deficiency or a relatively short-term absence of Vitamin A intake probably would have minimal effects on spermatogenesis.

  6. Dietary Fiber Intake Regulates Intestinal Microflora and Inhibits Ovalbumin-Induced Allergic Airway Inflammation in a Mouse Model

    PubMed Central

    Zhang, Zhiyu; Shi, Lei; Pang, Wenhui; Liu, Wenwen; Li, Jianfeng; Wang, Haibo; Shi, Guanggang

    2016-01-01

    Background Recently, academic studies suggest that global growth of airway allergic disease has a close association with dietary changes including reduced consumption of fiber. Therefore, appropriate dietary fiber supplementation might be potential to prevent airway allergic disease (AAD). Objective We investigated whether dietary fiber intake suppressed the induction of AAD and tried to elucidate the possible underlying mechanisms. Methods The control mice and AAD model mice fed with 4% standard-fiber chow, while low-fiber group of mice fed with a 1.75% low-fiber chow. The two fiber-intervened groups including mice, apart from a standard-fiber diet, were also intragastric (i.g.) administrated daily with poorly fermentable cellulose or readily fermentable pectin (0.4% of daily body weight), respectively. All animals except normal mice were sensitized and challenged with ovalbumin (OVA) to induce airway allergic inflammation. Hallmarks of AAD were examined by histological analysis and ELISA. The variation in intestinal bacterial composition was assessed by qualitative analysis of 16S ribosomal DNA (rDNA) content in fecal samples using real-time PCR. Results Low-fiber diet aggravated inflammatory response in ovalbumin-induced allergic mice, whereas dietary fiber intake significantly suppressed the allergic responses, attenuated allergic symptoms of nasal rubbing and sneezing, decreased the pathology of eosinophil infiltration and goblet cell metaplasia in the nasal mucosa and lung, inhibited serum OVA-specific IgE levels, and lowered the levels of Th2 cytokines in NALF and BALF, but, increased Th1 (IFN-γ) cytokines. Additionally, dietary fiber intake also increased the proportion of Bacteroidetes and Actinobacteria, and decreased Firmicutes and Proteobacteria. Levels of probiotic bacteria, such as Lactobacillus and Bifidobacterium, were upgraded significantly. Conclusion Long-term deficiency of dietary fiber intake increases the susceptibility to AAD, whereas proper

  7. Biphasic modulation of atherosclerosis induced by graded dietary copper supplementation in the cholesterol-fed rabbit.

    PubMed

    Lamb, D J; Avades, T Y; Ferns, G A

    2001-10-01

    There has been considerable debate about how copper status may affect the biochemical and cellular processes associated with atherogenesis. We have investigated the effects of graded dietary copper supplementation on processes likely to contribute to atherogenesis, using the cholesterol-fed New Zealand White rabbit model. Rabbits (n = 40) were fed a 0.25-1% cholesterol diet deficient in copper. Animals received either 0, 1, 3 or 20 mg copper/day and were killed after 13 weeks. Plasma cholesterol levels were similar in each dietary group. Aortic concentrations of copper were higher in the 20 mg copper/day animals compared to those receiving 0 mg copper/day (3.70 +/- 0.78 vs. 1.33 +/- 0.46 microg/g wet tissue; P < 0.05). Aortic superoxide dismutase activity was higher in animals receiving 20 mg copper/day (323 +/- 21 IU/mg tissue) compared to the other groups (187 +/- 21; 239 +/- 53; 201 +/- 33 IU/mg tissue) (P > 0.05). En face staining of aortae with oil red O showed that both high copper supplementation (20 mg/day) (67.1 +/- 5.5%) and a deficient diet (0 mg/day) (63.1 +/- 4.8%) was associated with significantly larger lesions (P < 0.05) compared to moderately supplemented animals (1 mg/day and 3 mg/day) (51.3 +/- 6.3 and 42.8 +/- 7.9%). These data indicate that in the cholesterol-fed rabbit, there is an optimal dietary copper intake and that dietary copper deficiency or excess are associated with an increased susceptibility to aortic atherosclerosis. Many Western diets contain insufficient copper and these findings indicate that a moderate dietary copper content may confer a degree of cardiac protection to the human population.

  8. A calcitonin receptor (CALCR) single nucleotide polymorphism is associated with growth performance and bone integrity in response to dietary phosphorus deficiency.

    PubMed

    Alexander, L S; Qu, A; Cutler, S A; Mahajan, A; Rothschild, M F; Cai, W; Dekkers, J C; Stahl, C H

    2010-03-01

    Although concerns over the environmental impact of excess P in the excreta from pig production and governmental regulations have driven research toward reducing dietary supplementation of P to swine diets for over a decade, recent dramatic increases in feed costs have further motivated researchers to identify means to further reduce dietary P supplementation. We have demonstrated that genetic background impacts P utilization in young pigs and have identified genetic polymorphisms in several target genes related to mineral utilization. In this study, we examined the impact of a SNP in the calcitonin receptor gene (CALCR) on P utilization in growing pigs. In Exp. 1, 36 gilts representing the 3 genotypes identified by this CALCR SNP (11, 12, and 22) were fed a P-adequate (PA) or a marginally P-deficient (approximately 20% less available P; PD) diet for 14 wk. As expected, P deficiency reduced plasma P concentration, bone strength, and mineral content (P < 0.05). However, the dietary P deficiency was mild enough to not affect the growth performance of these pigs. A genotype x dietary P interaction (P < 0.05) was observed in measures of bone integrity and mineral content, with the greatest reduction in bone strength and mineral content due to dietary P deficiency being associated with the allele 1. In Exp. 2, 168 pigs from a control line and low residual feed intake (RFI) line were genotyped for the CALCR SNP and fed a PA diet. As expected, pigs from the low RFI line consumed less feed but also gained less BW when compared with the control line (P < 0.05). Although ADFI did not differ between genotypes, pigs having the 11 genotype gained less BW (P < 0.05) than pigs having the 12 or 22 genotypes. Pigs of the 11 and 12 genotypes had bones that tolerated greater load when compared with animals having the 22 genotype (P < 0.05). A similar trend was observed in bone modulus and ash % (P < 0.10). These data are supportive of the association of this CALCR SNP with bone

  9. Deficiency of the Bax gene attenuates denervation-induced apoptosis

    PubMed Central

    Siu, P. M.; Alway, S. E.

    2015-01-01

    Apoptosis has been implicated in mediating denervation-induced muscle wasting. In this study we determined the effect of interference of apoptosis on muscle wasting during denervation by using mice genetically deficient in pro-apoptotic Bax. After denervation, muscle wasting was evident in both wild-type and Bax−/− muscles but reduction of muscle weight was attenuated in Bax−/− mice. Apoptotic DNA fragmentation increased in wild-type denervated muscles whereas there was no statistical increase in DNA fragmentation in denervated muscles from Bax−/− mice. Mitochondrial AIF and Smac/DIABLO releases and Bcl-2, p53 and HSP27 increased whereas XIAP and MnSOD decreased to a similar extent in muscles from wild-type and Bax−/− mice following denervation. Mitochondrial cytochrome c release was elevated in denervated muscles from wild-type mice but the increase was suppressed in muscles from Bax−/− mice. Increases in caspase-3 and -9 activities and oxidative stress markers H2O2, MDA/4-HAE and nitrotyrosine were all evident in denervated muscles from wild-type mice but these changes were absent in muscles from Bax−/− mice. Moreover, ARC increased exclusively in denervated Bax−/− muscle. Our data indicate that under conditions of denervation, pro-apoptotic signalling is suppressed and muscle wasting is attenuated when the Bax gene is lacking. These findings suggest that interventions targeting apoptosis may be valuable in ameliorating denervation-associated pathologic muscle wasting in certain neuromuscular disorders that involve partial or full denervation. PMID:16763784

  10. Dietary protein deficiency reduces lysosomal and nonlysosomal ATP-dependent proteolysis in muscle

    NASA Technical Reports Server (NTRS)

    Tawa, N. E. Jr; Kettelhut, I. C.; Goldberg, A. L.

    1992-01-01

    When rats are fed a protein deficient (PD) diet for 7 days, rates of proteolysis in skeletal muscle decrease by 40-50% (N. E. Tawa, Jr., and A. L. Goldberg. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E317-325, 1992). To identify the underlying biochemical adaptations, we measured different proteolytic processes in incubated muscles. The capacity for intralysosomal proteolysis, as shown by sensitivity to methylamine or lysosomal protease inhibitors, fell 55-75% in muscles from PD rats. Furthermore, extracts of muscles of PD rats showed 30-70% lower activity of many lysosomal proteases, including cathepsins B, H, and C, and carboxypeptidases A and C, as well as other lysosomal hydrolases. The fall in cathepsin B and proteolysis was evident by 3 days on the PD diet, and both returned to control levels 3 days after refeeding of the normal diet. In muscles maintained under optimal conditions, 80-90% of protein breakdown occurs by nonlysosomal pathways. In muscles of PD rats, this ATP-dependent process was also 40-60% slower. Even though overall proteolysis decreased in muscles of PD rats, their capacity for Ca(2+)-dependent proteolysis increased (by 66%), as did the activity of the calpains (+150-250%). Thus the lysosomal and the ATP-dependent processes decrease coordinately and contribute to the fall in muscle proteolysis in PD animals.

  11. Effect of dietary fiber on morphine-induced constipation in rats.

    PubMed

    Niwa, Takashi; Nakao, Makoto; Hoshi, Seiko; Yamada, Kiyofumi; Inagaki, Kazuhiro; Nishida, Mikio; Nabeshima, Toshitaka

    2002-06-01

    Morphine is used to alleviate chronic cancer pain. However, constipation is a major adverse effect that often detracts from the patient's quality of life. In this study, we investigated the effectiveness of dietary fiber on morphine-induced constipation. Rats were fed on a normal diet or one containing either 10% or 20% apple fiber for two weeks before morphine was administered. In the control diet group, the fecal number and dry weight were decreased by treating with morphine in a dose-dependent manner. Moreover, the motility of the small and large intestines was reduced. The fecal number and weight were increased and the colon motility was promoted by dietary fiber, regardless of whether morphine was being administered. The dietary fiber increased the concentration of short-chain fatty acids (SCFAs) in the cecum. These results suggest that dietary fiber has a preventative effect on morphine-induced constipation by increasing SCFAs in the cecum, and thereby promoting colon motility in rats.

  12. Prolonged Dietary Selenium Deficiency or Excess Does Not Globally Affect Selenoprotein Gene Expression and/or Protein Production in Various Tissues of Pigs123

    PubMed Central

    Liu, Yan; Zhao, Hua; Zhang, Qiaoshan; Tang, Jiayong; Li, Ke; Xia, Xin-Jie; Wang, Kang-Ning; Li, Kui; Lei, Xin Gen

    2012-01-01

    We previously determined the effects of dietary selenium (Se) deficiency or excess on mRNA abundance of 12 selenoprotein genes in pig tissues. In this study, we determined the effect of dietary Se on mRNA levels of the remaining porcine selenoprotein genes along with protein production of 4 selenoproteins (Gpx1, Sepp1, Selh, and Sels) and body glucose homeostasis. Weanling male pigs (n = 24) were fed a Se-deficient (<0.02 mg Se/kg), basal diet supplemented with 0, 0.3, or 3.0 mg Se/kg as Se-enriched yeast (Angel Yeast) for 16 wk. Although mRNA abundance of the 13 selenoproteins in 10 tissues responded to dietary Se in 3 patterns, there was no common regulation for any given gene across all tissues or for any given tissue across all genes. Dietary Se affected (P < 0.05) 2, 3, 3, 5, 6, 7, 7, and 8 selenoprotein genes in muscle, hypothalamus, liver, kidney, heart, spleen, thyroid, and pituitary, respectively. Protein abundance of Gpx1, Sepp1, Selh, and Sels in 6 tissues was regulated (P < 0.05) by dietary Se concentrations in 3 ways. Compared with those fed 0.3 mg Se/kg, pigs fed 3.0 mg Se/kg became hyperinsulinemic (P < 0.05) and had lower (P < 0.05) tissue levels of serine/threonine protein kinase. In conclusion, dietary Se exerted no global regulation of gene transcripts or protein levels of individual selenoproteins across porcine tissues. Pigs may be a good model for studying mechanisms related to the potential prodiabetic risk of high-Se intake in humans. PMID:22739382

  13. 1,25-Vitamin D3 Deficiency Induces Albuminuria.

    PubMed

    Sonneveld, Ramon; Hoenderop, Joost G J; Stavenuiter, Andrea W D; Ferrantelli, Evelina; Baltissen, Marijke P A; Dijkman, Henry B; Florquin, Sandrine; Rops, Angelique L; Wetzels, Jack F M; Berden, Jo H M; van der Vlag, Johan; Nijenhuis, Tom

    2016-04-01

    Vitamin D plays an important role in renal (patho)physiology. Patients with glomerular diseases have an injured renal filtration barrier, leading to proteinuria and reduced renal function. An impaired renal function also leads to 1,25-vitamin D3 deficiency as a result of reduced renal 1α-hydroxylase activity. Vitamin D treatment to reduce proteinuria remains controversial, although there is an inverse correlation between vitamin D levels and proteinuria. Herein, we showed that 1,25-vitamin D3-deficient 25-hydroxy-vitamin-D3-1α-hydroxylase knockout mice and 1,25-vitamin D3-deficient rats develop podocyte injury and renal dysfunction. Glomerular injury was characterized by proteinuria and partial podocyte foot process effacement. Expression of nephrin, podocin, desmin, and transient receptor potential channel C6 in the podocyte was significantly altered in 1,25-vitamin D3-deficient animals. Supplementation with 1,25-vitamin D3 or 1,25-vitamin D2 prevented podocyte effacement or reversed glomerular and tubulointerstitial damage in 1,25-vitamin D3-deficient animals, thereby preserving and restoring renal function, respectively. The effect of 1,25-vitamin D3 deficiency and 1,25-vitamin D3 and 1,25-vitamin D2 repletion on proteinuria could not be explained by hypocalcemia, changes in parathyroid hormone, or fibroblast growth factor 23. This study demonstrates that 1,25-vitamin D3 deficiency directly leads to renal injury in rodents. Translated to human subjects, this would underline the need for early vitamin D supplementation in patients with glomerular disease and chronic renal insufficiency, which might inhibit or potentially reverse renal injury.

  14. NO synthase-generated NO acts downstream of auxin in regulating Fe-deficiency-induced root branching that enhances Fe-deficiency tolerance in tomato plants

    PubMed Central

    Jin, Chong Wei; Shamsi, Imran Haider; Luo, Bing Fang; Lin, Xian Yong

    2011-01-01

    In response to Fe-deficiency, various dicots increase their root branching which contributes to the enhancement of ferric-chelate reductase activity. Whether this Fe-deficiency-induced response eventually enhances the ability of the plant to tolerate Fe-deficiency or not is still unclear and evidence is also scarce about the signals triggering it. In this study, it was found that the SPAD-chlorophyll meter values of newly developed leaves of four tomato (Solanum lycocarpum) lines, namely line227/1 and Roza and their two reciprocal F1 hybrid lines, were positively correlated with their root branching under Fe-deficient conditions. It indicates that Fe-deficiency-induced root branching is critical for plant tolerance to Fe-deficiency. In another tomato line, Micro-Tom, the increased root branching in Fe-deficient plants was accompanied by the elevation of endogenous auxin and nitric oxide (NO) levels, and was suppressed either by the auxin transport inhibitors NPA and TIBA or the NO scavenger cPTIO. On the other hand, root branching in Fe-sufficient plants was induced either by the auxin analogues NAA and 2,4-D or the NO donors NONOate or SNP. Further, in Fe-deficient plants, NONOate restored the NPA-terminated root branching, but NAA did not affect the cPTIO-terminated root branching. Fe-deficiency-induced root branching was inhibited by the NO-synthase (NOS) inhibitor L-NAME, but was not affected by the nitrate reductase (NR) inhibitor NH4+, tungstate or glycine. Taking all of these findings together, a novel function and signalling pathway of Fe-deficiency-induced root branching is presented where NOS-generated rather than NR-generated NO acts downstream of auxin in regulating this Fe-deficiency-induced response, which enhances the plant tolerance to Fe-deficiency. PMID:21511908

  15. Hypothyroxinemia induced by maternal mild iodine deficiency impairs hippocampal myelinated growth in lactational rats.

    PubMed

    Wei, Wei; Wang, Yi; Dong, Jing; Wang, Yuan; Min, Hui; Song, Binbin; Shan, Zhongyan; Teng, Weiping; Xi, Qi; Chen, Jie

    2015-11-01

    Hypothyroxinemia induced by maternal mild iodine deficiency causes neurological deficits and impairments of brain function in offspring. Hypothyroxinemia is prevalent in developing and developed countries alike. However, the mechanism underlying these deficits remains less well known. Given that the myelin plays an important role in learning and memory function, we hypothesize that hippocampal myelinated growth may be impaired in rat offspring exposed to hypothyroxinemia induced by maternal mild iodine deficiency. To test this hypothesis, the female Wistar rats were used and four experimental groups were prepared: (1) control; (2) maternal mild iodine deficiency diet inducing hypothyroxinemia; (3) hypothyroidism induced by maternal severe iodine deficiency diet; (4) hypothyroidism induced by maternal methimazole water. The rats were fed the diet from 3 months before pregnancy to the end of lactation. Our results showed that the physiological changes occuring in the hippocampal myelin were altered in the mild iodine deficiency group as indicated by the results of immunofluorescence of myelin basic proteins on postnatal day 14 and postnatal day 21. Moreover, hypothyroxinemia reduced the expressions of oligodendrocyte lineage transcription factor 2 and myelin-related proteins in the treatments on postnatal day 14 and postnatal day 21. Our data suggested that hypothyroxinemia induced by maternal mild iodine deficiency may impair myelinated growth of the offspring.

  16. Thiamine deficiency induced neurochemical, neuroanatomical, and neuropsychological alterations: a reappraisal.

    PubMed

    Nardone, Raffaele; Höller, Yvonne; Storti, Monica; Christova, Monica; Tezzon, Frediano; Golaszewski, Stefan; Trinka, Eugen; Brigo, Francesco

    2013-01-01

    Nutritional deficiency can cause, mainly in chronic alcoholic subjects, the Wernicke encephalopathy and its chronic neurological sequela, the Wernicke-Korsakoff syndrome (WKS). Long-term chronic ethanol abuse results in hippocampal and cortical cell loss. Thiamine deficiency also alters principally hippocampal- and frontal cortical-dependent neurochemistry; moreover in WKS patients, important pathological damage to the diencephalon can occur. In fact, the amnesic syndrome typical for WKS is mainly due to the damage in the diencephalic-hippocampal circuitry, including thalamic nuclei and mammillary bodies. The loss of cholinergic cells in the basal forebrain region results in decreased cholinergic input to the hippocampus and the cortex and reduced choline acetyltransferase and acetylcholinesterase activities and function, as well as in acetylcholine receptor downregulation within these brain regions. In this narrative review, we will focus on the neurochemical, neuroanatomical, and neuropsychological studies shedding light on the effects of thiamine deficiency in experimental models and in humans.

  17. Drug-induced haemolysis in glucose-6-phosphate dehydrogenase deficiency.

    PubMed Central

    Chan, T K; Todd, D; Tso, S C

    1976-01-01

    People with the variants of glucose-6-phosphate dehydrogenase (GPD) deficiency common in the southern Chinese (Canton, B(-)Chinese, and Hong Kong-Pokfulam) have a moderate shortening of red-cell survival but no anaemia when they are in the steady state. With a cross-transfusion technique, primaquine, nitrofurantoin, and large doses of aspirin were found to aggravate the haemolysis while sulphamethoxazole did so only in some people. Individual differences in drug metabolism may be the reason for this. Many commonly used drugs reported to accentuate haemolysis in GPD deficiency did not shorten red-cell survival. PMID:990860

  18. Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment.

    PubMed

    Jadavji, Nafisa M; Farr, Tracy D; Lips, Janet; Khalil, Ahmed A; Boehm-Sturm, Philipp; Foddis, Marco; Harms, Christoph; Füchtemeier, Martina; Dirnagl, Ulrich

    2015-04-15

    Dietary deficiencies in folic acid result in elevated levels of plasma homocysteine, which has been associated with the development of dementia and other neurodegenerative disorders. Previously, we have shown that elevated levels of plasma homocysteine in mice deficient for a DNA repair enzyme, uracil-DNA glycosylase (UNG), result in neurodegeneration. The goal of this study was to evaluate how deficiencies in folic acid and UNG along with elevated levels of homocysteine affect vascular cognitive impairment, via chronic hypoperfursion in an animal model. Ung(+/+) and Ung(-/-) mice were placed on either control (CD) or folic acid deficient (FADD) diets. Six weeks later, the mice either underwent implantation of microcoils around both common carotid arteries. Post-operatively, behavioral tests began at 3-weeks, angiography was measured after 5-weeks using MRI to assess vasculature and at completion of study plasma and brain tissue was collected for analysis. Learning impairments in the Morris water maze (MWM) were observed only in hypoperfused Ung(-/-) FADD mice and these mice had significantly higher plasma homocysteine concentrations. Interestingly, Ung(+/+) FADD produced significant remodeling of the basilar artery and arterial vasculature. Increased expression of GFAP was observed in the dentate gyrus of Ung(-/-) hypoperfused and FADD sham mice. Chronic hypoperfusion resulted in increased cortical MMP-9 protein levels of FADD hypoperfused mice regardless of genotypes. These results suggest that elevated levels of homocysteine only, as a result of dietary folic acid deficiency, don't lead to memory impairments and neurobiochemical changes. Rather a combination of either chronic hypoperfusion or UNG deficiency is required.

  19. Compared with saturated fatty acids, dietary monounsaturated fatty acids and carbohydrates increase atherosclerosis and VLDL cholesterol levels in LDL receptor-deficient, but not apolipoprotein E-deficient, mice.

    PubMed

    Merkel, M; Velez-Carrasco, W; Hudgins, L C; Breslow, J L

    2001-11-06

    Heart-healthy dietary recommendations include decreasing the intake of saturated fatty acids (SFA). However, the relative benefit of replacing SFA with monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), or carbohydrates (CARB) is still being debated. We have used two mouse models of atherosclerosis, low density lipoprotein receptor-deficient (LDLRKO) and apolipoprotein E-deficient (apoEKO) mice to measure the effects of four isocaloric diets enriched with either SFA, MUFA, PUFA, or CARB on atherosclerotic lesion area and lipoprotein levels. In LDLRKO mice, compared with the SFA diet, the MUFA and CARB diets significantly increased atherosclerosis in both sexes, but the PUFA diet had no effect. The MUFA and CARB diets also increased very low density lipoprotein-cholesterol (VLDL-C) and LDL-cholesterol (LDL-C) in males and VLDL-C levels in females. Analysis of data from LDLRKO mice on all diets showed that atherosclerotic lesion area correlated positively with VLDL-C levels (males: r = 0.47, P < 0.005; females: r = 0.52, P < 0.001). In contrast, in apoEKO mice there were no significant dietary effects on atherosclerosis in either sex. Compared with the SFA diet, the CARB diet significantly decreased VLDL-C in males and the MUFA, PUFA, and CARB diets decreased VLDL-C and the CARB diet decreased LDL-C in females. In summary, in LDLRKO mice the replacement of dietary SFA by either MUFA or CARB causes a proportionate increase in both atherosclerotic lesion area and VLDL-C. There were no significant dietary effects on atherosclerotic lesion area in apoEKO mice. These results are surprising and suggest that, depending on the underlying genotype, dietary MUFA and CARB can actually increase atherosclerosis susceptibility, probably by raising VLDL-C levels through a non-LDL receptor, apoE-dependent pathway.

  20. Raman studies of gluten proteins aggregation induced by dietary fibres.

    PubMed

    Nawrocka, Agnieszka; Szymańska-Chargot, Monika; Miś, Antoni; Kowalski, Radosław; Gruszecki, Wiesław I

    2016-03-01

    Interactions between gluten proteins and dietary fibre preparations are crucial in the baking industry. The addition of dietary fibre to bread causes significant reduction in its quality which is influenced by changes in the structure of gluten proteins. Fourier transform Raman spectroscopy was applied to determine changes in the structure of gluten proteins modified by seven dietary fibres. The commercially available gluten proteins without starch were mixed with the fibres in three concentrations: 3%, 6% and 9%. The obtained results showed that all fibres, regardless of their origin, caused the same kind of changes i.e. decrease in the α-helix content with a simultaneous increase in the content of antiparallel-β-sheet. The results indicated that presence of cellulose was the probable cause of these changes, and lead to aggregation or abnormal folding of the gluten proteins. Other changes observed in the gluten structure concerning β-structures, conformation of disulphide bridges, and aromatic amino acid environment, depended on the fibres chemical composition.

  1. Cd-induced Cu deficiency responses in Arabidopsis thaliana: are phytochelatins involved?

    PubMed

    Gielen, Heidi; Vangronsveld, Jaco; Cuypers, Ann

    2017-03-01

    Cadmium (Cd) exposure can disturb the homeostasis of essential elements. In Arabidopsis thaliana, Cd induces a squamosa promoter binding protein-like 7 (SPL7)-dependent Cu deficiency response. We investigated how Cd induces a Cu deficiency response. The Cu deficiency response consists of the active SPL7 transcription factor binding to GTAC motifs in promoters of among others several Cu transporters, a Cu chaperone, and cupro-miRNAs to regulate Cu homeostasis. We demonstrated that the addition of supplemental Cu to Cd-exposed A. thaliana plants diminished the Cu deficiency response in roots, while it even disappeared in leaves. Exposure of plants to Cd in combination with extra Cu reduced Cd levels in both roots and leaves resulting in an improved cellular oxidative state. Furthermore, we demonstrated a role for phytochelatins (PCs) in the Cd-induced Cu deficiency response, because it was reduced in roots of cad1-3 mutant plants exposed to Cd. In conclusion, a working mechanism is provided in which it is suggested that Cd increases PC levels that can complex both Cd and Cu. This results in cellular Cu deficiency and subsequently the activation of SPL7 and hence the induction of the Cu deficiency response.

  2. Dilated Cardiomyopathy Induced by Chronic Starvation and Selenium Deficiency

    PubMed Central

    2016-01-01

    Protein energy malnutrition (PEM) has been rarely documented as a cause of cardiovascular abnormalities, including dilated cardiomyopathy. Selenium is responsible for antioxidant defense mechanisms in cardiomyocytes, and its deficiency in the setting of PEM and disease related malnutrition (DRM) may lead to exacerbation of the dilated cardiomyopathy. We report a rare case of a fourteen-year-old boy who presented with symptoms of congestive heart failure due to DRM and PEM (secondary to chronic starvation) along with severe selenium deficiency. An initial echocardiogram showed severely depressed systolic function consistent with dilated cardiomyopathy. Aggressive nutritional support and replacement of selenium and congestive heart failure medications that included diuretics and ACE inhibitors with the addition of carvedilol led to normalization of the cardiac function within four weeks. He continues to have significant weight gain and is currently completely asymptomatic from a cardiovascular standpoint. PMID:27994905

  3. Fe deficiency induced changes in rice (Oryza sativa L.) thylakoids.

    PubMed

    Wang, Yuwen; Xu, Chao; Li, Kang; Cai, Xiaojie; Wu, Min; Chen, Guoxiang

    2017-01-01

    Iron deficiency is an important abiotic stress that limits productivity of crops all over the world. We selected a hybrid rice (Oryza sativa L.), LYPJ, which is super high-yield and widely cultured in China, to investigate changes in the components and structure of thylakoid membranes and photosynthetic performance in response to iron deficiency. Our results demonstrated that photosystem I (PSI) is the primary target for iron deficiency, while the changes in photosystem II (PSII) are important for rebuilding a balance in disrupted energy utilization and dissipation caused by differential degradation of photosynthetic components. The result of immunoblot analysis suggested that the core subunit PsaA declined drastically, while PsbA remained relatively stable. Furthermore, several organizational changes of the photosynthetic apparatus were found by BN-PAGE, including a marked decrease in the PSI core complexes, the Cytb 6 /f complex, and the trimeric form of the LHCII antenna, consistent with the observed unstacking grana. The fluorescence induction analysis indicated a descending PSII activity with energy dissipation enhanced markedly. In addition, we proposed that the crippled CO2 assimilation could be compensated by the enhanced of phosphoenolpyruvate carboxylase (PEPC), which is suggested by the decreased ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) and photosynthetic efficiency.

  4. Effects of dietary sialic acid in n-3 fatty acid-deficient dams during pregnancy and lactation on the learning abilities of their pups after weaning.

    PubMed

    Hiratsuka, Seiichi; Honma, Hiroyuki; Saitoh, Yoichi; Yasuda, Yuki; Yokogoshi, Hidehiko

    2013-01-01

    The effects of dietary sialic acid in dams on the learning abilities of their pups after weaning were investigated using rats deficient in n-3 fatty acids. Nine-week-old female Wistar rats were fed an n-3 fatty acid-deficient diet for 3 wk and were mated at 12 wk of age. During pregnancy and lactation, the female rats were fed the n-3 fatty acid-deficient diet, and were given water or water containing 1% N-acetylneuraminic acid (NANA) ad libitum. After weaning, the learning abilities of the pups were evaluated using a novel object recognition test. The recognition index of pups nursed by dams fed on water containing 1% NANA (NANA-intake dams) was significantly higher than that of pups nursed by dams fed only on water (NANA non-intake dams). There were no significant differences in the total sialic acid or docosahexaenoic acid contents in the cerebral cortex or hippocampus of pups nursed by dams fed on either type of water. The total dimethylacetal (DMA, from plasmalogen) level in the cerebral cortex of pups nursed by NANA-intake dams was significantly higher than that of pups nursed by NANA non-intake dams. These results suggest that dietary sialic acid in dams during pregnancy and lactation might be beneficial for the learning abilities of pups after weaning, which may be related to the plasmalogen level in the brain of pups.

  5. Induction of IRT1 by the nickel-induced iron-deficient response in Arabidopsis.

    PubMed

    Nishida, Sho; Aisu, Ayaka; Mizuno, Takafumi

    2012-03-01

    Excessive amounts of nickel (Ni) can be toxic for plants. Recently, we reported that IRT1, the primary iron (Fe) uptake transporter in roots, meditates excess Ni accumulation in Arabidopsis thaliana. We also found that Ni exposure increases IRT1 expression in roots, suggesting that Ni uptake is further induced by Ni stress. Here, we show that Ni exposure induces expression of not only IRT1, but also FRO2, a ferric reductase in the root epidermis, and FIT, a transcription factor regulating the expression of genes involved in Fe homeostasis including IRT1 and FRO2. This result suggests that Ni accumulation induces an Fe-deficient response and leads to the induction of IRT1. Our findings suggest that excess Ni causes Fe deficiency at the molecular level and induces Fe deficiency signaling in plant cells.

  6. Genetic AVP deficiency abolishes cold-induced diuresis but does not attenuate cold-induced hypertension.

    PubMed

    Sun, Zhongjie

    2006-06-01

    Chronic cold exposure causes hypertension and diuresis. The aim of this study was to determine whether vasopressin (AVP) plays a role in cold-induced hypertension and diuresis. Two groups of Long-Evans (LE) and two groups of homozygous AVP-deficient Brattleboro (VD) rats were used. Blood pressure (BP) was not different among the four groups during a 2-wk control period at room temperature (25 degrees C, warm). After the control period, one LE group and one VD group were exposed to cold (5 degrees C); the remaining groups were kept at room temperature. BP and body weight were measured weekly during exposure to cold. Food intake, water intake, urine output, and urine osmolality were measured during weeks 1, 3, and 5 of cold exposure. At the end of week 5, all animals were killed and blood was collected for measurement of plasma AVP. Kidneys were removed for measurement of renal medulla V2 receptor mRNA and aquaporin-2 (AQP-2) protein expression. BP of LE and VD rats increased significantly by week 2 of cold exposure and reached a high level by week 5. BP elevations developed at approximately the same rate and to the same degree in LE and VD rats. AVP deficiency significantly increased urine output and solute-free water clearance and decreased urine osmolality. Chronic cold exposure increased urine output and solute-free water clearance and decreased urine osmolality in LE rats, indicating that cold exposure caused diuresis in LE rats. Cold exposure failed to affect these parameters in VD rats, suggesting that the AVP system is responsible for cold-induced diuresis. Cold exposure did not alter plasma AVP in LE rats. Renal medulla V2 receptor mRNA and AQP-2 protein expression levels were decreased significantly in the cold-exposed LE rats, suggesting that cold exposure inhibited renal V2 receptors and AVP-inducible AQP-2 water channels. We conclude that 1) AVP may not be involved in the pathogenesis of cold-induced hypertension, 2) the AVP system plays a critical role

  7. Dietary restriction protects against chronic-ethanol-induced changes in exploratory behavior in Wistar rats.

    PubMed

    Pinto, Lucas S N M; Gualberto, Felipe A S; Pereira, Silvia R C; Barros, Paula A; Franco, Glaura C; Ribeiro, Angela M

    2006-03-17

    Chronic ethanol intake causes various types of neural damage and behavioral impairments, probably acting through oxidative stress and excitotoxicity, while dietary restriction is considered by some authors to protect the central nervous system from these kinds of damage. In the present study, a factorial experimental design was used to investigate the effects of chronic ethanol and dietary restriction treatments, associated or not, on Wistar rats' exploratory behavior, spatial memory aspects and cortical and hippocampal acetylcholinesterase (AChE) activity. Dietary restriction lasted for the whole experiment, while ethanol treatment lasted for only 3 weeks. Despite the short ethanol treatment duration, for two behavior categories assessed, moving and rearing, an interaction was observed between the effects of chronic ethanol and dietary restriction. There were no significant differences in AChE activities among the groups. Cerebellar neural nitric oxide synthase (nNOs) activity was measured as a first step to assess oxidative stress. Dietary restriction significantly reduced NO formation. The present results indicate that dietary restriction might exert a protective effect against chronic-ethanol-induced changes in exploratory behavior. It is hypothesized that the mechanisms underlying this protection can involve prevention of oxidative stress.

  8. Choline and betaine ameliorate liver lipid accumulation induced by vitamin B6 deficiency in rats.

    PubMed

    Kitagawa, Erina; Yamamoto, Tatsuya; Fujishita, Mayuko; Ota, Yuki; Yamamoto, Kohei; Nakagawa, Tomoyuki; Hayakawa, Takashi

    2017-02-01

    We investigated the efficacy of supplementing the diet with choline or betaine in ameliorating lipid accumulation induced by vitamin B6 (B6) deficiency in rat liver. Male Wistar rats were fed a control, B6-deficient, choline-supplemented (2, 4, or 6 g choline bitartrate/kg diet) B6-deficient diet or betaine-supplemented (1, 2, or 4 g betaine anhydrous/kg diet) B6-deficient diet for 35 d; all diets contained 9 g L-methionine (Met)/kg diet. Choline or betaine supplementation attenuated liver lipid deposition and restored plasma lipid profiles to control levels. These treatments restored the disruptions in Met metabolism and the phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio induced by B6 deficiency in liver microsomes. These results suggest that choline and betaine ameliorated liver lipid accumulation induced by B6 deficiency via recovery of Met metabolism and very low-density lipoprotein secretion by restoring the supply of PC derived from PE.

  9. Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. We show here that dietary supplementation with physiologically relevant levels of copper (Cu) reverses pre-established hypertrophic cardiomyopathy in the presence of pressure overload induced by ascending aor...

  10. Selenoprotein Gene Expression in Thyroid and Pituitary of Young Pigs Is Not Affected by Dietary Selenium Deficiency or Excess1–3

    PubMed Central

    Zhou, Ji-Chang; Zhao, Hua; Li, Jun-Gang; Xia, Xin-Jie; Wang, Kang-Ning; Zhang, Ya-Jun; Liu, Yan; Zhao, Ying; Lei, Xin Gen

    2009-01-01

    Expression and function of selenoproteins in endocrine tissues remain unclear, largely due to limited sample availability. Pigs have a greater metabolic similarity and tissue size than rodents as a model of humans for that purpose. We conducted 2 experiments: 1) we cloned 5 novel porcine selenoprotein genes; and 2) we compared the effects of dietary selenium (Se) on mRNA levels of 12 selenoproteins, activities of 4 antioxidant enzymes, and Se concentrations in testis, thyroid, and pituitary with those in liver of pigs. In Experiment 1, porcine Gpx2, Sephs2, Sep15, Sepn1, and Sepp1 were cloned and demonstrated 84–94% of coding sequence homology to human genes. In Experiment 2, weanling male pigs (n = 30) were fed a Se-deficient (0.02 mg Se/kg) diet added with 0, 0.3, or 3.0 mg Se/kg as Se-enriched yeast for 8 wk. Although dietary Se resulted in dose-dependent increases (P < 0.05) in Se concentrations and GPX activities in all 4 tissues, it did not affect the mRNA levels of any selenoprotein gene in thyroid or pituitary. Testis mRNA levels of Txnrd1 and Sep15 were decreased (P < 0.05) by increasing dietary Se from 0.3 to 3.0 mg/kg. Comparatively, expressions of Gpx2, Gpx4, Dio3, and Sep15 were high in pituitary and Dio1, Sepp1, Sephs2, and Gpx1 were high in liver. In conclusion, the mRNA abundances of the 12 selenoprotein genes in thyroid and pituitary of young pigs were resistant to dietary Se deficiency or excess. PMID:19357213

  11. Strategies to Rescue the Consequences of Inducible Arginase-1 Deficiency in Mice

    PubMed Central

    Ballantyne, Laurel L.; Sin, Yuan Yan; St. Amand, Tim; Si, Joshua; Goossens, Steven; Haenebalcke, Lieven; Haigh, Jody J.; Kyriakopoulou, Lianna; Schulze, Andreas; Funk, Colin D.

    2015-01-01

    Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible arginase-1 knockout mouse strain. Delivery of an arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken β-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue arginase-1 deficient mice to any great extent. Since the induced arginase-1 deficient mouse model displays a much more severe phenotype when compared to human arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies. PMID:25938595

  12. Strategies to rescue the consequences of inducible arginase-1 deficiency in mice.

    PubMed

    Ballantyne, Laurel L; Sin, Yuan Yan; St Amand, Tim; Si, Joshua; Goossens, Steven; Haenebalcke, Lieven; Haigh, Jody J; Kyriakopoulou, Lianna; Schulze, Andreas; Funk, Colin D

    2015-01-01

    Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible arginase-1 knockout mouse strain. Delivery of an arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken β-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue arginase-1 deficient mice to any great extent. Since the induced arginase-1 deficient mouse model displays a much more severe phenotype when compared to human arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies.

  13. Potassium inhibits dietary salt-induced transforming growth factor-beta production.

    PubMed

    Ying, Wei-Zhong; Aaron, Kristal; Wang, Pei-Xuan; Sanders, Paul W

    2009-11-01

    Human and animal studies demonstrate an untoward effect of excess dietary NaCl (salt) intake on cardiovascular function and life span. The endothelium in particular augments the production of transforming growth factor (TGF)-beta, a fibrogenic growth factor, in response to excess dietary salt intake. This study explored the initiating mechanism that regulates salt-induced endothelial cell production of TGF-beta. Male Sprague-Dawley rats were given diets containing different amounts of NaCl and potassium for 4 days. A bioassay for TGF-beta demonstrated increased (35.2%) amounts of active TGF-beta in the medium of aortic ring segments from rats on the high-salt diet compared with rats maintained on a 0.3% NaCl diet. Inhibition of the large-conductance, calcium-activated potassium channel inhibited dietary salt-induced vascular production of TGF-beta but did not affect production of TGF-beta by ring segments from rats on the low-salt diet. Immunohistochemical and Western analyses demonstrated the alpha subunit of the calcium-activated potassium channel in endothelial cells. Increasing medium [K+] inhibited production of dietary salt-induced vascular production levels of total and active TGF-beta but did not alter TGF-beta production by aortic rings from rats on the 0.3% NaCl diet. Increasing dietary potassium content decreased urinary active TGF-beta in animals receiving the high-salt diet but did not change urinary active TGF-beta in animals receiving the low-salt diet. The findings demonstrated an interesting interaction between the dietary intake of potassium and excess NaCl and further showed the fundamental role of the endothelial calcium-activated potassium channel in the vascular response to excess salt intake.

  14. Potassium Inhibits Dietary Salt-Induced Transforming Growth Factor-β Production

    PubMed Central

    Ying, Wei-Zhong; Aaron, Kristal; Wang, Pei-Xuan; Sanders, Paul W.

    2009-01-01

    Human and animal studies demonstrate an untoward effect of excess dietary NaCl (salt) intake on cardiovascular function and life span. The endothelium in particular augments the production of transforming growth factor (TGF)-β, a fibrogenic growth factor, in response to excess dietary salt intake. This study explored the initiating mechanism that regulates salt-induced endothelial cell production of TGF-β. Male Sprague-Dawley rats were given diets containing different amounts of NaCl and potassium for 4 days. A bioassay for TGF-β demonstrated increased (35.2%) amounts of active TGF-β in the medium of aortic ring segments from rats on the high-salt diet compared with rats maintained on a 0.3% NaCl diet. Inhibition of the large-conductance, calcium-activated potassium channel inhibited dietary salt-induced vascular production of TGF-β but did not affect production of TGF-β by ring segments from rats on the low-salt diet. Immunohistochemical and Western analyses demonstrated the α subunit of the calcium-activated potassium channel in endothelial cells. Increasing medium [K+] inhibited production of dietary salt-induced vascular production levels of total and active TGF-β but did not alter TGF-β production by aortic rings from rats on the 0.3% NaCl diet. Increasing dietary potassium content decreased urinary active TGF-β in animals receiving the high-salt diet but did not change urinary active TGF-β in animals receiving the low-salt diet. The findings demonstrated an interesting interaction between the dietary intake of potassium and excess NaCl and further showed the fundamental role of the endothelial calcium-activated potassium channel in the vascular response to excess salt intake. PMID:19738156

  15. Dietary nitrite induces occludin nitration in the stomach.

    PubMed

    Rocha, Bárbara S; Correia, Mariana G; Fernandes, Rita C; Gonçalves, João S; Laranjinha, João

    2016-01-01

    The clinical implications of the nitrate-nitrite-nitric oxide pathway have been extensively studied in recent years. However, the physiological impact of bioactive nitrogen oxides produced from dietary nitrate has remained largely elusive. Here, we report a hitherto unrecognized nitrite-dependent nitrating pathway that targets tight junction proteins in the stomach. Inorganic nitrate, nitrite or saliva obtained after the consumption of lettuce were administered by oral gavage to Wistar rats. The enterosalivary circulation of nitrate was allowed to occur for 4 h after which the animals were euthanized and the stomach collected. Nitrated occludin was detected by immunoprecipitation in the gastric epithelium upon inorganic nitrite administration (p < .05) but was not observed in the case of inorganic nitrate or human saliva administration. This observation, along with differences in (•)NO production rates from inorganic and salivary nitrite under simulated gastric conditions, suggests that competing reactions at acidic pH determine the production of nitrating agents ((•)NO2) or other, more stable, oxides. Accordingly, it is shown in vitro that salivary nitrite yields higher steady state concentrations of (•)NO (0.37 ± 0.01 μM) than sodium nitrite (0.12 ± 0.03 μM). Dietary-dependent reactions involving the production of nitrogen oxides should be further investigated as, in the context of occludin nitration, the consumption of green leafy vegetables (with high nitrate content), if able to modulate gut barrier function, may have important implications in the context of leaky gut disorders.

  16. A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 2: Cobalamin C deficiency (cblC).¶

    PubMed Central

    Manoli, Irini; Myles, Jennifer G.; Sloan, Jennifer L.; Carrillo-Carrasco, Nuria; Morava, Eva; Strauss, Kevin A.; Morton, Holmes; Venditti, Charles P.

    2015-01-01

    PURPOSE Cobalamin C (cblC) deficiency impairs the biosynthesis of adenosyl- and methylcobalamin resulting in methylmalonic acidemia combined with hyperhomocysteinemia and hypomethioninemia. However, some patients with cblC deficiency are treated with medical foods, devoid of methionine and high in leucine content, that are formulated for patients with isolated propionate oxidative defects. We examined the effects of imbalanced branched-chain amino acid intake on growth outcomes in cblC patients. METHODS Dietary intake was correlated with biochemical, anthropometric, body composition measurements and other disease parameters in a cohort of 28 early-onset cblC patients. RESULTS Protein restricted diets were followed by 21% of the patients, while 32% received medical foods. Patients on protein-restricted diets had lower height-for-age Z-score (P=0.034), while patients consuming medical foods had lower head-circumference Z-scores (P=0.037), plasma methionine concentrations (P=0.001) and predicted methionine influx through the blood brain barrier Z-score (−1.29 vs. −0.0617, P=0.007). The combination of age of diagnosis, a history of seizures and the leucine/valine dietary intake ratio best predicted head circumference Z-score based on multiple regression modeling (R2= 0.945). CONCLUSIONS Patients with cblC deficiency treated with medical foods designed for isolated methylmalonic acidemia are at risk for iatrogenic methionine deficiency that could adversely affect brain growth and development. TRIAL REGISTRATION This clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078 PMID:26270766

  17. [Methylenetetrahydrofolate reductase deficiency-induced schizophrenia in a school-age boy].

    PubMed

    Wang, Qiao; Liu, Jing; Liu, Yu-Peng; Li, Xi-Yuan; Ma, Yan-Yan; Wu, Tong-Fei; Ding, Yuan; Song, Jin-Qing; Wang, Yu-Jie; Yang, Yan-Ling

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. It is known that MTHFR deficiency may result in hyperhomocysteinemia, but MTHFR deficiency-induced schizophrenia has been rarely reported. Here we present the clinical course, biochemical and genetic characteristics of schizophrenia resulted from MTHFR deficiency in a school-age boy. He was 13 years old. He was admitted with a two-year history of fear, auditory hallucination, learning difficulty, sleeping problems, irascibility, drowsing and giggling. At admission, he had significantly elevated plasma and urine levels of total homocysteine, significantly decreased levels of folate in serum and cerebrospinal fluid, and a normal blood concentration of methionine. Further DNA sequencing analysis showed 665C>T homozygous mutations in the MTHFR gene. The patient was diagnosed with MTHFR deficiency-associated schizophrenia and treatment with calcium folinate, vitamin B12, vitamin B6, and betaine was initiated. After the treatment for 1 week, his plasma and urine levels of homocysteine were decreased to a normal range and the clinical symptoms were significantly improved. After 3 months of treatment, the patient returned to school. He is now living with normal school life. In summary, children with late-onset MTHFR deficiency and secondary cerebral folate deficiency may lead to schizophrenia. This rare condition can be early diagnosed through analyses of blood and urine total homocysteine, amino acids in blood and folate in blood and cerebral fluid and successfully treated with folinic acid, vitamin B6, vitamin B12 and betaine.

  18. Riboflavin deficiency induces a significant change in proteomic profiles in HepG2 cells

    PubMed Central

    Xin, Zhonghao; Pu, Lingling; Gao, Weina; Wang, Yawen; Wei, Jingyu; Shi, Tala; Yao, Zhanxin; Guo, Changjiang

    2017-01-01

    Riboflavin deficiency is widespread in many regions over the world, especially in underdeveloped countries. In this study, we investigated the effects of riboflavin deficiency on protein expression profiles in HepG2 cells in order to provide molecular information for the abnormalities induced by riboflavin deficiency. HepG2 cells were cultured in media containing different concentrations of riboflavin. Changes of cell viability and apoptosis were assessed. A comparative proteomic analysis was performed using a label-free shotgun method with LC–MS/MS to investigate the global changes of proteomic profiles in response to riboflavin deficiency. Immunoblotting test was used to validate the results of proteomic approach. The cell viability and apoptosis tests showed that riboflavin was vital in maintaining the cytoactivity of HepG2 cells. The label-free proteomic analysis revealed that a total of 37 proteins showing differential expression (±2 fold, p < 0.05) were identified after riboflavin deficiency. Bioinformatics analysis indicated that the riboflavin deficiency caused an up-regulation of Parkinson’s disease pathway, steroid catabolism, endoplasmic reticulum stress and apoptotic process, while the fatty acid metabolism, tricarboxylic citrate cycle, oxidative phosphorylation and iron metabolism were down-regulated. These findings provide a molecular basis for the elucidation of the effects caused by riboflavin deficiency. PMID:28367977

  19. Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

    PubMed Central

    Shirozu, Kazuhiro; Tokuda, Kentaro; Marutani, Eizo; Lefer, David; Wang, Rui

    2014-01-01

    Abstract Aims: Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H2S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine γ-lyase (CSE, an enzyme produces H2S) in ALF induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). Results: Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DL-propargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death without affecting LPS-induced TNF-α production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Akt- and Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice. Innovation: These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-apoptotic defense in the liver. Conclusion: Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-apoptotic mechanisms. Antioxid. Redox Signal. 20, 204

  20. Metformin administration induces hepatotoxic effects in paraoxonase-1-deficient mice.

    PubMed

    García-Heredia, Anabel; Riera-Borrull, Marta; Fort-Gallifa, Isabel; Luciano-Mateo, Fedra; Cabré, Noemí; Hernández-Aguilera, Anna; Joven, Jorge; Camps, Jordi

    2016-04-05

    Metformin is the first-line pharmacological treatment of diabetes. In these patients, metformin reduces body weight and decreases the risk of diabetes-related complications such as cardiovascular disease. However, whether metformin elicits beneficial effects on liver histology is a controversial issue and, as yet, there is no consensus. Paraoxonase-1 (PON1), an enzyme synthesized mainly by the liver, degrades lipid peroxides and reduces oxidative stress. PON1 activities are decreased in chronic liver diseases. We evaluated the effects of metformin in the liver of PON1-deficient mice which, untreated, present a mild degree of liver steatosis. Metformin administration aggravated inflammation in animals given a standard mouse chow and in those fed a high-fat diet. Also, it was associated with a higher degree of steatosis in animals fed a standard chow diet. This report is a cautionary note regarding the prescription of metformin for the treatment of diabetes in patients with concomitant liver impairment.

  1. Nrf2 deficiency prevents reductive stress-induced hypertrophic cardiomyopathy

    PubMed Central

    Kannan, Sankaranarayanan; Muthusamy, Vasanthi R.; Whitehead, Kevin J.; Wang, Li; Gomes, Aldrin V.; Litwin, Sheldon E.; Kensler, Thomas W.; Abel, E. Dale; Hoidal, John R.; Rajasekaran, Namakkal S.

    2013-01-01

    Aims Mutant protein aggregation (PA) cardiomyopathy (MPAC) is characterized by reductive stress (RS), PA (of chaperones and cytoskeletal components), and ventricular dysfunction in transgenic mice expressing human mutant CryAB (hmCryAB). Sustained activation of nuclear erythroid-2 like factor-2 (Nrf2) causes RS, which contributes to proteotoxic cardiac disease. The goals of this pre-clinical study were to (i) investigate whether disrupting Nrf2-antioxidant signalling prevents RS and rescues redox homeostasis in hearts expressing the mutant chaperone and (ii) elucidate mechanisms that could delay proteotoxic cardiac disease. Methods and results Non-transgenic (NTG), transgenic (TG) with MPAC and MPAC-TG:Nrf2-deficient (Nrf2-def) mice were used in this study. The effects of Nrf2 diminution (Nrf2±) on RS mediated MPAC in TG mice were assessed at 6–7 and 10 months of age. The diminution of Nrf2 prevented RS and prolonged the survival of TG mice (∼50 weeks) by an additional 20–25 weeks. The TG:Nrf2-def mice did not exhibit cardiac hypertrophy at even 60 weeks, while the MPAC-TG mice developed pathological hypertrophy and heart failure starting at 24–28 weeks of age. Aggregation of cardiac proteins was significantly reduced in TG:Nrf2-def when compared with TG mice at 7 months. Preventing RS and maintaining redox homeostasis in the TG:Nrf2-def mice ameliorated PA, leading to decreased ubiquitination of proteins. Conclusion Nrf2 deficiency rescues redox homeostasis, which reduces aggregation of mutant proteins, thereby delaying the proteotoxic pathological cardiac remodelling caused by RS and toxic protein aggregates. PMID:23761402

  2. Induction of heme oxygenase-1 with dietary quercetin reduces obesity-induced hepatic inflammation through macrophage phenotype switching

    PubMed Central

    Kim, Chu-Sook; Choi, Hye-Seon; Joe, Yeonsoo; Chung, Hun Taeg

    2016-01-01

    BACKGROUND/OBJECTIVES Obesity-induced steatohepatitis accompanied by activated hepatic macrophages/Kupffer cells facilitates the progression of hepatic fibrinogenesis and exacerbates metabolic derangements such as insulin resistance. Heme oxyganase-1 (HO-1) modulates tissue macrophage phenotypes and thus is implicated in protection against inflammatory diseases. Here, we show that the flavonoid quercetin reduces obesity-induced hepatic inflammation by inducing HO-1, which promotes hepatic macrophage polarization in favor of the M2 phenotype. MATERIALS/METHODS Male C57BL/6 mice were fed a regular diet (RD), high-fat diet (HFD), or HFD supplemented with quercetin (HF+Que, 0.5g/kg diet) for nine weeks. Inflammatory cytokines and macrophage markers were measured by ELISA and RT-PCR, respectively. HO-1 protein was measured by Western blotting. RESULTS Quercetin supplementation decreased levels of inflammatory cytokines (TNFα, IL-6) and increased that of the anti-inflammatory cytokine (IL-10) in the livers of HFD-fed mice. This was accompanied by upregulation of M2 macrophage marker genes (Arg-1, Mrc1) and downregulation of M1 macrophage marker genes (TNFα, NOS2). In co-cultures of lipid-laden hepatocytes and macrophages, treatment with quercetin induced HO-1 in the macrophages, markedly suppressed expression of M1 macrophage marker genes, and reduced release of MCP-1. Moreover, these effects of quercetin were blunted by an HO-1 inhibitor and deficiency of nuclear factor E2-related factor 2 (Nrf2) in macrophages. CONCLUSIONS Quercetin reduces obesity-induced hepatic inflammation by promoting macrophage phenotype switching. The beneficial effect of quercetin is associated with Nrf2-mediated HO-1 induction. Quercetin may be a useful dietary factor for protecting against obesity-induced steatohepatitis. PMID:27909560

  3. Phosphate Deficiency Induces the Jasmonate Pathway and Enhances Resistance to Insect Herbivory1[OPEN

    PubMed Central

    Glauser, Gaétan

    2016-01-01

    During their life cycle, plants are typically confronted by simultaneous biotic and abiotic stresses. Low inorganic phosphate (Pi) is one of the most common nutrient deficiencies limiting plant growth in natural and agricultural ecosystems, while insect herbivory accounts for major losses in plant productivity and impacts ecological and evolutionary changes in plant populations. Here, we report that plants experiencing Pi deficiency induce the jasmonic acid (JA) pathway and enhance their defense against insect herbivory. Pi-deficient Arabidopsis (Arabidopsis thaliana) showed enhanced synthesis of JA and the bioactive conjugate JA-isoleucine, as well as activation of the JA signaling pathway, in both shoots and roots of wild-type plants and in shoots of the Pi-deficient mutant pho1. The kinetics of the induction of the JA signaling pathway by Pi deficiency was influenced by PHOSPHATE STARVATION RESPONSE1, the main transcription factor regulating the expression of Pi starvation-induced genes. Phenotypes of the pho1 mutant typically associated with Pi deficiency, such as high shoot anthocyanin levels and poor shoot growth, were significantly attenuated by blocking the JA biosynthesis or signaling pathway. Wounded pho1 leaves hyperaccumulated JA/JA-isoleucine in comparison with the wild type. The pho1 mutant also showed an increased resistance against the generalist herbivore Spodoptera littoralis that was attenuated in JA biosynthesis and signaling mutants. Pi deficiency also triggered increased resistance to S. littoralis in wild-type Arabidopsis as well as tomato (Solanum lycopersicum) and Nicotiana benthamiana, revealing that the link between Pi deficiency and enhanced herbivory resistance is conserved in a diversity of plants, including crops. PMID:27016448

  4. Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase.

    PubMed

    Kronenberg, Golo; Harms, Christoph; Sobol, Robert W; Cardozo-Pelaez, Fernando; Linhart, Heinz; Winter, Benjamin; Balkaya, Mustafa; Gertz, Karen; Gay, Shanna B; Cox, David; Eckart, Sarah; Ahmadi, Michael; Juckel, Georg; Kempermann, Gerd; Hellweg, Rainer; Sohr, Reinhard; Hörtnagl, Heide; Wilson, Samuel H; Jaenisch, Rudolf; Endres, Matthias

    2008-07-09

    Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung-/- embryonic fibroblasts, and conferred death of cultured Ung-/- hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung-/- but not Ung+/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung-/- mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency.

  5. Inducible Arginase 1 Deficiency in Mice Leads to Hyperargininemia and Altered Amino Acid Metabolism

    PubMed Central

    St. Amand, Tim; Kyriakopoulou, Lianna; Schulze, Andreas; Funk, Colin D.

    2013-01-01

    Arginase deficiency is a rare autosomal recessive disorder resulting from a loss of the liver arginase isoform, arginase 1 (ARG1), which is the final step in the urea cycle for detoxifying ammonia. ARG1 deficiency leads to hyperargininemia, characterized by progressive neurological impairment, persistent growth retardation and infrequent episodes of hyperammonemia. Using the Cre/loxP-directed conditional gene knockout system, we generated an inducible Arg1-deficient mouse model by crossing “floxed” Arg1 mice with CreERT2 mice. The resulting mice (Arg-Cre) die about two weeks after tamoxifen administration regardless of the starting age of inducing the knockout. These treated mice were nearly devoid of Arg1 mRNA, protein and liver arginase activity, and exhibited symptoms of hyperammonemia. Plasma amino acid analysis revealed pronounced hyperargininemia and significant alterations in amino acid and guanidino compound metabolism, including increased citrulline and guanidinoacetic acid. Despite no alteration in ornithine levels, concentrations of other amino acids such as proline and the branched-chain amino acids were reduced. In summary, we have generated and characterized an inducible Arg1-deficient mouse model exhibiting several pathologic manifestations of hyperargininemia. This model should prove useful for exploring potential treatment options of ARG1 deficiency. PMID:24224027

  6. Epigenetic mechanisms of dietary restriction induced aging in Drosophila.

    PubMed

    Lian, Ting; Gaur, Uma; Yang, Deying; Li, Diyan; Li, Ying; Yang, Mingyao

    2015-12-01

    Aging is a long-standing problem that people are always interested in. Thus, it is critical to understand the underlying molecular mechanisms in aging and explore the most efficient method to extend life expectancy. To achieve this goal, a wide range of systems including cells, rodent models, budding yeast, worms and flies have been employed for decades. In recent years, the effect of dietary restriction (DR) on lifespan is in the prime focus. Although we have confirmed that reduced insulin and/or insulin-like growth factor (IGF) and the target of rapamycin (TOR) signaling can increase Drosophila lifespan; the precise molecular mechanisms and nutritional response landscape of diet-mediated aging is ambiguous. Epigenetic events have been considered as the major contributors to lifespan extension with response to DR. The role of DNA methylation in aging is well acknowledged in mammals and rodents where it has been shown to impact aging by regulating the transcription, though the mechanism of regulation is not limited to only transcription. In Drosophila, the contribution of methylation during DR in aging is definitely less explored. In this review, we will update the advances in mechanisms of DR, with a particular focus on methylation as an upcoming target for aging studies and discuss Drosophila as a powerful model to understand mechanisms of aging with response to diet.

  7. Resolution of adalimumab-induced psoriasis after vitamin D deficiency treatment.

    PubMed

    Werner de Castro, Gláucio Ricardo; Neves, Fabrício Souza; Pereira, Ivanio Alves; Fialho, Sonia Cristina Magalhaes Souza; Ribeiro, Giovana; Zimmermann, Adriana Fontes

    2012-05-01

    Tumoral necrosis factor alpha blockers are very efficient in the treatment of many inflammatory systemic diseases, including rheumatoid arthritis and psoriasis. However, a paradoxical arouse of psoriasiform lesions may occur in a few patients taking anti-TNFα. The etiology of this rare side effect is still a mystery, and its treatment may be difficult. The authors report the resolution of adalimumab-induced psoriasis in a woman with rheumatoid arthritis after the use of high vitamin D(3) doses for the treatment of vitamin D deficiency. This is the first report of resolution of anti-TNFα-induced psoriasiform lesions by high doses of vitamin D(3) in a patient with rheumatoid arthritis and vitamin D deficiency. This case raises interesting questions on the role of vitamin D deficiency in the pathogenesis of this side effect and on the possible usefulness of high-dose vitamin D(3) in its treatment.

  8. Selenium deficiency induced by zinc deprivation in a crustacean

    SciTech Connect

    Keating, K.I.; Caffrey, P.B. )

    1989-08-01

    For intact daphnids reared in circumstances of controlled trace element exposure, one consequence of insufficient zinc (Zn) is an increased demand on the animal's pool of available selenium (Se). This demand is manifested by the type of cuticle deterioration associated with Se deficiency and by a depression of reproduction. In the presence of 25 parts per billion (ppb) Zn, 1 ppb Se eliminates these symptoms. In the absence of detectable Zn, 5 ppb Se eliminates overt cuticle damage and substantially increases reproduction. A shortening of life span resulting from Zn deprivation is not ameliorated by Se addition. The authors suggest that the interplay between Zn and Se concentrations reflects an underlying interplay between interdependent, but distinct, metabolic pathways; i.e., (for Se) glutathione peroxidase and (for Zn) Cu,Zn-superoxide dismutase--each offering protection against free radical damage. Because they are not necessarily localized in a given tissue, the key to recognition of such subtle, complex trace nutrient interactions has been use of intact animals in circumstances of control previously attainable only in tissue cultures.

  9. Gastrointestinal protective effect of dietary spices during ethanol-induced oxidant stress in experimental rats.

    PubMed

    Prakash, Usha N S; Srinivasan, Krishnapura

    2010-04-01

    Spices are traditionally known to have digestive stimulant action and to cure digestive disorders. In this study, the protective effect of dietary spices with respect to activities of antioxidant enzymes in gastric and intestinal mucosa was examined. Groups of Wistar rats were fed for 8 weeks with diets containing black pepper (0.5%), piperine (0.02%), red pepper (3.0%), capsaicin (0.01%), and ginger (0.05%). All these spices significantly enhanced the activities of antioxidant enzymes--superoxide dismutase, catalase, glutathione reductase, and glutathione-S-transferase--in both gastric and intestinal mucosa, suggesting a gastrointestinal protective role for these spices. In a separate study, these dietary spices were found to alleviate the diminished activities of antioxidant enzymes in gastric and intestinal mucosa under conditions of ethanol-induced oxidative stress. The gastroprotective effect of the spices was also reflected in their positive effect on mucosal glycoproteins, thereby lowering mucosal injury. The amelioration of the ethanol-induced decrease in the activities of antioxidant enzymes in gastric and intestinal mucosa by dietary spices suggests their beneficial gastrointestinal protective role. This is the first report on the gastrointestinal protective potential of dietary spices.

  10. Vitamin D Deficiency Is Associated With the Severity of Radiation-Induced Proctitis in Cancer Patients

    SciTech Connect

    Ghorbanzadeh-Moghaddam, Amir; Gholamrezaei, Ali; Hemati, Simin

    2015-07-01

    Purpose: Radiation-induced injury to normal tissues is a common complication of radiation therapy in cancer patients. Considering the role of vitamin D in mucosal barrier hemostasis and inflammatory responses, we investigated whether vitamin D deficiency is associated with the severity of radiation-induced acute proctitis in cancer patients. Methods and Materials: This prospective observational study was conducted in cancer patients referred for pelvic radiation therapy. Serum concentration of 25-hydroxyvitamin D was measured before radiation therapy. Vitamin D deficiency was defined as 25-hydroxyvitamin D concentrations of <35 nmol/L and <40 nmol/L in male and female patients, respectively, based on available normative data. Acute proctitis was assessed after 5 weeks of radiation therapy (total received radiation dose of 50 Gy) and graded from 0 to 4 using Radiation Therapy Oncology Group (RTOG) criteria. Results: Ninety-eight patients (57.1% male) with a mean age of 62.8 ± 9.1 years were studied. Vitamin D deficiency was found in 57 patients (58.1%). Symptoms of acute proctitis occurred in 72 patients (73.4%) after radiation therapy. RTOG grade was significantly higher in patients with vitamin D deficiency than in normal cases (median [interquartile range] of 2 [0.5-3] vs 1 [0-2], P=.037). Vitamin D deficiency was associated with RTOG grade of ≥2, independent of possible confounding factors; odds ratio (95% confidence interval) = 3.07 (1.27-7.50), P=.013. Conclusions: Vitamin D deficiency is associated with increased severity of radiation-induced acute proctitis. Investigating the underlying mechanisms of this association and evaluating the effectiveness of vitamin D therapy in preventing radiation-induced acute proctitis is warranted.

  11. Endoplasmic Reticulum Stress–Related Genes in Yellow Catfish Pelteobagrus fulvidraco: Molecular Characterization, Tissue Expression, and Expression Responses to Dietary Copper Deficiency and Excess

    PubMed Central

    Song, Yu-Feng; Luo, Zhi; Huang, Chao; Chen, Qi-Liang; Pan, Ya–Xiong; Xu, Yi-Huan

    2015-01-01

    Two endoplasmic reticulum (ER) molecular chaperones [glucose-regulated protein 78 (grp78) and calreticulin (crt)] and three ER stress sensors [PKR-like ER kinase (perk), inositol requiring enzyme (ire)-1α, and activating transcription factor (atf)-6α] cDNAs were first characterized from yellow catfish, Pelteobagrus fulvidraco. The predicted amino acid sequences for the yellow catfish grp78, crt, perk, ire-1α, and atf-6α revealed that the proteins contained all of the structural features that were characteristic of the five genes in other species, including the KDEL motif, signal peptide, sensor domain, and effector domain. mRNAs of the five genes mentioned above were expressed in various tissues, but their mRNA levels varied among tissues. Dietary Cu excess, but not Cu deficiency, activated the chaperones (grp78 and crt) and folding sensors in ER, and the UPR signaling pathways (i.e., perk–eif2α and the ire1–xbp1) in a tissue-specific manner. For the first time, our study cloned grp78, crt, perk, ire-1α, and atf-6α genes in yellow catfish and demonstrated their differential expression among tissues. Moreover, the present study also indicated differential regulation of these ER stress–related genes by dietary Cu deficiency and excess, which will be beneficial for us to evaluate effects of dietary Cu levels in fish at the molecular level, based on the upstream pathway of lipid metabolism (the ER) and thus provide novel insights regarding the nutrition of Cu in fish. PMID:26276384

  12. Endoplasmic Reticulum Stress-Related Genes in Yellow Catfish Pelteobagrus fulvidraco: Molecular Characterization, Tissue Expression, and Expression Responses to Dietary Copper Deficiency and Excess.

    PubMed

    Song, Yu-Feng; Luo, Zhi; Huang, Chao; Chen, Qi-Liang; Pan, Ya-Xiong; Xu, Yi-Huan

    2015-08-13

    Two endoplasmic reticulum (ER) molecular chaperones [glucose-regulated protein 78 (grp78) and calreticulin (crt)] and three ER stress sensors [PKR-like ER kinase (perk), inositol requiring enzyme (ire)-1α, and activating transcription factor (atf)-6α] cDNAs were first characterized from yellow catfish, Pelteobagrus fulvidraco. The predicted amino acid sequences for the yellow catfish grp78, crt, perk, ire-1α, and atf-6α revealed that the proteins contained all of the structural features that were characteristic of the five genes in other species, including the KDEL motif, signal peptide, sensor domain, and effector domain. mRNAs of the five genes mentioned above were expressed in various tissues, but their mRNA levels varied among tissues. Dietary Cu excess, but not Cu deficiency, activated the chaperones (grp78 and crt) and folding sensors in ER, and the UPR signaling pathways (i.e., perk-eif2α and the ire1-xbp1) in a tissue-specific manner. For the first time, our study cloned grp78, crt, perk, ire-1α, and atf-6α genes in yellow catfish and demonstrated their differential expression among tissues. Moreover, the present study also indicated differential regulation of these ER stress-related genes by dietary Cu deficiency and excess, which will be beneficial for us to evaluate effects of dietary Cu levels in fish at the molecular level, based on the upstream pathway of lipid metabolism (the ER) and thus provide novel insights regarding the nutrition of Cu in fish.

  13. Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries

    PubMed Central

    Jain, Anil K; Tewari-Singh, Neera; Inturi, Swetha; Orlicky, David J.; White, Carl W.; Agarwal, Rajesh

    2014-01-01

    The pathologic mechanisms of skin injuries, following the acute inflammatory response induced by vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) exposure, are poorly understood. Neutrophils which accumulate at the site of injury, abundantly express myeloperoxidase (MPO), a heme protein that is implicated in oxidant-related antimicrobial and cytotoxic responses. Our previous studies have shown that exposure to SM analog 2-chloroethyl ethyl sulfide (CEES) or NM results in an inflammatory response including increased neutrophilic infiltration and MPO activity. To further define the role of neutrophil-derived MPO in NM-induced skin injury, here we used a genetic approach and examined the effect of NM exposure (12 h and 24 h) on previously established injury endpoints in C57BL/6J wild type (WT) and B6.129X1-MPOtm1Lus/J mice (MPO KO), homozygous null for MPO gene. NM exposure caused a significant increase in skin bi-fold thickness, epidermal thickness, microvesication, DNA damage and apoptosis in WT mice compared to MPO KO mice. MPO KO mice showed relatively insignificant effect. Similarly, NM-induced increases in the expression of inflammatory and proteolytic mediators, including COX-2, iNOS and MMP-9 in WT mice, while having a significantly lower effect in MPO KO mice. Collectively, these results show that MPO, which generates microbicidal oxidants, plays an important role in NM-induced skin injuries. This suggests the development of mechanism-based treatments against NM- and SM-induced skin injuries that inhibit MPO activity and attenuate MPO-derived oxidants. PMID:24631667

  14. Sirtuin-6 deficiency exacerbates diabetes induced impairment of wound healing

    PubMed Central

    Thandavarayan, Rajarajan A; Garikipati, Venkata Naga Srikanth; Joladarashi, Darukeshwara; Babu, Sahana Suresh; Jeyabal, Prince; Verma, Suresh K; Mackie, Alexander R; Khan, Mohsin; Arumugam, Somasundaram; Watanabe, Kenichi; Kishore, Raj; Krishnamurthy, Prasanna

    2015-01-01

    Delayed wound healing is one of the major complications in diabetes and is characterized by chronic proinflammatory response, and abnormalities in angiogenesis and collagen deposition. Sirtuin family proteins regulate numerous pathophysiological processes, including those involved in promotion of longevity, DNA repair, glycolysis and inflammation. However the role of sirtuin 6 (SIRT6), a NAD+-dependent nuclear deacetylase, in wound healing specifically under diabetic condition remains unclear. To analyze the role of SIRT6 in cutaneous wound healing, paired 6 mm stented wound were created in diabetic db/db mice and injected siRNA against SIRT6 in the wound margins (transfection agent alone and non-sensed siRNA served as controls). Wound time to closure was assessed by digital planimetry, and wounds were harvested for histology, immunohistochemistry and Western blotting. SIRT6-siRNA treated diabetic wound showed impaired healing, which was associated with reduced capillary density (CD31 staining vessels) when compared to control treatment. Interestingly, SIRT6 deficiency decreased vascular endothelial growth factor (VEGF) expression and proliferation markers in the wounds. Furthermore, SIRT6 ablation in diabetic wound promotes nuclear factor kB (NF-kB) activation resulting in increased expression of proinflammatory markers (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor-α and interleukin-1β) and increased oxidative stress. Collectively, our findings demonstrate that loss of SIRT6 in cutaneous wound aggravates proinflammatory response by increasing NF-kB activation, oxidative stress and decrease in angiogenesis in the diabetic mice. Based on these findings, we speculate that activation of SIRT6 signaling might be a potential therapeutic approach for promoting wound healing in diabetics. PMID:26010430

  15. Allergens induce enhanced bronchoconstriction and leukotriene production in C5 deficient mice

    PubMed Central

    McKinley, Laura; Kim, Jiyoun; Bolgos, Gerald L; Siddiqui, Javed; Remick, Daniel G

    2006-01-01

    Background Previous genetic analysis has shown that a deletion in the complement component 5 gene-coding region renders mice more susceptible to allergen-induced airway hyperresponsiveness (AHR) due to reduced IL-12 production. We investigated the role of complement in a murine model of asthma-like pulmonary inflammation. Methods In order to evaluate the role of complement B10 mice either sufficient or deficient in C5 were studied. Both groups of mice immunized and challenged with a house dust extract (HDE) containing high levels of cockroach allergens. Airways hyper-reactivity was determined with whole-body plesthysmography. Bronchoalveolar lavage (BAL) was performed to determine pulmonary cellular recruitment and measure inflammatory mediators. Lung homogenates were assayed for mediators and plasma levels of IgE determined. Pulmonary histology was also evaluated. Results C5-deficient mice showed enhanced AHR to methylcholine challenge, 474% and 91% increase above baseline Penh in C5-deficient and C5-sufficient mice respectively, p < 0.001. IL-12 levels in the lung homogenate (LH) were only slightly reduced and BAL IL-12 was comparable in C5-sufficient and C5-deficient mice. However, C5-deficient mice had significantly higher cysteinyl-leukotriene levels in the BAL fluid, 1913 +/- 246 pg/ml in C5d and 756 +/- 232 pg/ml in C5-sufficient, p = 0.003. Conclusion These data demonstrate that C5-deficient mice show enhanced AHR due to increased production of cysteinyl-leukotrienes. PMID:17044927

  16. Discovering the role of mitochondria in the iron deficiency-induced metabolic responses of plants.

    PubMed

    Vigani, Gianpiero

    2012-01-01

    In plants, iron (Fe) deficiency-induced chlorosis is a major problem, affecting both yield and quality of crops. Plants have evolved multifaceted strategies, such as reductase activity, proton extrusion, and specialised storage proteins, to mobilise Fe from the environment and distribute it within the plant. Because of its fundamental role in plant productivity, several issues concerning Fe homeostasis in plants are currently intensively studied. The activation of Fe uptake reactions requires an overall adaptation of the primary metabolism because these activities need the constant supply of energetic substrates (i.e., NADPH and ATP). Several studies concerning the metabolism of Fe-deficient plants have been conducted, but research focused on mitochondrial implications in adaptive responses to nutritional stress has only begun in recent years. Mitochondria are the energetic centre of the root cell, and they are strongly affected by Fe deficiency. Nevertheless, they display a high level of functional flexibility, which allows them to maintain the viability of the cell. Mitochondria represent a crucial target of studies on plant homeostasis, and it might be of interest to concentrate future research on understanding how mitochondria orchestrate the reprogramming of root cell metabolism under Fe deficiency. In this review, I summarise what it is known about the effect of Fe deficiency on mitochondrial metabolism and morphology. Moreover, I present a detailed view of the possible roles of mitochondria in the development of plant responses to Fe deficiency, integrating old findings with new and discussing new hypotheses for future investigations.

  17. High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring.

    PubMed

    Bahous, Renata H; Jadavji, Nafisa M; Deng, Liyuan; Cosín-Tomás, Marta; Lu, Jessica; Malysheva, Olga; Leung, Kit-Yi; Ho, Ming-Kai; Pallàs, Mercè; Kaliman, Perla; Greene, Nicholas DE; Bedell, Barry J; Caudill, Marie A; Rozen, Rima

    2017-01-09

    Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C>T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or folic acid-supplemented diet (FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for choline/methyl metabolite measurements, immunoblotting or gene expression of relevant enzymes. Brains were examined for morphology of hippocampus and cortex.Pups of FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR protein levels were reduced in FASD pup livers, with lower concentrations of phosphocholine and glycerophosphocholine in liver and hippocampus, respectively. FASD pup brains showed evidence of altered acetylcholine availability and Dnmt3a mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from FASD dams were smaller. MTHFR protein and mRNA were reduced in embryonic liver, with lower concentrations of choline, betaine and phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high folate intake during pregnancy leads to pseudo-MTHFR 3 deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid.

  18. Increased Sucrose in the Hypocotyls of Radish Sprouts Contributes to Nitrogen Deficiency-Induced Anthocyanin Accumulation

    PubMed Central

    Su, Nana; Wu, Qi; Cui, Jin

    2016-01-01

    Effects of nitrogen (N) deficiency and sucrose (Suc) addition on regulation of anthocyanin biosynthesis and their relationship were investigated in this study. Radish sprouts subjected to N deficiency had 50% higher anthocyanin accumulation than when grown in Hoagland solution (a nutrient medium with all macronutrients). The contents of endogenous soluble sugars (Suc, fructose, and glucose) in the hypocotyls were also markedly increased by N limitation, with Suc showing the highest increase. Inhibition of carbohydrate biosynthesis by addition of 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) also eliminated N deficiency-induced anthocyanin accumulation. The latter was further supported by the expression of anthocyanin biosynthesis related genes and decreased activities of nitrate reductase in the presence of Suc. Together our results indicate that N deficiency-induced anthocyanin accumulation was, at least partly, dependent on the increase of the soluble sugar, especially Suc. This work is the first comprehensive study on relationship between N deficiency and sugar content on anthocyanin accumulation in the hypocotyls of radish sprouts. PMID:28083009

  19. TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema.

    PubMed

    An, Chang Hyeok; Wang, Xiao Mei; Lam, Hilaire C; Ifedigbo, Emeka; Washko, George R; Ryter, Stefan W; Choi, Augustine M K

    2012-11-01

    Toll-like receptors (TLRs) exert important nonimmune functions in lung homeostasis. TLR4 deficiency promotes pulmonary emphysema. We examined the role of TLR4 in regulating cigarette smoke (CS)-induced autophagy, apoptosis, and emphysema. Lung tissue was obtained from chronic obstructive lung disease (COPD) patients. C3H/HeJ (Tlr4-mutated) mice and C57BL/10ScNJ (Tlr4-deficient) mice and their respective control strains were exposed to chronic CS or air. Human or mouse epithelial cells (wild-type, Tlr4-knockdown, and Tlr4-deficient) were exposed to CS-extract (CSE). Samples were analyzed for TLR4 expression, and for autophagic or apoptotic proteins by Western blot analysis or confocal imaging. Chronic obstructive lung disease lung tissues and human pulmonary epithelial cells exposed to CSE displayed increased TLR4 expression, and increased autophagic [microtubule-associated protein-1 light-chain-3B (LC3B)] and apoptotic (cleaved caspase-3) markers. Beas-2B cells transfected with TLR4 siRNA displayed increased expression of LC3B relative to control cells, basally and after exposure to CSE. The basal and CSE-inducible expression of LC3B and cleaved caspase-3 were elevated in pulmonary alveolar type II cells from Tlr4-deficient mice. Wild-type mice subjected to chronic CS-exposure displayed airspace enlargement;, however, the Tlr4-mutated or Tlr4-deficient mice exhibited a marked increase in airspace relative to wild-type mice after CS-exposure. The Tlr4-mutated or Tlr4-deficient mice showed higher levels of LC3B under basal conditions and after CS exposure. The expression of cleaved caspase-3 was markedly increased in Tlr4-deficient mice exposed to CS. We describe a protective regulatory function of TLR4 against emphysematous changes of the lung in response to CS.

  20. Prostaglandin E2 is critical for the development of niacin-deficiency-induced photosensitivity via ROS production

    NASA Astrophysics Data System (ADS)

    Sugita, Kazunari; Ikenouchi-Sugita, Atsuko; Nakayama, Yasuko; Yoshioka, Haruna; Nomura, Takashi; Sakabe, Jun-Ichi; Nakahigashi, Kyoko; Kuroda, Etsushi; Uematsu, Satoshi; Nakamura, Jun; Akira, Shizuo; Nakamura, Motonobu; Narumiya, Shuh; Miyachi, Yoshiki; Tokura, Yoshiki; Kabashima, Kenji

    2013-10-01

    Pellagra is a photosensitivity syndrome characterized by three ``D's'': diarrhea, dermatitis, and dementia as a result of niacin deficiency. However, the molecular mechanisms of photosensitivity dermatitis, the hallmark abnormality of this syndrome, remain unclear. We prepared niacin deficient mice in order to develop a murine model of pellagra. Niacin deficiency induced photosensitivity and severe diarrhea with weight loss. In addition, niacin deficient mice exhibited elevated expressions of COX-2 and PGE syntheses (Ptges) mRNA. Consistently, photosensitivity was alleviated by a COX inhibitor, deficiency of Ptges, or blockade of EP4 receptor signaling. Moreover, enhanced PGE2 production in niacin deficiency was mediated via ROS production in keratinocytes. In line with the above murine findings, human skin lesions of pellagra patients confirmed the enhanced expression of Ptges. Niacin deficiency-induced photosensitivity was mediated through EP4 signaling in response to increased PGE2 production via induction of ROS formation.

  1. CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-κB activation

    PubMed Central

    Grabiner, Brian C.; Blonska, Marzenna; Lin, Pei-Chun; You, Yun; Wang, Donghai; Sun, Jiyuan; Darnay, Bryant G.; Dong, Chen; Lin, Xin

    2007-01-01

    G protein-coupled receptors (GPCRs) play pivotal roles in regulating various cellular functions. Although many GPCRs induce NF-κB activation, the molecular mechanism of GPCR-induced NF-κB activation remains largely unknown. CARMA3 (CARD and MAGUK domain-containing protein 3) is a scaffold molecule with unknown biological functions. By generating CARMA3 knockout mice using the gene targeting approach, here we show CARMA3 is required for GPCR-induced NF-κB activation. Mechanistically, we found that CARMA3 deficiency impairs GPCR-induced IκB kinase (IKK) activation, although it does not affect GPCR-induced IKKα/β phosphorylation, indicating that inducible phosphorylation of IKKα/β alone is not sufficient to induce its kinase activity. We also found that CARMA3 is physically associated with NEMO/IKKγ, and induces polyubiquitination of an unknown protein(s) that associates with NEMO, likely by linking NEMO to TRAF6. Consistently, we found TRAF6 deficiency also abrogates GPCR-induced NF-κB activation. Together, our results provide the genetic evidence that CARMA3 is required for GPCR-induced NF-κB activation. PMID:17438001

  2. Adaptive response of the heart to long-term anemia induced by iron deficiency.

    PubMed

    Naito, Yoshiro; Tsujino, Takeshi; Matsumoto, Mika; Sakoda, Tsuyoshi; Ohyanagi, Mitsumasa; Masuyama, Tohru

    2009-03-01

    Anemia is common in patients with chronic heart failure and an independent predictor of poor prognosis. Chronic anemia leads to left ventricular (LV) hypertrophy and heart failure, but its molecular mechanisms remain largely unknown. We investigated the mechanisms, including the molecular signaling pathway, of cardiac remodeling induced by iron deficiency anemia (IDA). Weanling Sprague-Dawley rats were fed an iron-deficient diet for 20 wk to induce IDA, and the molecular mechanisms of cardiac remodeling were evaluated. The iron-deficient diet initially induced severe anemia, which resulted in LV hypertrophy and dilation with preserved systolic function associated with increased serum erythropoietin (Epo) concentration. Cardiac STAT3 phosphorylation and VEGF gene expression increased by 12 wk of IDA, causing angiogenesis in the heart. Thereafter, sustained IDA induced upregulation of cardiac hypoxia inducible factor-1alpha gene expression and maintained upregulation of cardiac VEGF gene expression and cardiac angiogenesis; however, sustained IDA promoted cardiac fibrosis and lung congestion, with decreased serum Epo concentration and cardiac STAT3 phosphorylation after 20 wk of IDA compared with 12 wk. Upregulation of serum Epo concentration and cardiac STAT3 phosphorylation is associated with a beneficial adaptive mechanism of anemia-induced cardiac hypertrophy, and later decreased levels of these molecules may be critical for the transition from adaptive cardiac hypertrophy to cardiac dysfunction in long-term anemia. Understanding the mechanism of cardiac maladaptation to anemia may lead to a new strategy for treatment of chronic heart failure with anemia.

  3. Lesions of the entopeduncular nucleus in rats prevent apomorphine-induced deficient sensorimotor gating.

    PubMed

    Lütjens, Götz; Krauss, Joachim K; Schwabe, Kerstin

    2011-07-07

    Dopamine-induced hyperactivity and deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR), are used as animal models for neuropsychiatric disorders such as schizophrenia and Tourette's syndrome. We here investigated whether excitotoxic lesions of the rat entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), would improve apomorphine-induced PPI-deficits and hyperactivity. Additionally, we investigated the effect of EPN lesions on cognition, motivation and motor skills. In male Sprague Dawley rats bilateral EPN lesions were induced by stereotactic injection of ibotenate (4 μg in 0.4 μl phosphate buffered saline, PBS) or sham-lesions by injection of vehicle PBS. After one week, rats were tested for learning and memory (continuous and delayed alternation, T-maze), for motivation (progressive ratio test with breakpoint of 3 min inactivity, Skinner box), and for motor skills (rotating rod). Thereafter, rats were tested for PPI of ASR (startle response system) after subcutaneous injection of apomorphine (1.0mg/kg and vehicle) and for locomotor activity (0.5mg/kg and vehicle). Ibotenate-induced EPN lesions did not affect learning and memory, motivation or motor skills. Basal locomotor activity and PPI was also not affected, but EPN lesions ameliorated apomorphine-induced hyperlocomotion and deficient PPI. This work indicates an important role of the EPN for the modulation of dopamine agonist-induced deficient sensorimotor gating and hyperlocomotion, without affecting normal behavioral function.

  4. Effect of dietary phosphorus deficiency on the growth, immune function and structural integrity of head kidney, spleen and skin in young grass carp (Ctenopharyngodon idella).

    PubMed

    Chen, Kang; Jiang, Wei-Dan; Wu, Pei; Liu, Yang; Kuang, Sheng-Yao; Tang, Ling; Tang, Wu-Neng; Zhang, Yong-An; Zhou, Xiao-Qiu; Feng, Lin

    2017-04-01

    This study evaluates the effects of dietary phosphorus on the growth, immune function and structural integrity (head kidney, spleen and skin) of young grass carp (Ctenopharyngodon idella) that were fed graded levels of available phosphorus (0.95-8.75 g/kg diet). Results indicated that phosphorus deficiency decreased the growth performance of young grass carp. In addition, the results first demonstrated that compared with the optimal phosphorus level, phosphorus deficiency depressed the lysozyme (LZ) and acid phosphatase (ACP) activities and the complement 3 (C3), C4 and immunoglobulin M (IgM) contents, and down-regulated the mRNA levels of antimicrobial peptides, anti-inflammatory cytokines, inhibitor of κBα (IκBα) and target of rapamycin (TOR), whereas it up-regulated pro-inflammatory cytokines, nuclear factor kappa B (NF-κB) p65 and NF-κB p52 mRNA levels to decrease fish head kidney and spleen immune functions. Moreover, phosphorus deficiency up-regulated the mRNA levels of Kelch-like-ECH-associated protein 1a (Keap1a), Fas ligand (FasL), apoptotic protease activating factor-1 (Apaf-1), Bcl-2 associated X protein (Bax), caspase -2, -3, -7, -8 and -9, p38 mitogen-activated protein kinase (MAPK) and myosin light chain kinase (MLCK), whereas it depressed the glutathione (GSH) contents and antioxidant enzymes activities, and down-regulated the mRNA levels of antioxidant enzymes, NF-E2-related factor 2 (Nrf2), B-cell lymphoma protein-2 (Bcl-2), myeloid cell leukemia-1 (Mcl-1) and tight junction complexes to attenuate fish head kidney and spleen structural integrity. In addition, phosphorus deficiency increased skin hemorrhage and lesions morbidity. Finally, based on the percent weight gain (PWG) and the ability to combat skin hemorrhage and lesions, the dietary available phosphorus requirements for young grass carp (254.56-898.23 g) were estimated to be 4.10 and 4.13 g/kg diet, respectively. In summary, phosphorus deficiency decreases the growth

  5. The Vacuolar Manganese Transporter MTP8 Determines Tolerance to Iron Deficiency-Induced Chlorosis in Arabidopsis.

    PubMed

    Eroglu, Seckin; Meier, Bastian; von Wirén, Nicolaus; Peiter, Edgar

    2016-02-01

    Iron (Fe) deficiency is a widespread nutritional disorder on calcareous soils. To identify genes involved in the Fe deficiency response, Arabidopsis (Arabidopsis thaliana) transfer DNA insertion lines were screened on a high-pH medium with low Fe availability. This approach identified METAL TOLERANCE PROTEIN8 (MTP8), a member of the Cation Diffusion Facilitator family, as a critical determinant for the tolerance to Fe deficiency-induced chlorosis, also on soil substrate. Subcellular localization to the tonoplast, complementation of a manganese (Mn)-sensitive Saccharomyces cerevisiae yeast strain, and Mn sensitivity of mtp8 knockout mutants characterized the protein as a vacuolar Mn transporter suitable to prevent plant cells from Mn toxicity. MTP8 expression was strongly induced on low-Fe as well as high-Mn medium, which were both strictly dependent on the transcription factor FIT, indicating that high-Mn stress induces Fe deficiency. mtp8 mutants were only hypersensitive to Fe deficiency when Mn was present in the medium, which further suggested an Mn-specific role of MTP8 during Fe limitation. Under those conditions, mtp8 mutants not only translocated more Mn to the shoot than did wild-type plants but suffered in particular from critically low Fe concentrations and, hence, Fe chlorosis, although the transcriptional Fe deficiency response was up-regulated more strongly in mtp8. The diminished uptake of Fe from Mn-containing low-Fe medium by mtp8 mutants was caused by an impaired ability to boost the ferric chelate reductase activity, which is an essential process in Fe acquisition. These findings provide a mechanistic explanation for the long-known interference of Mn in Fe nutrition and define the molecular processes by which plants alleviate this antagonism.

  6. Ethanol-induced developmental neurodegeneration in secretin receptor-deficient mice.

    PubMed

    Hwang, Dong-Woo; Givens, Bennet; Nishijima, Ichiko

    2009-05-06

    Alcohol exposure during brain development induces neuronal cell death in the brain. Several neuroactive peptides have been shown to protect against alcohol-induced cell death. Secretin is a peptide hormone, and the secretin receptor is expressed in the gut and the brain. To explore a potential role of secretin signal against ethanol neurotoxicity during brain development, secretin receptor-deficient mice were exposed to ethanol on postnatal day 4. We identified significant ethanol-induced apoptosis in the external granular layer of the secretin receptor-deficient cerebellum and in the striatum after ethanol treatment. During the early postnatal period, there is a proliferation of granular cell progenitors that reside in the external granular layer. The results suggest that secretin signal plays a neuroprotective role of neuronal progenitor cells against the neurotoxicity of ethanol.

  7. Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

    PubMed

    Li, Chao; Zhang, Yu Yao; Frieler, Ryan A; Zheng, Xiao Jun; Zhang, Wu Chang; Sun, Xue Nan; Yang, Qing Zhen; Ma, Shu Min; Huang, Baozhuan; Berger, Stefan; Wang, Wang; Wu, Yong; Yu, Ying; Duan, Sheng Zhong; Mortensen, Richard M

    2014-01-01

    Mineralocorticoid receptor (MR) blockade has been shown to suppress cardiac hypertrophy and remodeling in animal models of pressure overload (POL). This study aims to determine whether MR deficiency in myeloid cells modulates aortic constriction-induced cardiovascular injuries. Myeloid MR knockout (MMRKO) mice and littermate control mice were subjected to abdominal aortic constriction (AAC) or sham operation. We found that AAC-induced cardiac hypertrophy and fibrosis were significantly attenuated in MMRKO mice. Expression of genes important in generating reactive oxygen species was decreased in MMRKO mice, while that of manganese superoxide dismutase increased. Furthermore, expression of genes important in cardiac metabolism was increased in MMRKO hearts. Macrophage infiltration in the heart was inhibited and expression of inflammatory genes was decreased in MMRKO mice. In addition, aortic fibrosis and inflammation were attenuated in MMRKO mice. Taken together, our data indicated that MR deficiency in myeloid cells effectively attenuated aortic constriction-induced cardiac hypertrophy and fibrosis, as well as aortic fibrosis and inflammation.

  8. Iodine deficiency induces a VEGF-dependent microvascular response in salivary glands and in the stomach.

    PubMed

    Vanderstraeten, Jessica; Derradji, Hanane; Craps, Julie; Sonveaux, Pierre; Colin, Ides M; Many, Marie-Christine; Gérard, Anne-Catherine

    2016-08-01

    Despite efforts to optimize iodine supply in iodine deficient countries, iodine deficiency (ID) remains a global problem worldwide. Activation of the local microvasculature by ID in the thyroid gland aims at improving the local supply of iodide. For this purpose, the thyrocytes secrete vascular endothelial growth factor (VEGF) that acts on adjacent capillaries, via a reactive oxygen species (ROS)/Hypoxia Inducible factor (HIF)-dependent pathway. Beside the thyroid, other organs including salivary glands and the stomach do express the sodium/iodide symporter (NIS) and are able to take iodide up, potentially rendering them sensitive to ID. To verify this hypothesis, ID-induced effects on the local microvasculature were studied in salivary glands and in the stomach. ID was induced by feeding young mice with an iodide-deficient diet and NIS inhibitor perchlorate in the drinking water. In salivary glands, ID induced a transient increase in HIF-1α protein expression accompanied by a transient, VEGF-dependent increase in blood flow. In the gastric mucosa, ID transiently increased VEGF expression in the mucin-secreting epithelium and in ghrelin-secreting endocrine cells. These observations suggest that microvascular changes in response to ID occur in NIS-expressing tissues other than the thyroid. NIS expressing cells could be viewed as iodide sensors that respond to ID by inducing vascular changes, probably to optimize iodide bioavailability at regional or systemic levels.

  9. DIETARY VITAMIN E DEFICIENCY AS A MODIFIER OF THE ASSOCIATIONS OF RESPIRATORY OUTCOMES WITH AIR POLLUTION IN ADOLESCENTS

    EPA Science Inventory

    Introduction: We investigated whether low dietary intake of the lipophilic antioxidant vitamin E may act as a modifier of chronic air pollution's associations with respiratory outcomes among adolescents due to an increased respiratory response to the oxidative effects of air pol...

  10. Dietary linoleic acid-induced alterations in pro- and anti-nociceptive lipid autacoids

    PubMed Central

    Ringel, Amit; Majchrzak-Hong, Sharon F; Yang, Jun; Blanchard, Helene; Zamora, Daisy; Loewke, James D; Rapoport, Stanley I; Hibbeln, Joseph R; Davis, John M; Hammock, Bruce D; Taha, Ameer Y

    2016-01-01

    Background Chronic idiopathic pain syndromes are major causes of personal suffering, disability, and societal expense. Dietary n-6 linoleic acid has increased markedly in modern industrialized populations over the past century. These high amounts of linoleic acid could hypothetically predispose to physical pain by increasing the production of pro-nociceptive linoleic acid-derived lipid autacoids and by interfering with the production of anti-nociceptive lipid autacoids derived from n-3 fatty acids. Here, we used a rat model to determine the effect of increasing dietary linoleic acid as a controlled variable for 15 weeks on nociceptive lipid autacoids and their precursor n-6 and n-3 fatty acids in tissues associated with idiopathic pain syndromes. Results Increasing dietary linoleic acid markedly increased the abundance of linoleic acid and its pro-nociceptive derivatives and reduced the abundance of n-3 eicosapentaenoic acid and docosahexaenoic acid and their anti-nociceptive monoepoxide derivatives. Diet-induced changes occurred in a tissue-specific manner, with marked alterations of nociceptive lipid autacoids in both peripheral and central tissues, and the most pronounced changes in their fatty acid precursors in peripheral tissues. Conclusions The present findings provide biochemical support for the hypothesis that the high linoleic acid content of modern industrialized diets may create a biochemical susceptibility to develop chronic pain. Dietary linoleic acid lowering should be further investigated as part of an integrative strategy for the prevention and management of idiopathic pain syndromes. PMID:27030719

  11. Phyto-power dietary supplement potently inhibits dimethylnitrosamine-induced liver fibrosis in rats.

    PubMed

    Lee, Ming-Fen; Tsai, Mei-Ling; Sun, Pei-Pei; Chien, Ling-Lung; Cheng, An-Chin; Ma, Nianhan Jia-Lin; Ho, Chi-Tang; Pan, Min-Hsiung

    2013-02-26

    Curcumin has been extensively studied for its therapeutic effects in a variety of disorders. Fermented soy consumption is associated with a low incidence rate of chronic diseases in many Asian countries. The aim of this study was to investigate the potential underlying mechanisms of the effect of a phyto-power dietary supplement on liver fibrosis. Sprague-Dawley rats were intraperitoneally injected with dimethylnitrosamine (DMN; 10 mg kg(-1)) three times a week for four consecutive weeks. A phyto-power dietary supplement (50 or 100 mg kg(-1)) was administered by oral gavage daily for four weeks. Liver morphology, function, and fibrotic status were examined in DMN induced hepatic fibrogenesis. However, a phyto-power dietary supplement alleviated liver damage as indicated by histopathological examination of the α-smooth muscle actin (α-SMA) and collagen I, accompanied by the concomitant reduction of transforming growth factor-β1 (TGF-β1) and matrix metalloproteinase 2 (MMP2). These data indicate that the phyto-power dietary supplement may inhibit the TGF-β1/Smad signaling and relieve liver damage in experimental fibrosis.

  12. Is Metformin-Induced Vitamin B12 Deficiency Responsible for Cognitive Decline in Type 2 Diabetes?

    PubMed Central

    Khattar, Deepti; Khaliq, Farah; Vaney, Neelam; Madhu, S. V.

    2016-01-01

    Introduction: Diabetes mellitus has its deleterious effects on various aspects of cognition such as memory function, executive function, and information-processing speed. The present study aims to assess cognition in diabetes patients and also tries to find its association with Vitamin B12 deficiency induced by metformin. Materials and Methods: Thirty diabetics taking metformin and thirty nondiabetic controls were enrolled. Event-related potentials (ERPs) and serum Vitamin B12 levels were evaluated in them. Results: Vitamin B12 levels were found to be deficient, and latencies of waves P200 and P300 were prolonged in the diabetics as compared to the controls. The dose and duration of metformin had no association with the ERPs. Conclusions: Although the Vitamin B12 levels were deficient in diabetics on metformin, this is not the reason behind the cognitive impairment found in them. PMID:27570337

  13. Dietary strategies to recover from exercise-induced muscle damage.

    PubMed

    Sousa, Mónica; Teixeira, Vítor H; Soares, José

    2014-03-01

    Exhaustive or unaccustomed intense exercise can cause exercise-induced muscle damage (EIMD) and its undesirable consequences may decrease the ability to exercise and to adhere to a training programme. This review briefly summarises the muscle damage process, focusing predominantly on oxidative stress and inflammation as contributing factors, and describes how nutrition may be positively used to recover from EIMD. The combined intake of carbohydrates and proteins and the use of antioxidants and/or anti-inflammatory nutrients within physiological ranges are interventions that may assist the recovery process. Although the works studying food instead of nutritional supplements are very scarce, their results seem to indicate that food might be a favourable option as a recovery strategy. To date, the only tested foods were milk, cherries, blueberries and pomegranate with promising results. Other potential solutions are foods rich in protein, carbohydrates, antioxidants and/or anti-inflammatory nutrients.

  14. FKBP12 deficiency reduces strength deficits after eccentric contraction-induced muscle injury.

    PubMed

    Corona, Benjamin T; Rouviere, Clement; Hamilton, Susan L; Ingalls, Christopher P

    2008-08-01

    Strength deficits associated with eccentric contraction-induced muscle injury stem, in part, from excitation-contraction uncoupling. FKBP12 is a 12-kDa binding protein known to bind to the skeletal muscle sarcoplasmic reticulum Ca2+ release channel [ryanodine receptor (RyR1)] and plays an important role in excitation-contraction coupling. To assess the effects of FKBP12 deficiency on muscle injury and recovery, we measured anterior crural muscle (tibialis anterior and extensor digitorum longus muscles) strength in skeletal muscle-specific FKBP12-deficient and wild-type (WT) mice before and after a single bout of 150 eccentric contractions, as well as before and after the performance of six injury bouts. Histological damage of the tibialis anterior muscle was assessed after injury. Body weight and peak isometric and eccentric torques were lower in FKBP12-deficient mice compared with WT mice. There were no differences between FKBP12-deficient and WT mice in preinjury peak isometric and eccentric torques when normalized to body weight, and no differences in the relative decreases in eccentric torque with a single or multiple injury bouts. After a single injury bout, FKBP12-deficient mice had less initial strength deficits and recovered faster (especially females) than WT mice, despite no differences in the degree of histological damage. After multiple injury bouts, FKBP12-deficient mice recovered muscle strength faster than WT mice and exhibited significantly less histological muscle damage than WT mice. In summary, FKBP12 deficiency results in less initial strength deficits and enhanced recovery from single (especially females) and repeated bouts of injury than WT mice.

  15. Mechanism of phytohormone involvement in feedback regulation of cotton leaf senescence induced by potassium deficiency

    PubMed Central

    Tian, Xiaoli

    2012-01-01

    To elucidate the phytohormonal basis of the feedback regulation of leaf senescence induced by potassium (K) deficiency in cotton (Gossypium hirsutum L.), two cultivars contrasting in sensitivity to K deficiency were self- and reciprocally grafted hypocotyl-to-hypocotyl, using standard grafting (one scion grafted onto one rootstock), Y grafting (two scions grafted onto one rootstock), and inverted Y grafting (one scion grafted onto two rootstocks) at the seedling stage. K deficiency (0.03mM for standard and Y grafting, and 0.01mM for inverted Y grafting) increased the root abscisic acid (ABA) concentration by 1.6- to 3.1-fold and xylem ABA delivery rates by 1.8- to 4.6-fold. The K deficiency also decreased the delivery rates of xylem cytokinins [CKs; including the zeatin riboside (ZR) and isopentenyl adenosine (iPA) type] by 29–65% and leaf CK concentration by 16–57%. The leaf ABA concentration and xylem ABA deliveries were consistently greater in CCRI41 (more sensitive to K deficiency) than in SCRC22 (less sensitive to K deficiency) scions under K deficiency, and ZR- and iPA-type levels were consistently lower in the former than in the latter, irrespective of rootstock cultivar or grafting type, indicating that cotton shoot influences the levels of ABA and CKs in leaves and xylem sap. Because the scions had little influence on phytohormone levels in the roots (rootstocks) of all three types of grafts and rootstock xylem sap (collected below the graft union) of Y and inverted Y grafts, it appears that the site for basipetal feedback signal(s) involved in the regulation of xylem phytohormones is the hypocotyl of cotton seedlings. Also, the target of this feedback signal(s) is more likely to be the changes in xylem phytohormones within tissues of the hypocotyl rather than the export of phytohormones from the roots. PMID:22962680

  16. The effect of a moderate zinc deficiency and dietary fat source on the activity and expression of the Δ(3)Δ (2)-enoyl-CoA isomerase in the liver of growing rats.

    PubMed

    Justus, Jennifer; Weigand, Edgar

    2014-06-01

    Auxiliary enzymes participate in β-oxidation of unsaturated fatty acids. The objective of the study was to investigate the impact of a moderate zinc deficiency and a high intake of polyunsaturated fat on Δ(3)Δ(2)-enoyl-CoA isomerase (ECI) in the liver and other tissues. Five groups of eight weanling rats each were fed moderately zinc-deficient (ZD) or zinc-adequate (ZA) semisynthetic diets (7 or 50 mg Zn/kg) enriched with 22 % cocoa butter (CB) or 22 % safflower oil (SO) for 4 weeks: (1) ZD-CB, fed free choice; (2) ZA-CBR, ZA-CB diet fed in equivalent amounts consumed by the ZD-CB group; (3) ZD-SO, fed free choice; (4) ZA-SOR, ZA-SO diet fed in equivalent amounts consumed by the ZD-SO group; and (5) ZA-SO, fed free choice. Growth and Zn status markers were markedly reduced in the ZD groups. ECI activity in the liver of the animals fed the ZD- and ZA-SO diets were significantly higher (approximately 2- and 3-fold, respectively) as compared with the CB-fed animals, whereas activities in extrahepatic tissues (kidneys, heart, skeletal muscle, testes, adipose tissue) were not altered by dietary treatments. Transcript levels of the mitochondrial Eci gene in the liver did not significantly differ between ZD and ZA rats, but were 1.6-fold higher in the ZA-SO- than in the ZD-CB-fed animals (P < 0.05). It is concluded that diets enriched with safflower oil as a source high in linoleic acid induce markedly increased hepatic ECI activities and that a moderate Zn deficiency does not affect transcription of the mitochondrial Eci gene in the liver.

  17. Lamp-2 deficiency prevents high-fat diet-induced obese diabetes via enhancing energy expenditure

    SciTech Connect

    Yasuda-Yamahara, Mako; Kume, Shinji; Yamahara, Kosuke; Nakazawa, Jun; Chin-Kanasaki, Masami; Araki, Hisazumi; Araki, Shin-ichi; Koya, Daisuke; Haneda, Masakzu; Ugi, Satoshi; Maegawa, Hiroshi; Uzu, Takashi

    2015-09-18

    Autophagy process is essential for maintaining intracellular homeostasis and consists of autophagosome formation and subsequent fusion with lysosome for degradation. Although the role of autophagosome formation in the pathogenesis of diabetes has been recently documented, the role of the latter process remains unclear. This study analyzed high-fat diet (HFD)-fed mice lacking lysosome-associated membrane protein-2 (lamp-2), which is essential for the fusion with lysosome and subsequent degradation of autophagosomes. Although lamp-2 deficient mice showed little alteration in glucose metabolism under normal diet feeding, they showed a resistance against high-fat diet (HFD)-induced obesity, hyperinsulinemic hyperglycemia and tissues lipid accumulation, accompanied with higher energy expenditure. The expression levels of thermogenic genes in brown adipose tissue were significantly increased in HFD-fed lamp-2-deficient mice. Of some serum factors related to energy expenditure, the serum level of fibroblast growth factor (FGF) 21 and its mRNA expression level in the liver were significantly higher in HFD-fed lamp-2-deficient mice in an ER stress-, but not PPARα-, dependent manner. In conclusion, a lamp-2-depenedent fusion and degradation process of autophagosomes is involved in the pathogenesis of obese diabetes, providing a novel insight into autophagy and diabetes. - Highlights: • Lamp-2 is essential for autophagosome fusion with lysosome and its degradation. • Lamp-2 deficiency lead to a resistance to diet-induced obese diabetes in mice. • Lamp-2 deficiency increased whole body energy expenditure under HFD-feeding. • Lamp-2 deficiency elevated the serum level of FGF21 under HFD-feeding.

  18. Combined Tlr2 and Tlr4 Deficiency Increases Radiation-Induced Pulmonary Fibrosis in Mice

    SciTech Connect

    Paun, Alexandra; Fox, Jessica; Balloy, Viviane; Chignard, Michel; Qureshi, Salman T.; Haston, Christina K.

    2010-07-15

    Purpose: To determine whether Toll-like receptor 2 or 4 genotype alters the lung response to irradiation in C57BL/6 mice using a model developing a phenotype that resembles radiotherapy-induced fibrosis in both histological characteristics and onset post-treatment. Methods and Materials: The pulmonary phenotype of C57BL/6 mice deficient in each or both of these genes was assessed after an 18-Gy single dose to the thoracic cavity by survival time postirradiation, bronchoalveolar lavage cell differential, histological evidence of alveolitis and fibrosis, and gene expression levels, and compared with that of wild-type mice. Results: The lung phenotype of Tlr4-deficient and Tlr2-deficient mice did not differ from that of wild-type mice in terms of survival time postirradiation, or by histological evidence of alveolitis or fibrosis. In contrast, mice deficient in both receptors developed respiratory distress at an earlier time than did wild-type mice and presented an enhanced fibrotic response (13.5% vs. 5.8% of the lung by image analysis of histological sections, p < 0.001). No differences in bronchoalveolar cell differential counts, nor in numbers of apoptotic cells in the lung as detected through active caspase-3 staining, were evident among the irradiated mice grouped by Tlr genotype. Gene expression analysis of lung tissue revealed that Tlr2,4-deficient mice have increased levels of hyaluronidase 2 compared with both wild-type mice and mice lacking either Tlr2 or Tlr4. Conclusion: We conclude that a combined deficiency in both Tlr2 and Tlr4, but not Tlr2 or Tlr4 alone, leads to enhanced radiation-induced fibrosis in the C57BL/6 mouse model.

  19. Resistin deficiency in mice has no effect on pulmonary responses induced by acute ozone exposure

    PubMed Central

    Razvi, Shehla S.; Richards, Jeremy B.; Malik, Farhan; Cromar, Kevin R.; Price, Roger E.; Bell, Cynthia S.; Weng, Tingting; Atkins, Constance L.; Spencer, Chantal Y.; Cockerill, Katherine J.; Alexander, Amy L.; Blackburn, Michael R.; Alcorn, Joseph L.; Haque, Ikram U.

    2015-01-01

    Acute exposure to ozone (O3), an air pollutant, causes pulmonary inflammation, airway epithelial desquamation, and airway hyperresponsiveness (AHR). Pro-inflammatory cytokines—including IL-6 and ligands of chemokine (C-X-C motif) receptor 2 [keratinocyte chemoattractant (KC) and macrophage inflammatory protein (MIP)-2], TNF receptor 1 and 2 (TNF), and type I IL-1 receptor (IL-1α and IL-1β)—promote these sequelae. Human resistin, a pleiotropic hormone and cytokine, induces expression of IL-1α, IL-1β, IL-6, IL-8 (the human ortholog of murine KC and MIP-2), and TNF. Functional differences exist between human and murine resistin; yet given the aforementioned observations, we hypothesized that murine resistin promotes O3-induced lung pathology by inducing expression of the same inflammatory cytokines as human resistin. Consequently, we examined indexes of O3-induced lung pathology in wild-type and resistin-deficient mice following acute exposure to either filtered room air or O3. In wild-type mice, O3 increased bronchoalveolar lavage fluid (BALF) resistin. Furthermore, O3 increased lung tissue or BALF IL-1α, IL-6, KC, TNF, macrophages, neutrophils, and epithelial cells in wild-type and resistin-deficient mice. With the exception of KC, which was significantly greater in resistin-deficient compared with wild-type mice, no genotype-related differences in the other indexes existed following O3 exposure. O3 caused AHR to acetyl-β-methylcholine chloride (methacholine) in wild-type and resistin-deficient mice. However, genotype-related differences in airway responsiveness to methacholine were nonexistent subsequent to O3 exposure. Taken together, these data demonstrate that murine resistin is increased in the lungs of wild-type mice following acute O3 exposure but does not promote O3-induced lung pathology. PMID:26386120

  20. Benzo(a)pyrene induced lung cancer: Role of dietary phytochemicals in chemoprevention.

    PubMed

    Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Barua, Chandana C; Sriram, Chandra Shekhar; Gogoi, Ranadeep

    2015-10-01

    Lung cancer is the major cause of overall cancer deaths, and chemoprevention is a promising strategy to control this disease. Benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon, is one among the principal constituents of tobacco smoke that plays a key role in lung carcinogenesis. The B(a)P induced lung cancer in mice offers a relevant model to study the effect of natural products and has been widely used by many researchers and found considerable success in ameliorating the pathophysiological changes of lung cancer. Currently available synthetic drugs that constitute the pharmacological armamentarium are themselves effective in managing the condition but not without setbacks. These hunches have accelerated the requisite for natural products, which may be used as dietary supplement to prevent the progress of lung cancer. Besides, these agents also supplement the conventional treatment and offer better management of the condition with less side effects. In the context of soaring interest toward dietary phytochemicals as newer pharmacological interventions for lung cancer, in the present review, we are attempting to give a silhouette of mechanisms of B(a)P induced lung carcinogenesis and the role of dietary phytochemicals in chemoprevention.

  1. Benefits of dietary phytochemical supplementation on eccentric exercise-induced muscle damage: Is including antioxidants enough?

    PubMed

    Pereira Panza, Vilma Simões; Diefenthaeler, Fernando; da Silva, Edson Luiz

    2015-09-01

    The purpose of this review was to critically discuss studies that investigated the effects of supplementation with dietary antioxidant phytochemicals on recovery from eccentric exercise-induced muscle damage. The performance of physical activities that involve unaccustomed eccentric muscle actions-such as lowering a weight or downhill walking-can result in muscle damage, oxidative stress, and inflammation. These events may be accompanied by muscle weakness and delayed-onset muscle soreness. According to the current evidences, supplementation with dietary antioxidant phytochemicals appears to have the potential to attenuate symptoms associated with eccentric exercise-induced muscle damage. However, there are inconsistencies regarding the relationship between muscle damage and blood markers of oxidative stress and inflammation. Furthermore, the effectiveness of strategies appear to depend on a number of aspects inherent to phytochemical compounds as well as its food matrix. Methodological issues also may interfere with the proper interpretation of supplementation effects. Thus, the study may contribute to updating professionals involved in sport nutrition as well as highlighting the interest of scientists in new perspectives that can widen dietary strategies applied to training.

  2. Nitric oxide ameliorates the damaging effects of oxidative stress induced by iron deficiency in cyanobacterium Anabaena 7120.

    PubMed

    Kaushik, Manish Singh; Srivastava, Meenakshi; Srivastava, Alka; Singh, Anumeha; Mishra, Arun Kumar

    2016-11-01

    In cyanobacterium Anabaena 7120, iron deficiency leads to oxidative stress with unavoidable consequences. Nitric oxide reduces pigment damage and supported the growth of Anabaena 7120 in iron-deficient conditions. Elevation in nitric oxide accumulation and reduced superoxide radical production justified the role of nitric oxide in alleviating oxidative stress in iron deficiency. Increased activities of antioxidative enzymes and higher levels of ROS scavengers (ascorbate, glutathione and thiol) in iron deficiency were also observed in the presence of nitric oxide. Nitric oxide also supported the membrane integrity of Anabaena cells and reduces protein and DNA damage caused by oxidative stress induced by iron deficiency. Results suggested that nitric oxide alleviates the damaging effects of oxidative stress induced by iron deficiency in cyanobacterium Anabaena 7120.

  3. Extracellular norepinephrine, norepinephrine receptor and transporter protein and mRNA levels are differentially altered in the developing rat brain due to dietary iron deficiency and manganese exposure.

    PubMed

    Anderson, Joel G; Fordahl, Steven C; Cooney, Paula T; Weaver, Tara L; Colyer, Christa L; Erikson, Keith M

    2009-07-24

    Manganese (Mn) is an essential trace element, but overexposure is characterized by Parkinson's like symptoms in extreme cases. Previous studies have shown that Mn accumulation is exacerbated by dietary iron deficiency (ID) and disturbances in norepinephrine (NE) have been reported. Because behaviors associated with Mn neurotoxicity are complex, the goal of this study was to examine the effects of Mn exposure and ID-associated Mn accumulation on NE uptake in synaptosomes, extracellular NE concentrations, and expression of NE transport and receptor proteins. Sprague-Dawley rats were assigned to four dietary groups: control (CN; 35 mg Fe/kg diet), iron-deficient (ID; 6 mg Fe/kg diet), CN with Mn exposure (via the drinking water; 1 g Mn/L) (CNMn), and ID with Mn (IDMn). (3)H-NE uptake decreased significantly (R=-0.753, p=0.001) with increased Mn concentration in the locus coeruleus, while decreased Fe was associated with decreased uptake of (3)H-NE in the caudate putamen (R=0.436, p=0.033) and locus coeruleus (R=0.86; p<0.001). Extracellular concentrations of NE in the caudate putamen were significantly decreased in response to Mn exposure and ID (p<0.001). A diverse response of Mn exposure and ID was observed on mRNA and protein expression of NE transporter (NET) and alpha(2) adrenergic receptor. For example, elevated brain Mn and decreased Fe caused an approximate 50% decrease in NET and alpha(2) adrenergic receptor protein expression in several brain regions, with reductions in mRNA expression also observed. These data suggest that Mn exposure results in a decrease in NE uptake and extracellular NE concentrations via altered expression of transport and receptor proteins.

  4. Dietary Curcumin Increases Antioxidant Defenses in Lung, Ameliorates Radiation-Induced Pulmonary Fibrosis, and Improves Survival in Mice

    PubMed Central

    Lee, James C.; Kinniry, Paul A.; Arguiri, Evguenia; Serota, Matthew; Kanterakis, Stathis; Chatterjee, Shampa; Solomides, Charalambos C.; Javvadi, Prashanthi; Koumenis, Constantinos; Cengel, Keith A.; Christofidou-Solomidou, Melpo

    2010-01-01

    The effectiveness of lung radiotherapy is limited by radiation tolerance of normal tissues and by the intrinsic radiosensitivity of lung cancer cells. The chemopreventive agent curcumin has known antioxidant and tumor cell radiosensitizing properties. Its usefulness in preventing radiation-induced pneumonopathy has not been tested previously. We evaluated dietary curcumin in radiation-induced pneumonopathy and lung tumor regression in a murine model. Mice were given 1%or 5%(w/w) dietary curcumin or control diet prior to irradiation and for the duration of the experiment. Lungs were evaluated at 3 weeks after irradiation for acute lung injury and inflammation by evaluating bronchoalveolar lavage (BAL) fluid content for proteins, neutrophils and at 4 months for pulmonary fibrosis. In a separate series of experiments, an orthotopic model of lung cancer using intravenously injected Lewis lung carcinoma (LLC) cells was used to exclude possible tumor radioprotection by dietary curcumin. In vitro, curcumin boosted antioxidant defenses by increasing heme oxygenase 1 (HO-1) levels in primary lung endothelial and fibroblast cells and blocked radiation-induced generation of reactive oxygen species (ROS). Dietary curcumin significantly increased HO-1 in lungs as early as after 1 week of feeding, coinciding with a steady-state level of curcumin in plasma. Although both 1% and 5% w/w dietary curcumin exerted physiological changes in lung tissues by significantly decreasing LPS-induced TNF-α production in lungs, only 5%dietary curcumin significantly improved survival of mice after irradiation and decreased radiation-induced lung fibrosis. Importantly, dietary curcumin did not protect LLC pulmonary metastases from radiation killing. Thus dietary curcumin ameliorates radiation-induced pulmonary fibrosis and increases mouse survival while not impairing tumor cell killing by radiation. PMID:20426658

  5. Fish oil supplementation maintains adequate plasma arachidonate in cats, but similar amounts of vegetable oils lead to dietary arachidonate deficiency from nutrient dilution.

    PubMed

    Angell, Rebecca J; McClure, Melena K; Bigley, Karen E; Bauer, John E

    2012-05-01

    Because fatty acid (FA) metabolism of cats is unique, effects of dietary fish and vegetable oil supplementation on plasma lipids, lipoproteins, lecithin/cholesterol acyl transferase activities, and plasma phospholipid and esterified cholesterol (EC) FAs were investigated. Cats were fed a commercial diet supplemented with 8 g oil/100 g diet for 4 weeks using either high-oleic-acid sunflower oil (diet H), Menhaden fish oil (diet M), or safflower oil (diet S). When supplemented, diet M contained sufficient arachidonate (AA), but diets H and S were deficient. We hypothesized that diet M would modify plasma lipid metabolism, increase FA long-chain n-3 (LCn-3) FA content but not deplete AA levels. Also, diet S would show linoleic acid (LA) accumulation without conversion to AA, and both vegetable oil supplements would dilute dietary AA content when fed to meet cats' energy needs. Plasma samples on weeks 0, 2, and 4 showed no alterations in total cholesterol or nonesterified FA concentrations. Unesterified cholesterol decreased and EC increased in all groups, whereas lecithin/cholesterol acyl transferase activities were unchanged. Diet M showed significant triacylglycerol lowering and decreased pre-β-lipoprotein cholesterol. Plasma phospholipid FA profiles revealed significant enrichment of 18:1n-9 with diet H, LA and 20:2n-6 with diet S, and FA LCn-3FA with diet M. Depletion of AA was observed with diets H and S but not with diet M. Diet M EC FA profiles revealed specificities for LA and 20:5n-3 but not 22:5n-3 or 22:6n-3. Oversupplementation of some commercial diets with vegetable oils causes AA depletion in young cats due to dietary dilution. Findings are consistent with the current recommendations for at least 0.2 g AA/kg diet and that fish oil supplements provide both preformed LCn-3 polyunsaturated FA and AA.

  6. Aryl hydrocarbon receptor deficiency in T cells suppresses the development of collagen-induced arthritis

    PubMed Central

    Nakahama, Taisuke; Kimura, Akihiro; Nguyen, Nam Trung; Chinen, Ichino; Hanieh, Hamza; Nohara, Keiko; Fujii-Kuriyama, Yoshiaki; Kishimoto, Tadamitsu

    2011-01-01

    The contributions of aryl hydrocarbon receptor (Ahr) to the pathogenesis of rheumatoid arthritis have not been elucidated. Here, we show that Ahr deficiency ameliorated collagen-induced arthritis, a mouse model of RA. Collagen-immunized Ahr KO mice showed decreased serum levels of such proinflammatory cytokines as IL-1β and IL-6. The Th17 and Th1 cell populations in lymph nodes from these mice decreased and increased, respectively, whereas the percentage of regulatory T cells was unchanged. Interestingly, a lack of Ahr specifically in T cells significantly suppressed collagen-induced arthritis development, whereas Ahr deficiency in macrophages had no effect. These finding indicate that the development of experimental autoimmune arthritis depends on the presence of Ahr in T cells, and that Th1/Th17 balance may be particularly important for this process. PMID:21825138

  7. Mice deficient in Group VIB phospholipase A2 (iPLA2γ) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet

    PubMed Central

    Song, Haowei; Wohltmann, Mary; Bao, Shunzhong; Ladenson, Jack H.; Semenkovich, Clay F.

    2010-01-01

    Phospholipases A2 (PLA2) play important roles in metabolic processes, and the Group VI PLA2 family is comprised of intracellular enzymes that do not require Ca2+ for catalysis. Mice deficient in Group VIA PLA2 (iPLA2β) develop more severe glucose intolerance than wild-type (WT) mice in response to dietary stress. Group VIB PLA2 (iPLA2γ) is a related enzyme distributed in membranous organelles, including mitochondria, and iPLA2γ knockout (KO) mice exhibit altered mitochondrial morphology and function. We have compared metabolic responses of iPLA2γ-KO and WT mice fed a Western diet (WD) with a high fat content. We find that KO mice are resistant to WD-induced increases in body weight and adiposity and in blood levels of cholesterol, glucose, and insulin, even though WT and KO mice exhibit similar food consumption and dietary fat digestion and absorption. KO mice are also relatively resistant to WD-induced insulin resistance, glucose intolerance, and altered patterns of fat vs. carbohydrate fuel utilization. KO skeletal muscle exhibits impaired mitochondrial β-oxidation of fatty acids, as reflected by accumulation of larger amounts of long-chain acylcarnitine (LCAC) species in KO muscle and liver compared with WT in response to WD feeding. This is associated with increased urinary excretion of LCAC and much reduced deposition of triacylglycerols in liver by WD-fed KO compared with WT mice. The iPLA2γ-deficient genotype thus results in a phenotype characterized by impaired mitochondrial oxidation of fatty acids and relative resistance to the metabolic abnormalities induced by WD. PMID:20179248

  8. Dietary polyphenols generate nitric oxide from nitrite in the stomach and induce smooth muscle relaxation.

    PubMed

    Rocha, Bárbara S; Gago, Bruno; Barbosa, Rui M; Laranjinha, João

    2009-11-09

    Nitrite, considered a biological waste and toxic product, is being regarded as an important physiological molecule in nitric oxide (NO) biochemistry. Because the interaction of dietary phenolic compounds and nitrite would be kinetically (due to the high concentrations achieved) and thermodynamically (on basis of the redox potentials) feasible in the stomach, we have studied the potential reduction of nitrite by polyphenols present in several dietary sources. By measuring the time courses of *NO production in simulated gastric juice (pH 2), the efficiency of the compounds studied is as follows: Epicatechin-3-O-gallate>quercetin>procyanidin B8 dimer>oleuropein>procyanidin B2 dimer>chlorogenic acid>epicatechin>catechin>procyanidin B5 dimer. The initial rates of *NO production fall in a narrow range (ca. 1-5 microMs(-1)) but the distinct kinetics of the decay of *NO signals suggest that competition reactions for *NO are operative. The proof of concept that, in the presence of nitrite, phenol-containing dietary products induce a strong increase of *NO in the stomach was established in an in vivo experiment with healthy volunteers consuming lettuce, onions, apples, wine, tea, berries and cherries. Moreover, selected mixtures of oleuropein and catechin with low nitrite (1 microM) were shown to induce muscle relaxation of stomach strips in a structure-dependent way. Data presented here brings strong support to the concept that polyphenols consumed in a variety of dietary products, under gastric conditions, reduce nitrite to *NO that, in turn, may exert a biological impact as a local relaxant.

  9. Dietary medium-chain triglycerides prevent chemically induced experimental colitis in rats.

    PubMed

    Kono, Hiroshi; Fujii, Hideki; Ishii, Kenichi; Hosomura, Naohiro; Ogiku, Masahito

    2010-03-01

    The effects of dietary medium-chain triglycerides (MCTs) on experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid (TNBS) were investigated in rats. Male Wistar rats were given an intracolonic injection of TNBS and were then fed liquid diets containing MCTs or corn oil (AIN93) as controls. Serum and tissue samples were collected 1 week after TNBS enema. The severity of colitis was evaluated pathologically, and tissue myeloperoxidase (MPO) activity was measured. Furthermore, messenger RNA (mRNA) and protein levels for inflammatory cytokines and a chemokine were assessed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. In another set of experiments, the protein expression of Toll-like receptor (TLR)-4 in the colon was measured 1 week after feeding of liquid diets. To investigate the effects of MCTs on macrophages, RAW246.7 macrophages were incubated with media containing albumin conjugated with MCT or linoleic acid, which is the major component of corn oil. Then, the production of tumor necrosis factor-alpha (TNF-alpha) was measured. Dietary MCTs blunted significantly the protein levels of TLR-4 in the colon. Furthermore, the expression of TLR-4 was significantly blunted in RAW264.7 cells incubated with MCTs compared with cells incubated with linoleic acid. Induction of interleukin 1beta (IL-1beta), TNF-alpha, and macrophage inflammatory protein-2 (MIP-2) in the colon was attenuated by dietary MCT. Furthermore, MPO activities in the colonic tissue were significantly blunted in animals fed the MCT diets compared with those fed the control diets. As a result, dietary MCTs improved chemically induced colitis significantly. MCTs most likely are useful for the therapy of inflammatory bowel disease as an anti-inflammatory immunomodulating nutrient.

  10. C5a receptor signaling prevents folate deficiency-induced neural tube defects in mice.

    PubMed

    Denny, Kerina J; Coulthard, Liam G; Jeanes, Angela; Lisgo, Steven; Simmons, David G; Callaway, Leonie K; Wlodarczyk, Bogdan; Finnell, Richard H; Woodruff, Trent M; Taylor, Stephen M

    2013-04-01

    The complement system is involved in a range of diverse developmental processes, including cell survival, growth, differentiation, and regeneration. However, little is known about the role of complement in embryogenesis. In this study, we demonstrate a novel role for the canonical complement 5a receptor (C5aR) in the development of the mammalian neural tube under conditions of maternal dietary folic acid deficiency. Specifically, we found C5aR and C5 to be expressed throughout the period of neurulation in wild-type mice and localized the expression to the cephalic regions of the developing neural tube. C5aR was also found to be expressed in the neuroepithelium of early human embryos. Ablation of the C5ar1 gene or the administration of a specific C5aR peptide antagonist to folic acid-deficient pregnant mice resulted in a high prevalence of severe anterior neural tube defect-associated congenital malformations. These findings provide a new and compelling insight into the role of the complement system during mammalian embryonic development.

  11. RAGE deficiency attenuates the protective effect of Lidocaine against sepsis-induced acute lung injury.

    PubMed

    Zhang, Zhuo; Zhou, Jie; Liao, Changli; Li, Xiaobing; Liu, Minghua; Song, Daqiang; Jiang, Xian

    2017-04-01

    Lidocaine (Lido) is reported to suppress inflammatory responses and exhibit a therapeutic effect in models of cecal ligation and puncture (CLP)-induced acute lung injury (ALI). The receptor for advanced glycation end product (RAGE) exerts pro-inflammatory effects by enhancing pro-inflammatory cytokine production. However, the precise mechanism by which Lido confers protection against ALI is not clear. ALI was induced in RAGE WT and RAGE knockout (KO) rats using cecal ligation and puncture (CLP) operations for 24 h. The results showed that Lido significantly inhibited CLP-induced lung inflammation and histopathological lung injury. Furthermore, Lido significantly reduced CLP-induced upregulation of HMGB1 and RAGE expression and activation of the NF-κB and MAPK signaling pathways. With the use of RAGE KO rats, we demonstrate here that RAGE deficiency attenuates the protective effect of Lido against CLP-induced lung inflammatory cell infiltration and histopathological lung injury. These results suggest that RAGE deficiency attenuates the protective effect of Lido against CLP-induced ALI by attenuating the pro-inflammatory cytokines production.

  12. Effect of copper deficiency on cocaine-induced seizures in rats

    SciTech Connect

    Kishore, V. )

    1991-03-11

    The objective of the present study was to study the effects of nutritional copper (Cu) deficiency on cocaine-induced seizures in rats. Following results were obtained when cocaine was given to 10 each of Cu-deficient (CUD) and Cu-sufficient (CUS) rats after 45 days on respective diets. For CUD and CUS groups of rats, respectively, (a) incidence of seizures was 60% and 40%; (b) time of onset for seizures was 8.42 {plus minus} 0.72 and 7.63 {plus minus} 1.00; (c) seizure severity was 2.5 {plus minus} 0.75 and 1.1 {plus minus} 0.45; and (d) 24 h mortality was 40% and none. Thus, except for time of onset, all other parameters for cocaine-induced seizures were significantly higher in CUD rats. These results clearly demonstrate that Cu deficiency enhances seizure-inducing effects of cocaine in rats. It is likely that the enhancement observed is due to a decrease in the hepatic metabolism of cocaine in CUD rats. This possibility is currently being investigated.

  13. Protease-activated receptor-1 deficiency protects against streptozotocin-induced diabetic nephropathy in mice

    PubMed Central

    Waasdorp, Maaike; Duitman, JanWillem; Florquin, Sandrine; Spek, C. Arnold

    2016-01-01

    Endogenously administered activated protein C ameliorates diabetic nephropathy (DN) in a protease-activated receptor-1 (PAR-1)-dependent manner, suggesting that PAR-1 activation limits the progression of DN. Activation of PAR-1 in fibroblast-like cells, however, induces proliferation and extracellular matrix production, thereby driving fibrotic disease. Considering the key role of mesangial proliferation and extracellular matrix production during DN, PAR-1 may in fact potentiate diabetes-induced kidney injury. To determine the net effect of PAR-1 in DN, streptozotocin-induced DN was studied in wild type and PAR-1 deficient mice. Subsequent mechanistic insight was obtained by assessing profibrotic responses of mesangial and tubular epithelial cells in vitro, following PAR-1 stimulation and inhibition. Despite having similar glucose levels, PAR-1 deficient mice developed less kidney damage after induction of diabetes, as evidenced by diminished proteinuria, plasma cystatin C levels, expansion of the mesangial area, and tubular atrophy. In vitro, PAR-1 signaling in mesangial cells led to increased proliferation and expression of matrix proteins fibronectin and collagen IV. Conversely, a reduction in both proliferation and fibronectin deposition was observed in diabetic PAR-1 deficient mice. Overall, we show that PAR-1 plays an important role in the development of DN and PAR-1 might therefore be an attractive therapeutic target to pursue in DN. PMID:27618774

  14. Pancreas Recovery Following Caerulein-induced Pancreatitis is Impaired in Plasminogen Deficient Mice

    PubMed Central

    Lugea, Aurelia; Nan, Li; French, Samuel W.; Bezerra, Jorge A.; Gukovskaya, Anna S; Pandol, Stephen J.

    2006-01-01

    Background & Aims: The plasminogen (plg) system participates in tissue repair in several organs, but its role in pancreas repair remains poorly characterized. To better understand the role of plg in pancreas recovery following injury, we examined the course of caerulein-induced pancreatitis in plg deficient and sufficient mice. Methods: Pancreatitis was induced by caerulein administration (50 μg/kg, 7 ip injections). Mice were sacrificed either at the acute phase (7 hours after the first caerulein injection) or during recovery (at 2, 4 and 7 days). In pancreatic sections we examined: pancreatic morphology, trypsin activation, inflammatory cell infiltration, acinar cell death, cell proliferation, extracellular matrix (ECM) deposition, activation of stellate cells (PSCs), and components of the plg and metalloproteinase systems. Results: In plg sufficient mice, pancreatic plg levels and plasmin activity increased during the acute phase and remained elevated during recovery. Pancreatitis resolved in plg sufficient mice within 7 days. Pancreas recovery involved reorganization of the parenchyma structure, removal of necrotic debris, cell proliferation, transient activation of PSCs and moderate deposition of ECM proteins. Acute pancreatitis (7-h) was indistinguishable between plg deficient and sufficient mice. In contrast, pancreas recovery was impaired in plg deficient mice. Plg deficiency led to disorganized parenchyma, extensive acinar cell loss, poor removal of necrotic debris, reduced cell proliferation and fibrosis. Fibrosis was characterized by deposition of collagens and fibronectin, persistent activation of PSCs and upregulation of pancreatic TGF-β1. Conclusions: Plg/plasmin deficiency leads to features similar to those found in chronic pancreatitis such as parenchymal atrophy and fibrosis. PMID:16952557

  15. Dietary fiber suppresses elevation of uric acid and urea nitrogen concentrations in serum of rats with renal dysfunction induced by dietary adenine.

    PubMed

    Koguchi, Takashi; Koguchi, Hiromi; Nakajima, Hisao; Takano, Saburo; Yamamoto, Yuji; Innami, Satoshi; Maekawa, Akio; Tadokoro, Tadahiro

    2004-07-01

    This study was conducted to examine the effects of several kinds of dietary fiber (DF) with different physical properties on the elevation of uric acid and urea nitrogen concentrations in serum of rats induced by dietary adenine. DF decreased an uptake of 14C-labeled adenine in the rat jejunum in vitro, but the reduction varied with the physical property of DF. Male Wistar rats (3 weeks old) were fed a diet with or without a 0.4% adenine and a 5% DF (cellulose, chitin, chitosan, or xanthan gum) for 20 days. Feeding of adenine in the fiber-free group elevated the concentrations of uric acid, creatinine, and urea nitrogen in serum, but decreased the excretions of these compounds into urine and increased the amounts of 2,8-dihydroxyadenine (2,8-DHA) in kidney and urine. The test DF was found to suppress the elevation of uric acid, creatinine, and urea nitrogen concentrations in serum induced by dietary adenine, and to mitigate the decreased excretions of these compounds into urine and the increased retention of 2,8-DHA in kidney and urine. This phenomenon was remarkable in the xanthan gum group. These results suggest that DF suppresses the elevation of uric acid and urea nitrogen concentrations in serum by attenuating the absorption of dietary adenine.

  16. Nitric oxide is involved in phosphorus deficiency-induced cluster root development and citrate exudation in white lupin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    White lupin (Lupinus albus) forms specialized cluster roots characterized by exudation of organic anions under phosphorus (P) deficiency. Here, we evaluated the role of nitric oxide (NO) in P deficiency-induced cluster-root formation and citrate exudation in white lupin. Plants were treated with NO ...

  17. Occurrence of cleft-palate and alteration of Tgf-β(3) expression and the mechanisms leading to palatal fusion in mice following dietary folic-acid deficiency.

    PubMed

    Maldonado, Estela; Murillo, Jorge; Barrio, Carmen; del Río, Aurora; Pérez-Miguelsanz, Juliana; López-Gordillo, Yamila; Partearroyo, Teresa; Paradas, Irene; Maestro, Carmen; Martínez-Sanz, Elena; Varela-Moreiras, Gregorio; Martínez-Álvarez, Concepción

    2011-01-01

    Folic acid (FA) is essential for numerous bodily functions. Its decrease during pregnancy has been associated with an increased risk of congenital malformations in the progeny. The relationship between FA deficiency and the appearance of cleft palate (CP) is controversial, and little information exists on a possible effect of FA on palate development. We investigated the effect of a 2-8 weeks' induced FA deficiency in female mice on the development of CP in their progeny as well as the mechanisms leading to palatal fusion, i.e. cell proliferation, cell death, and palatal-shelf adhesion and fusion. We showed that an 8 weeks' maternal FA deficiency caused complete CP in the fetuses although a 2 weeks' maternal FA deficiency was enough to alter all the mechanisms analyzed. Since transforming growth factor-β(3) (TGF-β(3)) is crucial for palatal fusion and since most of the mechanisms impaired by FA deficiency were also observed in the palates of Tgf-β(3)null mutant mice, we investigated the presence of TGF-β(3) mRNA, its protein and phospho-SMAD2 in FA-deficient (FAD) mouse palates. Our results evidenced a large reduction in Tgf-β(3) expression in palates of embryos of dams fed an FAD diet for 8 weeks; Tgf-β(3) expression was less reduced in palates of embryos of dams fed an FAD diet for 2 weeks. Addition of TGF-β(3) to palatal-shelf cultures of embryos of dams fed an FAD diet for 2 weeks normalized all the altered mechanisms. Thus, an insufficient folate status may be a risk factor for the development of CP in mice, and exogenous TGF-β(3) compensates this deficit in vitro.

  18. Prevalence of prenatal zinc deficiency and its association with socio-demographic, dietary and health care related factors in Rural Sidama, Southern Ethiopia: A cross-sectional study

    PubMed Central

    2011-01-01

    Background Several studies witnessed that prenatal zinc deficiency (ZD) predisposes to diverse pregnancy complications. However, scientific evidences on the determinants of prenatal ZD are scanty and inconclusive. The purpose of the present study was to assess the prevalence and determinants of prenatal ZD in Sidama zone, Southern Ethiopia. Methods A community based, cross-sectional study was conducted in Sidama zone in January and February 2011. Randomly selected 700 pregnant women were included in the study. Data on potential determinants of ZD were gathered using a structured questionnaire. Serum zinc concentration was measured using Atomic Absorption Spectrometry. Statistical analysis was done using logistic regression and linear regression. Results The mean serum zinc concentration was 52.4 (+/-9.9) μg/dl (95% CI: 51.6-53.1 μg/dl). About 53.0% (95% CI: 49.3-56.7%) of the subjects were zinc deficient. The majority of the explained variability of serum zinc was due to dietary factors like household food insecurity level, dietary diversity and consumption of animal source foods. The risk of ZD was 1.65 (95% CI: 1.02-2.67) times higher among women from maize staple diet category compared to Enset staple diet category. Compared to pregnant women aged 15-24 years, those aged 25-34 and 35-49 years had 1.57 (95% CI: 1.04-2.34) and 2.18 (95% CI: 1.25-3.63) times higher risk of ZD, respectively. Women devoid of self income had 1.74 (95% CI: 1.11-2.74) time increased risk than their counterparts. Maternal education was positively associated to zinc status. Grand multiparas were 1.74 (95% CI: 1.09-3.23) times more likely to be zinc deficient than nulliparas. Frequency of coffee intake was negatively association to serum zinc level. Positive association was noted between serum zinc and hemoglobin concentrations. Altitude, history of iron supplementation, maternal workload, physical access to health service, antenatal care and nutrition education were not associated to

  19. Genotypic variability within Tunisian grapevine varieties (Vitis vinifera L.) facing bicarbonate-induced iron deficiency.

    PubMed

    Ksouri, Riadh; Debez, Ahmed; Mahmoudi, Henda; Ouerghi, Zeineb; Gharsalli, Mohamed; Lachaâl, Mokhtar

    2007-05-01

    Morpho-physiological responses to bicarbonate-induced Fe deficiency were investigated in five Vitis vinifera L. Tunisian varieties (Khamri, Blanc3, Arich Dressé, Beldi, and Balta4). One-month-old woody cuttings were cultivated for 85days on a free calcareous soil irrigated with tap water containing increasing bicarbonate levels (0, 4, 8, 12, and 16mM NaHCO(3)). After this screening, a second experiment compared root biochemical responses of two contrasting genotypes (tolerant-sensitive) dealing with bicarbonate-induced iron deprivation (20microM Fe+/-10mM HCO(3)(-)) for 75days. Using morpho-physiological criteria, grapevine tolerance to HCO(3)(-)-induced Fe shortage appeared to be genotype-dependent: Balta4 and Beldi varieties showed the highest leaf-chlorosis score (especially at the extreme HCO(3)(-) levels), in contrast to Khamri variety. Growth parameters (shoot height, total leaf area, leaf number, and biomass production) as well as juvenile leaf chlorophyll content were also differently affected depending on both genotype and bicarbonate dose. At 16mM HCO(3)(-), Khamri was the less sensitive variety, contrasting with Balta4. On the other hand, chlorophyll content correlated positively with HCl-extractible Fe content of the juvenile leaves, suggesting that the grapevine response to iron deficiency may partly depend on to the plant ability to adequately supply young leaves with this element. Root biochemical responses revealed a relatively higher root acidification capacity in Khamri (tolerant) under Fe-deficiency while no significant changes occurred in Balta4 (sensitive). In addition, Fe(III)-reductase and phosphoenolpyruvate carboxylase (PEPC, EC 4.1.1.31) activities were strongly stimulated by Fe-deficiency in Khamri, while remaining constant in Balta4. These findings suggest that biochemical parameters may constitute reliable criteria for the selection of tolerant grapevine genotypes to iron chlorosis.

  20. Effect of expectoration on inflammation in induced sputum in alpha-1-antitrypsin deficiency.

    PubMed

    Gompertz, Simon; Hill, Adam T; Bayley, Darren L; Stockley, Robert A

    2006-06-01

    It is unclear how chronic expectoration influences airway inflammation in patients with chronic lung disease. The aim of this study was to investigate factors influencing inflammation in induced sputum samples, including, in particular, chronic sputum production. Myeloperoxidase, interleukin-8, leukotriene B4 (LTB4), neutrophil elastase, secretory leukoprotease inhibitor (SLPI) and protein leakage were compared in induced sputum samples from 48 patients (36 with chronic expectoration) with COPD (with and without alpha-1-antitrypsin deficiency; AATD), 9 individuals with AATD but without lung disease and 14 healthy controls. There were no differences in inflammation in induced sputum samples from healthy control subjects and from AATD deficient patients with normal lung function but without chronic expectoration (P>0.05). Inflammation in induced sputum from AATD patients with airflow obstruction and chronic sputum expectoration was significantly greater than for similar patients who did not expectorate: Interleukin-8 (P<0.01), elastase activity (P=0.01), and protein leakage (P<0.01). The presence of spontaneous sputum expectoration in AATD patients with airflow obstruction was associated with increased neutrophilic airway inflammation in induced sputum samples. The presence of chronic expectoration in some patients will clearly complicate interpretation of studies employing sputum induction where this feature has not been identified.

  1. Dietary homocysteine promotes atherosclerosis in apoE-deficient mice by inducing scavenger receptors expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Elevated plasma homocysteine (Hcy) levels have been recognized as an independent risk factor for cardiovascular and cerebrovascular diseases. However, the causative mechanisms have not been delineated. Scavenger receptors such as scavenger receptor-AI/II (SR-A), CD36, and lectin-like oxidized LDL ...

  2. Animal Models for the Study of the Relationships between Diet and Obesity: A Focus on Dietary Protein and Estrogen Deficiency.

    PubMed

    Chalvon-Demersay, Tristan; Blachier, François; Tomé, Daniel; Blais, Anne

    2017-01-01

    Obesity is an increasing major public health concern asking for dietary strategies to limit weight gain and associated comorbidities. In this review, we present animal models, particularly rats and mice, which have been extensively used by scientists to understand the consequences of diet quality on weight gain and health. Notably, modulation of dietary protein quantity and/or quality has been shown to exert huge effects on body composition homeostasis through the modulation of food intake, energy expenditure, and metabolic pathways. Interestingly, the perinatal window appears to represent a critical period during which the protein intake of the dam can impact the offspring's weight gain and feeding behavior. Animal models are also widely used to understand the processes and mechanisms that contribute to obesity at different physiological and pathophysiological stages. An interesting example of such aspect is the situation of decreased estrogen level occurring at menopause, which is linked to weight gain and decreased energy expenditure. To study metabolic disorders associated with such situation, estrogen withdrawal in ovariectomized animal models to mimic menopause are frequently used. According to many studies, clear species-specific differences exist between rats and mice that need to be taken into account when results are extrapolated to humans.

  3. Animal Models for the Study of the Relationships between Diet and Obesity: A Focus on Dietary Protein and Estrogen Deficiency

    PubMed Central

    Chalvon-Demersay, Tristan; Blachier, François; Tomé, Daniel; Blais, Anne

    2017-01-01

    Obesity is an increasing major public health concern asking for dietary strategies to limit weight gain and associated comorbidities. In this review, we present animal models, particularly rats and mice, which have been extensively used by scientists to understand the consequences of diet quality on weight gain and health. Notably, modulation of dietary protein quantity and/or quality has been shown to exert huge effects on body composition homeostasis through the modulation of food intake, energy expenditure, and metabolic pathways. Interestingly, the perinatal window appears to represent a critical period during which the protein intake of the dam can impact the offspring’s weight gain and feeding behavior. Animal models are also widely used to understand the processes and mechanisms that contribute to obesity at different physiological and pathophysiological stages. An interesting example of such aspect is the situation of decreased estrogen level occurring at menopause, which is linked to weight gain and decreased energy expenditure. To study metabolic disorders associated with such situation, estrogen withdrawal in ovariectomized animal models to mimic menopause are frequently used. According to many studies, clear species-specific differences exist between rats and mice that need to be taken into account when results are extrapolated to humans. PMID:28373974

  4. Dietary Yucca schidigera supplementation reduces arsenic-induced oxidative stress in Swiss albino mice.

    PubMed

    Ince, Sinan; Kucukkurt, Ismail; Turkmen, Ruhi; Demirel, Hasan Huseyin; Sever, Emine

    2013-11-01

    The aim of this study was to clarify the effects of dietary supplementation with Yucca schidigera (Ys) on lipid peroxidation (LPO), antioxidant activity, some biochemical parameters and histopathological changes in arsenic-exposed mice. Forty Swiss albino male mice were divided into five equal groups. Group I (control group) was given normal diet and tap water for 28 days. Group II (arsenic group) was given normal diet and 100 mg/L arsenic along with drinking water for 28 days. Groups III-V were given three different doses of Ys (50, 100 and 200 mg/kg) in supplemented diet and arsenic (100 mg/L) along with drinking water throughout the entire period of 28 days. The arsenic significantly increased serum biochemical parameters and malondialdehyde levels in blood and tissue. However, arsenic significantly decreased tissue glutathione concentration, erythrocyte superoxide dismutase and catalase activities. In contrast, dietary supplementation of Ys, in a dose-dependent manner, resulted in reversal of arsenic-induced oxidative stress, LPO and activities of antioxidant enzymes. Moreover, Ys also exhibited protective action against the arsenic-induced focal gliosis and hyperemi in brain, necrosis and degeneration in liver, degeneration and dilatation in Bowman's capsule of kidney and hyaline degeneration in heart tissue of mice. Consequently, our results demonstrate that Ys especially high-dose supplementation in diet decreases arsenic-induced oxidative stress and enhances the antioxidant defence mechanism and regenerate of tissues in Swiss albino mice.

  5. Dietary Restriction Induced Longevity Is Mediated by Nuclear Receptor NHR-62 in Caenorhabditis elegans

    PubMed Central

    Heestand, Bree N.; Shen, Yidong; Liu, Wei; Magner, Daniel B.; Storm, Nadia; Meharg, Caroline; Habermann, Bianca; Antebi, Adam

    2013-01-01

    Dietary restriction (DR) extends lifespan in a wide variety of species, yet the underlying mechanisms are not well understood. Here we show that the Caenorhabditis elegans HNF4α-related nuclear hormone receptor NHR-62 is required for metabolic and physiologic responses associated with DR-induced longevity. nhr-62 mediates the longevity of eat-2 mutants, a genetic mimetic of dietary restriction, and blunts the longevity response of DR induced by bacterial food dilution at low nutrient levels. Metabolic changes associated with DR, including decreased Oil Red O staining, decreased triglyceride levels, and increased autophagy are partly reversed by mutation of nhr-62. Additionally, the DR fatty acid profile is altered in nhr-62 mutants. Expression profiles reveal that several hundred genes induced by DR depend on the activity of NHR-62, including a putative lipase required for the DR response. This study provides critical evidence of nuclear hormone receptor regulation of the DR longevity response, suggesting hormonal and metabolic control of life span. PMID:23935515

  6. The thioredoxin TRX-1 regulates adult lifespan extension induced by dietary restriction in Caenorhabditis elegans

    SciTech Connect

    Fierro-Gonzalez, Juan Carlos; Gonzalez-Barrios, Maria; Miranda-Vizuete, Antonio

    2011-03-18

    Highlights: {yields} First in vivo data for thioredoxin in dietary-restriction-(DR)-induced longevity. {yields} Thioredoxin (trx-1) loss suppresses longevity of eat-2 mutant, a genetic DR model. {yields} trx-1 overexpression extends wild-type longevity, but not that of eat-2 mutant. {yields} Longevity by dietary deprivation (DD), a non-genetic DR model, requires trx-1. {yields} trx-1 expression in ASJ neurons of aging adults is increased in response to DD. -- Abstract: Dietary restriction (DR) is the only environmental intervention known to extend adult lifespan in a wide variety of animal models. However, the genetic and cellular events that mediate the anti-aging programs induced by DR remain elusive. Here, we used the nematode Caenorhabditis elegans to provide the first in vivo evidence that a thioredoxin (TRX-1) regulates adult lifespan extension induced by DR. We found that deletion of the gene trx-1 completely suppressed the lifespan extension caused by mutation of eat-2, a genetic surrogate of DR in the worm. However, trx-1 deletion only partially suppressed the long lifespan caused by mutation of the insulin-like receptor gene daf-2 or by mutation of the sensory cilia gene osm-5. A trx-1::GFP translational fusion expressed from its own promoter in ASJ neurons (Ptrx-1::trx-1::GFP) rescued the trx-1 deletion-mediated suppression of the lifespan extension caused by mutation of eat-2. This rescue was not observed when trx-1::GFP was expressed from the ges-1 promoter in the intestine. In addition, overexpression of Ptrx-1::trx-1::GFP extended lifespan in wild type, but not in eat-2 mutants. trx-1 deletion almost completely suppressed the lifespan extension induced by dietary deprivation (DD), a non-genetic, nutrient-based model of DR in the worm. Moreover, DD upregulated the expression of a trx-1 promoter-driven GFP reporter gene (Ptrx-1::GFP) in ASJ neurons of aging adults, but not that of control Pgpa-9::GFP (which is also expressed in ASJ neurons). We propose

  7. Dietary protein-induced hepatic IGF-1 secretion mediated by PPARγ activation

    PubMed Central

    Wan, Xiaojuan; Wang, Songbo; Xu, Jingren; Zhuang, Lu; Xing, Kongping; Zhang, Mengyuan; Zhu, Xiaotong; Wang, Lina; Gao, Ping; Xi, Qianyun; Sun, Jiajie; Zhang, Yongliang; Li, Tiejun; Shu, Gang; Jiang, Qingyan

    2017-01-01

    Dietary protein or amino acid (AA) is a crucial nutritional factor to regulate hepatic insulin-like growth factor-1 (IGF-1) expression and secretion. However, the underlying intracellular mechanism by which dietary protein or AA induces IGF-1 expression remains unknown. We compared the IGF-1 gene expression and plasma IGF-1 level of pigs fed with normal crude protein (CP, 20%) and low-protein levels (LP, 14%). RNA sequencing (RNA-seq) was performed to detect transcript expression in the liver in response to dietary protein. The results showed that serum concentrations and mRNA levels of IGF-1 in the liver were higher in the CP group than in the LP group. RNA-seq analysis identified a total of 1319 differentially expressed transcripts (667 upregulated and 652 downregulated), among which the terms “oxidative phosphorylation”, “ribosome”, “gap junction”, “PPAR signaling pathway”, and “focal adhesion” were enriched. In addition, the porcine primary hepatocyte and HepG2 cell models also demonstrated that the mRNA and protein levels of IGF-1 and PPARγ increased with the increasing AA concentration in the culture. The PPARγ activator troglitazone increased IGF-1 gene expression and secretion in a dose dependent manner. Furthermore, inhibition of PPARγ effectively reversed the effects of the high AA concentration on the mRNA expression of IGF-1 and IGFBP-1 in HepG2 cells. Moreover, the protein levels of IGF-1 and PPARγ, as well as the phosphorylation of mTOR, significantly increased in HepG2 cells under high AA concentrations. mTOR phosphorylation can be decreased by the mTOR antagonist, rapamycin. The immunoprecipitation results also showed that high AA concentrations significantly increased the interaction of mTOR and PPARγ. In summary, PPARγ plays an important role in the regulation of IGF-1 secretion and gene expression in response to dietary protein. PMID:28257428

  8. Dietary inclusion of local salt substitutes induces oxidative stress and renal dysfunction in rats.

    PubMed

    Akinyemi, Ayodele J; Oboh, Ganiyu; Ademiluyi, Adedayo O; Araoye, Obafemi O; Oyeleye, Sunday I

    2014-01-01

    Our earlier report has shown that salt substitutes (Obu-Otoyo) contain some toxic heavy metals. This study, therefore, investigated the effect of the dietary inclusion of salt substitutes (Obu-Otoyo), namely, salt "A" and "B", on biomarkers of oxidative stress and renal function in rats. Salt "A", which has a gray color, is the product of a process in which ash is produced by burning palm kernel shaft soaked in water overnight and extracting the residue to produce the salt substitute while Salt "B", which has a white color, is a rock salt mined from a local site at Ilobu town, Osun-State, Nigeria. Salt substitutes were fed to normal rats as dietary inclusion at 0.5% and 1.0% for 21 days. The dietary inclusion of the salt substitutes caused a significant (p<0.05) increase in plasma activities of creatinine, urea, uric acid, and blood urea nitrogen compared with the control. Meanwhile, the dietary inclusion of the salt substitutes caused a significant (p<0.05) decrease in renal superoxide dismutase, catalase, reduced glutathione level, glutathione-S-transferase, and glutathione peroxidase activities with a concomitant increase in the malondialdehyde level compared with the control. Furthermore, there was a significant (p<0.05) increase in the concentrations of heavy metals, such as Pb, Co, Cu, Fe, Zn and Cr, in kidney of rats fed with the salt substitute Obu-Otoyo. Therefore, this finding indicates that Obu-Otoyo induces nephrotoxicity in rats. The nephrotoxicity of Obu-Otoyo could be attributed to the induction of oxidative stress as a result of the presence of some heavy metals, suggesting possible health hazards in subjects who consume it.

  9. Dietary protein-induced hepatic IGF-1 secretion mediated by PPARγ activation.

    PubMed

    Wan, Xiaojuan; Wang, Songbo; Xu, Jingren; Zhuang, Lu; Xing, Kongping; Zhang, Mengyuan; Zhu, Xiaotong; Wang, Lina; Gao, Ping; Xi, Qianyun; Sun, Jiajie; Zhang, Yongliang; Li, Tiejun; Shu, Gang; Jiang, Qingyan

    2017-01-01

    Dietary protein or amino acid (AA) is a crucial nutritional factor to regulate hepatic insulin-like growth factor-1 (IGF-1) expression and secretion. However, the underlying intracellular mechanism by which dietary protein or AA induces IGF-1 expression remains unknown. We compared the IGF-1 gene expression and plasma IGF-1 level of pigs fed with normal crude protein (CP, 20%) and low-protein levels (LP, 14%). RNA sequencing (RNA-seq) was performed to detect transcript expression in the liver in response to dietary protein. The results showed that serum concentrations and mRNA levels of IGF-1 in the liver were higher in the CP group than in the LP group. RNA-seq analysis identified a total of 1319 differentially expressed transcripts (667 upregulated and 652 downregulated), among which the terms "oxidative phosphorylation", "ribosome", "gap junction", "PPAR signaling pathway", and "focal adhesion" were enriched. In addition, the porcine primary hepatocyte and HepG2 cell models also demonstrated that the mRNA and protein levels of IGF-1 and PPARγ increased with the increasing AA concentration in the culture. The PPARγ activator troglitazone increased IGF-1 gene expression and secretion in a dose dependent manner. Furthermore, inhibition of PPARγ effectively reversed the effects of the high AA concentration on the mRNA expression of IGF-1 and IGFBP-1 in HepG2 cells. Moreover, the protein levels of IGF-1 and PPARγ, as well as the phosphorylation of mTOR, significantly increased in HepG2 cells under high AA concentrations. mTOR phosphorylation can be decreased by the mTOR antagonist, rapamycin. The immunoprecipitation results also showed that high AA concentrations significantly increased the interaction of mTOR and PPARγ. In summary, PPARγ plays an important role in the regulation of IGF-1 secretion and gene expression in response to dietary protein.

  10. Dietary Supplement Enriched in Antioxidants and Omega-3 Protects from Progressive Light-Induced Retinal Degeneration

    PubMed Central

    Ramchani-Ben Othman, Khaoula; Cercy, Christine; Amri, Mohamed; Doly, Michel; Ranchon-Cole, Isabelle

    2015-01-01

    In the present study, we have evaluated one of the dietary supplements enriched with antioxidants and fish oil used in clinical care for patient with age-related macular degeneration. Rats were orally fed by a gastric canula daily with 0.2 ml of water or dietary supplement until they were sacrificed. After one week of treatment, animals were either sacrificed for lipid analysis in plasma and retina, or used for evaluation of rod-response recovery by electroretinography (ERG) followed by their sacrifice to measure rhodopsin content, or used for progressive light-induced retinal degeneration (PLIRD). For PLIRD, animals were transferred to bright cyclic light for one week. Retinal damage was quantified by ERG, histology and detection of apoptotic nuclei. Animals kept in dim-cyclic-light were processed in parallel. PLIRD induced a thinning of the outer nuclear layer and a reduction of the b-wave amplitude of the ERG in the water group. Retinal structure and function were preserved in supplemented animals. Supplement induced a significant increase in omega-3 fatty acids in plasma by 168% for eicosapentaenoic acid (EPA), 142% for docosapentaenoic acid (DPA) and 19% for docosahexaenoic acid (DHA) and a decrease in the omega-6 fatty acids, DPA by 28%. In the retina, supplement induced significant reduction of linolenic acid by 67% and an increase in EPA and DPA by 80% and 72%, respectively, associated with significant decrease in omega-6 DPA by 42%. Supplement did not affect rhodopsin content or rod-response recovery. The present data indicate that supplement rapidly modified the fatty acid content and induced an accumulation of EPA in the retina without affecting rhodopsin content or recovery. In addition, it protected the retina from oxidative stress induced by light. Therefore, this supplement might be beneficial to slow down progression of certain retinal degeneration. PMID:26042773

  11. Androgen Deficiency Exacerbates High-Fat Diet-Induced Metabolic Alterations in Male Mice.

    PubMed

    Dubois, Vanessa; Laurent, Michaël R; Jardi, Ferran; Antonio, Leen; Lemaire, Katleen; Goyvaerts, Lotte; Deldicque, Louise; Carmeliet, Geert; Decallonne, Brigitte; Vanderschueren, Dirk; Claessens, Frank

    2016-02-01

    Androgen deficiency is associated with obesity, metabolic syndrome, and type 2 diabetes mellitus in men, but the mechanisms behind these associations remain unclear. In this study, we investigated the combined effects of androgen deficiency and high-fat diet (HFD) on body composition and glucose homeostasis in C57BL/6J male mice. Two models of androgen deficiency were used: orchidectomy (ORX) and androgen receptor knockout mice. Both models displayed higher adiposity and serum leptin levels upon HFD, whereas no differences were seen on a regular diet. Fat accumulation in HFD ORX animals was accompanied by increased sedentary behavior and occurred in spite of reduced food intake. HFD ORX mice showed white adipocyte hypertrophy, correlated with decreased mitochondrial content but not function as well as increased lipogenesis and decreased lipolysis suggested by the up-regulation of fatty acid synthase and the down-regulation of hormone-sensitive lipase. Both ORX and androgen receptor knockout exacerbated HFD-induced glucose intolerance by impairing insulin action in liver and skeletal muscle, as evidenced by the increased triglyceride and decreased glycogen content in these tissues. In addition, serum IL-1β levels were elevated, and pancreatic insulin secretion was impaired after ORX. Testosterone but not dihydrotestosterone supplementation restored the castration effects on body composition and glucose homeostasis. We conclude that sex steroid deficiency in combination with HFD exacerbates adiposity, insulin resistance, and β-cell failure in 2 preclinical male mouse models. Our findings stress the importance of a healthy diet in a clinical context of androgen deficiency and may have implications for the prevention of metabolic alterations in hypogonadal men.

  12. RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation

    PubMed Central

    Jones, Robert A.; Robinson, Tyler J.; Liu, Jeff C.; Shrestha, Mariusz; Voisin, Veronique; Ju, YoungJun; Chung, Philip E.D.; Pellecchia, Giovanna; Fell, Victoria L.; Bae, SooIn; Muthuswamy, Lakshmi; Egan, Sean E.; Jiang, Zhe; Leone, Gustavo; Bader, Gary D.; Schimmer, Aaron

    2016-01-01

    Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low–like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications. Gene set enrichment analysis revealed that Rb/p53-deficient tumors showed elevated expression of the mitochondrial protein translation (MPT) gene pathway relative to tumors harboring p53 deletion alone. Accordingly, bioinformatic, functional, and biochemical analyses showed that RB1-E2F complexes bind to MPT gene promoters to regulate transcription and control MPT. Additionally, a screen of US Food and Drug Administration–approved (FDA-approved) drugs identified the MPT antagonist tigecycline (TIG) as a potent inhibitor of Rb/p53-deficient tumor cell proliferation. TIG preferentially suppressed RB1-deficient TNBC cell proliferation, targeted both the bulk and cancer stem cell fraction, and strongly attenuated xenograft growth. It also cooperated with sulfasalazine, an FDA-approved inhibitor of cystine xCT antiporter, in culture and xenograft assays. Our results suggest that RB1 deficiency promotes cancer cell proliferation in part by enhancing mitochondrial function and identify TIG as a clinically approved drug for RB1-deficient TNBC. PMID:27571409

  13. Surgical treatment for a paraplegic patient induced by congenital factor X deficiency

    PubMed Central

    Lin, Weicheng; Zhou, Jing; Wang, Tianbing; Zhang, Peixun

    2015-01-01

    Congenital factor X (FX) deficiency is a rare disease which usually leads to coagulation disorders. We reported a case of paraplegic patient induced by traumatic spinal epidural hematoma which was associated with congenital FX deficiency. The treatments of this patient included elevating FX activity (FX: C) by adding fresh-frozen plasma (FFP) or prothrombin complex concentration (PCC) to improve his coagulation function, and doing operation to remove his spinal hematoma. Symptoms started to resolve after operation. Besides, we found one of his elder brother had the same disease as the patient himself via family follow-up. They can survive because their FX: C are relatively high enough to keep them away from fatal bleeding. PMID:26550274

  14. Akt activation prevents the force drop induced by eccentric contractions in dystrophin-deficient skeletal muscle.

    PubMed

    Blaauw, Bert; Mammucari, Cristina; Toniolo, Luana; Agatea, Lisa; Abraham, Reimar; Sandri, Marco; Reggiani, Carlo; Schiaffino, Stefano

    2008-12-01

    Skeletal muscles of the mdx mouse, a model of Duchenne Muscular Dystrophy, show an excessive reduction in the maximal tetanic force following eccentric contractions. This specific sign of the susceptibility of dystrophin-deficient muscles to mechanical stress can be used as a quantitative test to measure the efficacy of therapeutic interventions. Using inducible transgenesis in mice, we show that when Akt activity is increased the force drop induced by eccentric contractions in mdx mice becomes similar to that of wild-type mice. This effect is not correlated with muscle hypertrophy and is not blocked by rapamycin treatment. The force drop induced by eccentric contractions is similar in skinned muscle fibers from mdx and Akt-mdx mice when stretch is applied directly to skinned fibers. However, skinned fibers isolated from mdx muscles exposed to eccentric contractions in vivo develop less isometric force than wild-type fibers and this force depression is completely prevented by Akt activation. These experiments indicate that the myofibrillar-cytoskeletal system of dystrophin-deficient muscle is highly susceptible to a damage caused by eccentric contraction when elongation is applied in vivo, and this damage can be prevented by Akt activation. Microarray and PCR analyses indicate that Akt activation induces up-regulation of genes coding for proteins associated with Z-disks and costameres, and for proteins with anti-oxidant or chaperone function. The protein levels of utrophin and dysferlin are also increased by Akt activation.

  15. Low molybdenum state induced by tungsten as a model of molybdenum deficiency in rats.

    PubMed

    Yoshida, Munehiro; Nakagawa, Mikihito; Hosomi, Ryota; Nishiyama, Toshimasa; Fukunaga, Kenji

    2015-05-01

    Organ molybdenum (Mo) concentration and the activity of hepatic sulfite oxidase and xanthine oxidase were compared in tungsten-administered rats as well as rats fed with a low Mo diet to evaluate the use of tungsten-administered rats as a model of Mo deficiency. Twenty-four male 6-week-old Wistar rats were divided into four groups according to diet (AIN93G diet (control diet) or the control diet minus ammonium molybdate (low Mo diet)) and drinking water (deionized water or deionized water containing 200 μg/mL tungsten in the form of sodium tungstate). Mo content in the control and low Mo diets were 196 and 42 ng/g, respectively. Intake of the low Mo diet significantly reduced the Mo content of several organs and serum. Decrease in hepatic sulfite oxidase activity was also induced by the low Mo diet. The administration of tungsten induced marked decreases in organ Mo content and the activity of hepatic sulfite oxidase and xanthine oxidase. These decreases induced by tungsten administration were more pronounced than those induced by just a low Mo diet. Serum uric acid was also reduced by tungsten administration irrespective of Mo intake. Although a comparatively high accumulation of tungsten (3 to 9 μg/g) was observed in the kidneys and liver, adverse effects of tungsten accumulation on liver and kidney function were not observed in serum biochemical tests. These results indicate that tungsten-administered animals may be used as a model of Mo deficiency.

  16. Suppressive effect of viscous dietary fiber on elevations of uric acid in serum and urine induced by dietary RNA in rats is associated with strength of viscosity.

    PubMed

    Koguchi, Takashi; Nakajima, Hisao; Koguchi, Hiromi; Wada, Masahiro; Yamamoto, Yuji; Innami, Satoshi; Maekawa, Akio; Tadokoro, Tadahiro

    2003-10-01

    This study was performed to clarify how dietary fiber (DF) with different viscosities would be associated with dietary RNA metabolism. Male Wistar strain rats, four weeks old, were fed diets containing a 3% (w/w) yeast RNA and a 5% (w/w) viscous DF for five days. Viscosity of DF samples used, in order of strength, were xanthan gum (XG) > guar gum (GG) > locust bean gum (LBG) > karaya gum (KG) > pectin (PE) = arabic gum (AG) > CM-cellulose (CMC) = inulin (IN). The serum uric acid concentration in the viscous DF groups significantly decreased as compared with that in the cellulose (CL) group. The urinary excretions of uric acid and allantoin in the respective groups given AG, GG, IN, KG, PE, and XG were significantly suppressed as compared with those in the CL group. The fecal RNA excretion was markedly increased in the IN, KG, PE, and XG groups in comparison to the CL group. The DF with high viscosity significantly suppressed RNA digestion by RNase A and decreased uptakes of 14C-labeled adenosine and adenosine 5'-monophosphate (5'-AMP) in rat jejunum. The results reveal that the suppressive effect of DF on elevation of serum uric acid concentration induced by dietary RNA in rats is associated with the strength of DF viscosity. The mechanism by which this is accomplished is suggested to be attributed to the inhibitions of digestion for dietary RNA and/or absorption of the hydrolyzed compounds.

  17. Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency

    NASA Technical Reports Server (NTRS)

    Mukhopadhyay, C. K.; Mazumder, B.; Fox, P. L.

    2000-01-01

    A role of the copper protein ceruloplasmin (Cp) in iron metabolism is suggested by its ferroxidase activity and by the tissue iron overload in hereditary Cp deficiency patients. In addition, plasma Cp increases markedly in several conditions of anemia, e.g. iron deficiency, hemorrhage, renal failure, sickle cell disease, pregnancy, and inflammation. However, little is known about the cellular and molecular mechanism(s) involved. We have reported that iron chelators increase Cp mRNA expression and protein synthesis in human hepatocarcinoma HepG2 cells. Furthermore, we have shown that the increase in Cp mRNA is due to increased rate of transcription. We here report the results of new studies designed to elucidate the molecular mechanism underlying transcriptional activation of Cp by iron deficiency. The 5'-flanking region of the Cp gene was cloned from a human genomic library. A 4774-base pair segment of the Cp promoter/enhancer driving a luciferase reporter was transfected into HepG2 or Hep3B cells. Iron deficiency or hypoxia increased luciferase activity by 5-10-fold compared with untreated cells. Examination of the sequence showed three pairs of consensus hypoxia-responsive elements (HREs). Deletion and mutation analysis showed that a single HRE was necessary and sufficient for gene activation. The involvement of hypoxia-inducible factor-1 (HIF-1) was shown by gel-shift and supershift experiments that showed HIF-1alpha and HIF-1beta binding to a radiolabeled oligonucleotide containing the Cp promoter HRE. Furthermore, iron deficiency (and hypoxia) did not activate Cp gene expression in Hepa c4 hepatoma cells deficient in HIF-1beta, as shown functionally by the inactivity of a transfected Cp promoter-luciferase construct and by the failure of HIF-1 to bind the Cp HRE in nuclear extracts from these cells. These results are consistent with in vivo findings that iron deficiency increases plasma Cp and provides a molecular mechanism that may help to understand these

  18. The impact of FANCD2 deficiency on formaldehyde-induced toxicity in human lymphoblastoid cell lines.

    PubMed

    Ren, Xuefeng; Ji, Zhiying; McHale, Cliona M; Yuh, Jessica; Bersonda, Jessica; Tang, Maycky; Smith, Martyn T; Zhang, Luoping

    2013-01-01

    Formaldehyde (FA), a major industrial chemical and ubiquitous environmental pollutant, has recently been classified by the International Agency for Research on Cancer as a human leukemogen. The major mode of action of FA is thought to be the formation of DNA-protein cross-links (DPCs). Repair of DPCs may be mediated by the Fanconi anemia pathway; however, data supporting the involvement of this pathway are limited, particularly in human hematopoietic cells. Therefore, we assessed the role of FANCD2, a critical component of the Fanconi anemia pathway, in FA-induced toxicity in human lymphoblast cell models of FANCD2 deficiency (PD20 cells) and FANCD2 sufficiency (PD20-D2 cells). After treatment of the cells with 0-150 μM FA for 24 h, DPCs were increased in a dose-dependent manner in both cell lines, with greater increases in FANCD2-deficient PD20 cells. FA also induced cytotoxicity, micronuclei, chromosome aberrations, and apoptosis in a dose-dependent manner in both cell lines, with greater increases in cytotoxicity and apoptosis in PD20 cells. Increased levels of γ-ATR and γ-H2AX in both cell lines suggested the recognition of FA-induced DNA damage; however, the induction of BRCA2 was compromised in FANCD2-deficient PD20 cells, potentially reducing the capacity to repair DPCs. Together, these findings suggest that FANCD2 protein and the Fanconi anemia pathway are essential to protect human lymphoblastoid cells against FA toxicity. Future studies are needed to delineate the role of this pathway in mitigating FA-induced toxicity, particularly in hematopoietic stem cells, the target cells in leukemia.

  19. CCR5 deficiency increased susceptibility to lipopolysaccharide-induced acute renal injury.

    PubMed

    Lee, Dong Hun; Park, Mi Hee; Hwang, Chul Ju; Hwang, Jae Yeon; Yoon, Hae Suk; Yoon, Do Young; Hong, Jin Tae

    2016-05-01

    C-C chemokine receptor 5 (CCR5) regulates leukocyte chemotaxis and activation, and its deficiency exacerbates development of nephritis. Therefore, we investigated the role of CCR5 during lipopolysaccharide (LPS)-induced acute kidney injury. CCR5-deficient (CCR5-/-) and wild-type (CCR5+/+) mice, both aged about 10 months, had acute renal injury induced by intraperitoneal injection of LPS (10 mg/kg). Compared with CCR5+/+ mice, CCR5-/- mice showed increased mortality and renal injury, including elevated creatinine and blood urea nitrogen levels, following LPS challenge. Compared to CCR5+/+ mice, CCR5-/- mice also exhibited greater increases in the serum concentrations of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β following LPS challenge. Furthermore, infiltration of macrophages and neutrophils, expression of intracellular adhesion molecule (ICAM)-1, and the number of apoptotic cells were more greatly increased by LPS treatment in CCR5-/- mice than in CCR5+/+ mice. The concentrations of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β were also significantly increased in the kidney of CCR5-/- mice after LPS challenge. Moreover, primary kidney cells from CCR5-/- mice showed greater increases in TNF-α production and p38 MAP kinase activation following treatment with LPS compared with that observed in the cells from CCR5+/+ mice. LPS-induced TNF-α production and apoptosis in the primary kidney cells from CCR5-/- mice were inhibited by treatment with p38 MAP kinase inhibitor. These results suggest that CCR5 deficiency increased the production of TNF-α following LPS treatment through increased activation of the p38 pathway in the kidney, resulting in renal apoptosis and leukocyte infiltration and led to exacerbation of LPS-induced acute kidney injury.

  20. Intercellular adhesion molecule-1 (ICAM-1) deficiency protects mice against severe forms of experimentally induced colitis

    PubMed Central

    Bendjelloul, F; Malý, P; Mandys, V; Jirkovská, M; Prokešová, L; Tučková, L; Tlaskalová-Hogenová, H

    2000-01-01

    ICAM-1 (CD54), the ligand for LFA-1 and Mac-1, is up-regulated during inflammatory reaction on the activated vascular endothelium. To determine its role in intestinal inflammation, we induced acute experimental colitis in mice with a deleted ICAM-1 gene, by feeding them with 3% dextran sodium sulphate (DSS) in drinking water for 7 days. Chronic colitis was elicited by DSS similarly, followed by 2 weeks with water. In the acute phase of inflammation, ICAM-1-deficient mice exhibited a significantly lower mortality rate (5%) than control C57Bl/6J mice (35%). Control animals, but not the ICAM-1-deficient mice, exhibited diarrhoea and rectal bleeding. Histological examination of large-bowel samples evaluated the intensity of inflammatory changes, and type and extent of mucosal lesions. In the acute phase, 33.3% of samples from ICAM-1-deficient mice exhibited mucosal defects (flat and fissural ulcers), predominantly mild to moderate inflammatory infiltrate within the lamina propria mucosae and lower grades of mucosal lesions. Much stronger inflammatory changes were present in control animals, flat ulcers (sometimes multiple) and fissural ulcers being observed in 62.5% of samples. Mucosal inflammatory infiltrate was moderate to severe, typically with higher grades of mucosal lesions. In chronic colitis, smaller inflammatory changes were found in the large bowel. The two mouse strains differed, the chronic colitis being accompanied by an increased serum level of anti-epithelial IgA autoantibodies in C57Bl/6 control mice but not in ICAM-1-deficient mice. These findings provide direct evidence of the participation of ICAM-1 molecule in the development of experimentally induced intestinal inflammation. PMID:10606964

  1. Vasodilator-Stimulated Phosphoprotein Deficiency Potentiates PAR-1-induced Increase in Endothelial Permeability in Mouse Lungs

    PubMed Central

    Profirovic, Jasmina; Han, Jingyan; Andreeva, Alexandra V.; Neamu, Radu F.; Pavlovic, Sasha; Vogel, Stephen M.; Walter, Ulrich; Voyno-Yasenetskaya, Tatyana A.

    2010-01-01

    Vasodilator-stimulated phosphoprotein (VASP) is implicated in the protection of the endothelial barrier in vitro and in vivo. VASP function in thrombin signaling in the endothelial cells (ECs) is not known. For the first time we studied the effects of VASP deficiency on EC permeability and pulmonary vascular permeability in response to thrombin receptor stimulation. We provided the evidence that VASP deficiency potentiates the increase in endothelial permeability induced by activation of thrombin receptor in cultured human umbilical vein endothelial cells (HUVECs) and isolated mouse lungs. Using transendothelial resistance measurement, we showed that siRNA-mediated VASP downregulation in HUVECs leads to a potentiation of thrombin- and protease-activated receptor 1 (PAR-1) agonist-induced increase in endothelial permeability. Compared to control cells, VASP-deficient HUVECs had delayed endothelial junctional reassembly and abrogated VE-cadherin cytoskeletal anchoring in the recovery phase after thrombin stimulation, as demonstrated by immunofluorescence studies and cell fractionation analysis, respectively. Measurement of the capillary filtration coefficient in isolated mouse lungs demonstrated that VASP−/− mice have increased microvascular permeability in response to infusion with PAR-1 agonist compared to wild type mice. Lack of VASP led to decreased Rac1 activation both in VASP-deficient HUVECs after thrombin stimulation and VASP−/− mouse lungs after PAR-1 agonist infusion, indicating that VASP effects on thrombin signaling may correlated with changes in Rac1 activity. This study demonstrates that VASP may play critical and complex role in the regulation of thrombin-dependent disruption of the endothelial barrier function. PMID:20945373

  2. Complement component C5 deficiency reduces edema formation in murine ligation-induced acute pancreatitis.

    PubMed

    Merriam, L T; Webster, C; Joehl, R J

    1997-01-01

    The complement cascade is activated in humans and animals with acute pancreatitis. Activation of complement component C5 liberates C5a, C5a-desarg, and terminal complement complexes (TCCs) that increase capillary permeability, edema, and leukocyte chemotaxis at injured sites. Complement activation plays a major role in pathogenesis of capillary leak and edema formation in severe acute pancreatitis; however, the contribution of C5 (C5a/C5a-desarg, TCCs) has not been defined. Using He gene mutant mice lacking circulating C5, the role of C5 in ligation-induced acute pancreatitis was evaluated. We performed the following experiments: C5-sufficient (Hc1/Hc1) and C5-deficient (Hc0/Hc0) mice had bile and pancreatic ducts ligated. Sham-operated mice had ducts dissected but not ligated. Mice were killed at 4, 8, and 24 hr after bilepancreatic duct ligation. Serologic and morphologic evidences of acute pancreatitis were evaluated. Pancreatic edema was assessed using analysis of pancreatic water content, histologic edema score, and determination of wet weight ratio. After 4, 8, and 24 hr of bile-pancreatic duct ligation, hyperamylasemia and histologic changes of acute pancreatitis were observed in both C5-deficient and C5-sufficient mice. Edema developed in all mice with acute pancreatitis. However, when compared to C5-sufficient mice, mice deficient in C5 developed significantly less pancreatic edema at both 8 and 24 hr of bile-pancreatic duct ligation. This difference was not observed 4 hr after induction of acute pancreatitis. We conclude that C5 contributes to edema formation in murine ligation-induced acute pancreatitis. The presence of an early C5-independent phase, in conjunction with the observation of significant edema in mice deficient in C5, suggests there are other mediators of edema formation in this acute pancreatitis model.

  3. Dietary Supplementation with Fresh Pineapple Juice Decreases Inflammation and Colonic Neoplasia in IL-10-deficient Mice with Colitis

    PubMed Central

    Hale, Laura P.; Chichlowski, Maciej; Trinh, Chau T.; Greer, Paula K.

    2010-01-01

    Background Bromelain, a mixture of proteolytic enzymes typically derived from pineapple stem, decreases production of pro-inflammatory cytokines and leukocyte homing to sites of inflammation. We previously showed that short-term oral treatment with bromelain purified from pineapple stem decreased the severity of colonic inflammation in C57BL/6 Il10−/− mice with chronic colitis. Since fresh pineapple fruit contains similar bromelain enzymes but at different proportions, this study aimed to determine whether long-term dietary supplementation with pineapple (supplied as juice) could decrease colon inflammation and neoplasia in Il10−/− mice with chronic colitis as compared with bromelain derived from stem. Results Experimental mice readily consumed fresh pineapple juice at a level that generated mean stool proteolytic activities equivalent to 16 mg bromelain purified from stem, while control mice received boiled juice with inactive enzymes. Survival was increased in the group supplemented with fresh rather than boiled juice (p = 0.01). Mice that received fresh juice also had decreased histologic colon inflammation scores and a lower incidence of inflammation-associated colonic neoplasia (35% vs. 66%; p< 0.02), with fewer neoplastic lesions/colon (p = 0.05). Flow cytometric analysis of murine splenocytes exposed to fresh pineapple juice in vitro demonstrated proteolytic removal of cell surface molecules that can affect leukocyte trafficking and activation. Conclusions These results demonstrate that long-term dietary supplementation with fresh or unpasteurized frozen pineapple juice with proteolytically active bromelain enzymes is safe and decreases inflammation severity and the incidence and multiplicity of inflammation-associated colonic neoplasia in this commonly used murine model of inflammatory bowel disease. PMID:20848493

  4. Attenuation of Chondrogenic Transformation in Vascular Smooth Muscle by Dietary Quercetin in the MGP-Deficient Mouse Model

    PubMed Central

    Borras, Teresa; Nurminskaya, Maria

    2013-01-01

    Rationale Cartilaginous metaplasia of vascular smooth muscle (VSM) is characteristic for arterial calcification in diabetes and uremia and in the background of genetic alterations in matrix Gla protein (MGP). A better understanding of the molecular details of this process is critical for the development of novel therapeutic approaches to VSM transformation and arterial calcification. Objective This study aimed to identify the effects of bioflavonoid quercetin on chondrogenic transformation and calcification of VSM in the MGP-null mouse model and upon TGF-β3 stimulation in vitro, and to characterize the associated alterations in cell signaling. Methods and Results Molecular analysis revealed activation of β-catenin signaling in cartilaginous metaplasia in Mgp-/- aortae in vivo and during chondrogenic transformation of VSMCs in vitro. Quercetin intercepted chondrogenic transformation of VSM and blocked activation of β-catenin both in vivo and in vitro. Although dietary quercetin drastically attenuated calcifying cartilaginous metaplasia in Mgp-/- animals, approximately one-half of total vascular calcium mineral remained as depositions along elastic lamellae. Conclusion Quercetin is potent in preventing VSM chondrogenic transformation caused by diverse stimuli. Combined with the demonstrated efficiency of dietary quercetin in preventing ectopic chondrogenesis in the MGP-null vasculature, these findings indicate a potentially broad therapeutic applicability of this safe for human consumption bioflavonoid in the therapy of cardiovascular conditions linked to cartilaginous metaplasia of VSM. Elastocalcinosis is a major component of MGP-null vascular disease and is controlled by a mechanism different from chondrogenic transformation of VSM and not sensitive to quercetin. PMID:24098781

  5. Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity.

    PubMed

    Alvheim, Anita R; Malde, Marian K; Osei-Hyiaman, Douglas; Lin, Yu Hong; Pawlosky, Robert J; Madsen, Lise; Kristiansen, Karsten; Frøyland, Livar; Hibbeln, Joseph R

    2012-10-01

    Suppressing hyperactive endocannabinoid tone is a critical target for reducing obesity. The backbone of both endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) is the ω-6 fatty acid arachidonic acid (AA). Here we posited that excessive dietary intake of linoleic acid (LA), the precursor of AA, would induce endocannabinoid hyperactivity and promote obesity. LA was isolated as an independent variable to reflect the dietary increase in LA from 1 percent of energy (en%) to 8 en% occurring in the United States during the 20th century. Mice were fed diets containing 1 en% LA, 8 en% LA, and 8 en% LA + 1 en% eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in medium-fat diets (35 en% fat) and high-fat diets (60 en%) for 14 weeks from weaning. Increasing LA from 1 en% to 8 en% elevated AA-phospholipids (PL) in liver and erythrocytes, tripled 2-AG + 1-AG and AEA associated with increased food intake, feed efficiency, and adiposity in mice. Reducing AA-PL by adding 1 en% long-chain ω-3 fats to 8 en% LA diets resulted in metabolic patterns resembling 1 en% LA diets. Selectively reducing LA to 1 en% reversed the obesogenic properties of a 60 en% fat diet. These animal diets modeled 20th century increases of human LA consumption, changes that closely correlate with increasing prevalence rates of obesity. In summary, dietary LA increased tissue AA, and subsequently elevated 2-AG + 1-AG and AEA resulting in the development of diet-induced obesity. The adipogenic effect of LA can be prevented by consuming sufficient EPA and DHA to reduce the AA-PL pool and normalize endocannabinoid tone.

  6. Role of dietary fiber in formation and prevention of small intestinal ulcers induced by nonsteroidal anti-inflammatory drug.

    PubMed

    Satoh, Hiroshi

    2010-01-01

    Recent advances in endoscopic techniques such as capsule endoscopy have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) often cause ulcers in the small intestine in humans, but there are few effective agents for treatment of small intestinal ulcers. Although the pathogenesis of NSAID-induced intestinal ulcer has been widely studied, dietary factors have seldom been considered. In the present review, the role of dietary fiber (DF) in the formation of NSAID-induced intestinal ulcers is discussed. In previous studies, small intestinal lesions were not observed when NSAIDs were administered to fasted rats, dogs, and cats, but were observed in conventionally-fed animals, suggesting the importance of feeding in the formation of intestinal lesions induced by NSAIDs. However, in animals fed diets containing low or no DF, indomethacin (IND) did not produce lesions in the small intestine, but did produce lesions in animals fed diets supplemented with insoluble dietary fiber (IDF, cellulose). The results suggest that IDF in the diet plays an important role in the formation of NSAID-induced intestinal lesions. On the other hand, addition of soluble dietary fibers (SDFs) such as pectin or mucin to regular diet markedly decreased NSAID-induced intestinal lesions. Thus, IDF and SDF have opposing effects on IND-induced intestinal lesions, i.e., IDF is harmful while SDF is protective. SDFs potentially represent a novel and safe means for protecting the small intestine against NSAID-induced intestinal lesions.

  7. Carnitine deficiency and oxidative stress provoke cardiotoxicity in an ifosfamide-induced Fanconi Syndrome rat model

    PubMed Central

    Darweesh, Amal Q; Fatani, Amal J

    2010-01-01

    In addition to hemorrhagic cystitis, Fanconi Syndrome is a serious clinical side effect during ifosfamide (IFO) therapy. Fanconi syndrome is a generalized dysfunction of the proximal tubule which is characterized by excessive urinary excretion of glucose, phosphate, bicarbonate, amino acids and other solutes excreted by this segment of the nephron including L-carnitine. Carnitine is essential cofactor for β-oxidation of long-chain fatty acids in the myocardium. IFO therapy is associated with increased urinary carnitine excretion with subsequent secondary deficiency of the molecule. Cardiac abnormalities in IFO-treated cancer patients were reported as isolated clinical cases. This study examined whether carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, provoke IFO-induced cardiomyopathy as well as exploring if carnitine supplementation using Propionyl-L-carnitine (PLC) could offer protection against this toxicity. In the current study, an animal model of carnitine deficiency was developed in rats by D-carnitine-mildronate treatment Adult male Wistar albino rats were assigned to one of six treatment groups: the first three groups were injected intraperitoneally with normal saline, D-carnitine (DC, 250 mg/kg/day) combined with mildronate (MD, 200 mg/kg/day) and PLC (250 mg/kg/day), respectively, for 10 successive days. The 4th, 5th and 6th groups were injected with the same doses of normal saline, DC-MD and PLC, respectively for 5 successive days before and 5 days concomitant with IFO (50 mg/kg/day). IFO significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion and clearance, creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), intramitochondrial acetyl-CoA/CoA-SH and thiobarbituric acid reactive substances (TBARS) in cardiac tissues and significantly decreased adenosine triphosphate (ATP) and total carnitine and reduced glutathione (GSH) content in cardiac tissues. In carnitine

  8. Dietary restriction protects against diethylnitrosamine-induced hepatocellular tumorigenesis by restoring the disturbed gene expression profile

    PubMed Central

    Duan, Ting; Sun, Wenjie; Zhang, Mohan; Ge, Juan; He, Yansu; Zhang, Jun; Zheng, Yifan; Yang, Wei; Shen, Han-ming; Yang, Jun; Zhu, Xinqiang; Yu, Peilin

    2017-01-01

    Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent malignancies, worse still, there are very limited therapeutic measures with poor clinical outcomes. Dietary restriction (DR) has been known to inhibit spontaneous and induced tumors in several species, but the mechanisms are little known. In the current study, by using a diethylnitrosamine (DEN)-induced HCC mice model, we found that DR significantly reduced the hepatic tumor number and size, delayed tumor development, suppressed proliferation and promoted apoptosis. Further transcriptome sequencing of liver tissues from the DEN and the DEN accompanied with DR (DEN+DR) mice showed that DEN induced profound changes in the gene expression profile, especially in cancer-related pathways while DR treatment reversed most of the disturbed gene expression induced by DEN. Finally, transcription factor enrichment analysis uncovered the transcription factor specificity protein 1 (SP1) probably functioned as the main regulator of gene changes, orchestrating the protective effects of DR on DEN induced HCC. Taken together, by the first comprehensive transcriptome analysis, we elucidate that DR protects aginst DEN-induced HCC by restoring the disturbed gene expression profile, which holds the promise to provide effective molecular targets for cancer therapies. PMID:28262799

  9. Inhibition of Diethylnitrosamine-Induced Hepatocarcinogenesis in Mice by a High Dietary Protein Intake.

    PubMed

    Shou, Qiyang; Chen, Fangming; Cai, Yueqin; Zhang, Shanxin; Tu, Jue; Zhang, Lizong; Wang, Dejun; Wang, Jianchao; Chen, Minli; Fu, Huiying

    2015-01-01

    Epidemiological and experimental evidence supports the key role of diet in the development of many types of cancer. Recent studies have suggested that dietary modifications may be beneficial for individuals at high risk for hepatocellular carcinoma (HCC). In this study, we investigated the effect of a high-protein (HP; 20% casein) dietondiethylnitrosamine (DEN)-induced hepatocarcinogenesis. Mice were given free access to water with 30 μg/ml DEN and fed a normal or HP diet for 22 wk. The results showed mice consuming HP diets had reduced mortality rates and body weights and lower hepatic enzyme activity compared to DEN-treated mice on a normal diet. HP consumption also promoted collagen accumulation in the liver, and reduced numbers of proliferating hepatocytes and infiltrating inflammatory cells, as well as decreased expression of inflammatory factor interleukin-1β, and nuclear factor κB activation. These data indicate that HP diets can inhibit DEN-induced hepatocarcinogenesis via suppression of the inflammatory response and provide a new evidence for the dietary management of clinical patients with hepatocellular carcinoma.

  10. Studies on the protective effect of dietary fish oil on cisplatin induced nephrotoxicity in rats.

    PubMed

    Naqshbandi, Ashreeb; Khan, Md Wasim; Rizwan, Sana; Rehman, Sayeed Ur; Khan, Farah

    2012-02-01

    Cisplatin (CP) is a major antineoplastic drug for the treatment of solid tumors, however, dose dependent nephrotoxicity remains the major concern for its long term use. Several agents/strategies were attempted to prevent CP nephrotoxicity but were not found suitable for clinical practice. Dietary fish oil (FO) enriched in ω-3 fatty acids has been shown to prevent/reduce the progression of certain types of cancers, cardiovascular and renal disorders. The present study was undertaken to see whether FO can prevent CP-induced nephrotoxic and other deleterious effects. Rats were prefed experimental diets for 10days and then received a single dose of CP (6mg/kg body weight) intraperitoneally while still on diet. Serum/urine parameters, enzymes of carbohydrate metabolism, brush border membrane (BBM) and oxidative stress in rat kidney were analyzed. CP nephrotoxicity was recorded by increased serum creatinine and blood urea nitrogen. CP decreased the activities of metabolic enzymes, antioxidant defense system and BBM enzymes. In contrast, FO alone increased enzyme activities of carbohydrate metabolism and brush border membrane (BBM). FO feeding to CP treated rats markedly enhanced resistance to CP-elicited deleterious effects. Dietary FO supplementation ameliorated CP induced specific metabolic alterations and oxidative damage due to its intrinsic biochemical antioxidant properties.

  11. Individualized long-term outcomes in blood phenylalanine concentrations and dietary phenylalanine tolerance in 11 patients with primary phenylalanine hydroxylase (PAH) deficiency treated with Sapropterin-dihydrochloride.

    PubMed

    Stockler-Ipsiroglu, Sylvia; Yuskiv, Nataliya; Salvarinova, Ramona; Apatean, Delia; Ho, Gloria; Cheng, Barbara; Giezen, Alette; Lillquist, Yolanda; Ueda, Keiko

    2015-03-01

    We analyzed long-term sustainability of improved blood Phenylalanine (Phe) control and changes to dietary Phe tolerance in 11 patients (1 month to 16 years), with various forms of primary PAH deficiency (classic, moderate, severe phenylketonuria [PKU], mild hyperphenylalaninemia [HPA]), who were treated with 15-20mg/kg/d Sapropterin-dihydrochloride during a period of 13-44 months. 7/11 patients had a sustainable, significant reduction of baseline blood Phe concentrations and 6 of them also had an increase in mg/kg/day Phe tolerance. In 2 patients with mild HPA, blood Phe concentrations remained in the physiologic range even after a 22 and 36% increase in mg/kg/day Phe tolerance and an achieved Phe intake at 105% and 268% of the dietary reference intake (DRI) for protein. 2 of these responders had classic PKU. 1 patient with mild HPA who started treatment at 2 months of life, had a significant and sustainable reduction in pretreatment blood Phe concentrations, but no increase in the mg/kg/day Phe tolerance. An increase in Phe tolerance could only be demonstrated when expressing the patient's daily Phe tolerance with the DRI for protein showing an increase from 58% at baseline to 78% of normal DRI at the end of the observation. Long-term follow-up of patients with an initial response to treatment with Sapropterin is essential to determine clinically meaningful outcomes. Phenylalanine tolerance should be expressed in mg/kg/day and/or % of normal DRI to differentiate medical therapy related from physiologic growth related increase in daily Phe intake.

  12. The effects of dietary phosphorus deficiency on surface pH and membrane composition of the mucosa epithelium in caprine jejunum.

    PubMed

    Busche, R; Schröder, B; Huber, K; Sallmann, H P; Breves, G

    2007-01-01

    In ruminants, the uptake of inorganic phosphate (P(i)) across the intestinal mucosa epithelium by Na-dependent and Na-independent mechanisms is a main regulatory factor in P homeostasis. The aim of the study was to elucidate to which extent Na-independent mechanisms, including pH effects or composition of mucosal brush-border membranes, could be involved in positive stimulation of P(i) absorptive processes seen under the P deficient condition. Therefore, luminal, surface and intracellular pH of the jejunal epithelial cells in control and P depleted goats were compared and biochemical analyses of membrane phospholipids in the apical membrane of the jejunal epithelium were performed. Dietary P depletion resulted in decreased plasma P(i) levels. While pH in jejunal ingesta was not significantly changed, P depletion resulted in a significantly lower surface pH in the crypt region compared to control animals (7.62 +/- 0.02 vs. 7.77 +/- 0.04, n = 4, P < 0.01). Inhibition of apical Na(+)/H(+)-exchange resulted in an increase of the jejunal surface pH in P depleted animals by 0.07 +/- 0.01 (n = 6, P < 0.01) and 0.05 +/- 0.01 (n = 6, P < 0.01) for the villus and the crypt region, respectively. This increase were inversely correlated with the initial surface pH prior to inhibition. In contrast to surface pH, intracellular pH of the jejunal epithelium and the phospholipid composition of the apical jejunal membrane were not affected by P depletion. Although the data suggest the existence of a Na(+)/H(+)-exchange mechanism at the luminal surface of goat jejunum they do not support the hypothesis that adaptational processes of active P(i) absorption from goat jejunum in response to low dietary P could be based on "non P(i) transporter events".

  13. Dietary copper level affects copper metabolism during lipopolysaccharide-induced immunological stress in chicks.

    PubMed

    Koh, T S; Peng, R K; Klasing, K C

    1996-07-01

    Two experiments were conducted to examine the effect of dietary Cu level on Cu metabolism during the acute phase response in broiler chicks with adequate (Experiment 1) or deficient (Experiment 2) Cu. Diets based on cornstarch and isolated soybean protein were used to formulate a basal diet, and basal diet plus either 5, 10, or 15 mg/kg additional Cu as either CuO or CuSO4. Each diet was fed to six pens of five chicks per pen (Experiment 1) or eight pens of five chicks (Experiment 2). Half of the chicks on each diet were injected with Salmonella typhymurium lipopolysaccharide (LPS) on alternate days. In Experiment 1, LPS significantly decreased daily gain, feed intake, and feed efficiency (P < 0.01) and increased the concentration of Cu in blood plasma (P < 0.01). In the uninjected birds, adding 5, 10, or 15 mg/kg Cu as CuO or 15 mg/kg Cu as CuSO4 increased the rate of gain over that of chicks fed the basal diet. In the birds challenged with LPS, 10 mg/kg Cu as CuO increased the rate of gain and efficiency compared to those of chicks fed the basal diet. Addition of CuSO4 to the diet of chicks challenged with LPS did not affect gain, intake, or feed efficiency compared to those of chicks fed the basal diet. Ceruloplasmin levels were higher in chicks challenged with LPS than in control chicks (P = 0.03), and this difference tended to be greater in chickens fed CuO than in chickens fed CuSO4 (P = 0.07). In chicks challenged with LPS, feeding CuO at all levels and feeding CuSO4 to give 10 or 15 mg/kg Cu increased ceruloplasmin levels above that of chicks fed the basal diet. Hepatic Mn superoxide dismutase (SOD) and Cu/Zn SOD were not influenced by dietary Cu level or source or LPS. Results of Experiment 2 were similar to those of Experiment 1 except that supplemental CuSO4 and CuO gave similar increases in gain and CuSO4 was more effective at increasing ceruloplasmin levels. Chicks given supplemental Cu had higher ceruloplasmin levels following challenge with LPS than

  14. Abnormality of epiphyseal plate induced by selenium deficiency diet in two generation DA rats.

    PubMed

    Min, Zixin; Zhao, Wenxiang; Zhong, Nannan; Guo, Yuanxu; Sun, Mengyao; Wang, Quancheng; Zhang, Rui; Yan, Jidong; Tian, Lifang; Zhang, Fujun; Han, Yan; Ning, Qilan; Meng, Liesu; Sun, Jian; Lu, Shemin

    2015-08-01

    This study aimed to observe the effects of Se deficiency on epiphyseal plates of two generation DA rats fed with artificial total synthetic low Se diet. All F0 and F1 DA rats were fed with synthetic low Se diet (SeD group) and low Se diet supplied with Se (SeS group). The levels of selenium and enzyme activities of GPx were detected in plasma of the rats. General growth of bone and articular cartilage was measured macroscopically and microscopically. The epiphyseal plate of femur heads or tibia were obtained to histological and immunohistochemical examinations. The cartilage from left knee joints and femur heads was used to detect the gene expression of collagens, ADAMTSs and several selenoproteins by RT-qPCR. Two generation SeD rats showed Se insufficiency status. The thicknesses of the femur and tibial epiphyseal plates in both F0 and F1 SeD rats were significantly less than that of SeS rats. In F1 generation, SeD rats showed much fewer proliferative chondrocyte layers than SeS ones. Importantly, two generation SeD rats both showed significantly more serious pathological changes of epiphyseal plates. In two generation rats, gene expressions of COL II, GPx1 and GPx4 were significantly down-regulated in SeD rats than SeS ones; meanwhile ADAMTS-4 showed an up-regulated expression in cartilage. Dietary Se deficiency can apparently cause epiphyseal plate lesion and decrease cartilage type II collagen production and GPx1 activity in two generation DA rats fed with the artificial total synthesis low Se diet.

  15. Diet-induced weight loss: the effect of dietary protein on bone.

    PubMed

    Tang, Minghua; O'Connor, Lauren E; Campbell, Wayne W

    2014-01-01

    High-protein (>30% of energy from protein or >1.2 g/kg/day) and moderately high-protein (22% to 29% of energy from protein or 1.0 to 1.2 g/kg/day) diets are popular for weight loss, but the effect of dietary protein on bone during weight loss is not well understood. Protein may help preserve bone mass during weight loss by stimulating insulin-like growth factor 1, a potent bone anabolism stimulator, and increasing intestinal calcium absorption. Protein-induced acidity is considered to have minimal effect on bone resorption in adults with normal kidney function. Both the quantity and predominant source of protein influence changes in bone with diet-induced weight loss. Higher-protein, high-dairy diets may help attenuate bone loss during weight loss.

  16. Dietary obesity-induced Egr-1 in adipocytes facilitates energy storage via suppression of FOXC2

    PubMed Central

    Zhang, Jifeng; Zhang, Yuan; Sun, Tingwan; Guo, Fang; Huang, Shengping; Chandalia, Menisha; Abate, Nicola; Fan, Daping; Xin, Hong-Bo; Chen, Y. Eugene; Fu, Mingui

    2013-01-01

    The molecular mechanism to regulate energy balance is not completely understood. Here we observed that Egr-1 expression in white adipose tissue (WAT) was highly correlated with dietary-induced obesity and insulin resistance both in mice and humans. Egr-1 null mice were protected from diet-induced obesity and obesity-associated pathologies such as fatty liver, insulin resistance, hyperlipidemia and hyperinsulinemia. This phenotype can be largely explained by the increase of energy expenditure in Egr-1 null mice. Characterization of these mice revealed that the expression of FOXC2 and its target genes were significantly elevated in white adipose tissues, leading to WAT energy expenditure instead of energy storage. Altogether, these studies suggest an important role for Egr-1, which, by repressing FOXC2 expression, promotes energy storage in WAT and favored the development of obesity under high energy intake. PMID:23502673

  17. Red meat and colon cancer: dietary haem-induced colonic cytotoxicity and epithelial hyperproliferation are inhibited by calcium.

    PubMed

    Sesink, A L; Termont, D S; Kleibeuker, J H; Van der Meer, R

    2001-10-01

    High intake of red meat is associated with increased colon cancer risk. We have shown earlier that this may be due to the high haem content of red meat, because dietary haem increased cytolytic activity of faecal water and colonic epithelial proliferation. Dietary calcium inhibits diet-induced epithelial hyperproliferation. Furthermore, it has been shown that supplemental calcium inhibited the recurrence of colorectal adenomas. Therefore, we studied whether dietary calcium phosphate can exert its protective effects by inhibiting the deleterious effects of haem. In vitro, calcium phosphate precipitated haem and inhibited the haem-induced cytotoxicity. Subsequently, rats were fed diets, differing in haem (0 or 1.3 micromol/g) and calcium phosphate content only (20 or 180 micromol/g). Faeces were collected for biochemical analyses. Cytolytic activity of faecal water was determined from the degree of lysis of erythrocytes by faecal water. Colonic epithelial proliferation was measured in vivo using [(3)H]thymidine incorporation. In rats fed low calcium diets, dietary haem increased cytolytic activity of faecal water (98 +/- 1 versus 1 +/- 1%, P < 0.001) and the concentration of cations in faeces (964 +/- 31 versus 254 +/- 20 micromol/g), when compared with controls. This indicates that dietary haem increased colonic mucosal exposure to luminal irritants. Colonic epithelial proliferation was increased compared with controls (70 +/- 4 versus 48 +/- 8 d.p.m./microg DNA, P < 0.001). This was accompanied by metabolism of the ingested haem and solubilization of haem compounds in the faecal water. A high calcium diet largely prevented this metabolism and solubilization. It also inhibited the haem-induced cytolytic activity of faecal water and increase in faecal cation concentration. In accordance, the haem-induced colonic epithelial hyperproliferation was prevented. We therefore suggest that dietary calcium phosphate acts as a chemopreventive agent in colon carcinogenesis by

  18. Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB₁ receptors: implications for schizophrenia.

    PubMed

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-08-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB₁-dependent manner, whereas pharmacological blockade of CB₁ receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB₁ receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB₁-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB₁ receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

  19. Costs and trade-offs of grazer-induced defenses in Scenedesmus under deficient resource

    NASA Astrophysics Data System (ADS)

    Zhu, Xuexia; Wang, Jun; Chen, Qinwen; Chen, Ge; Huang, Yuan; Yang, Zhou

    2016-03-01

    The green alga Scenedesmus obliquus can form inducible defensive morphs under grazing threat. Costs and trade-offs of inducible defense are expected to accompany the benefits of defensive morphs, but are hard to detect under nutrient-sufficient experimental conditions. To test the existence of costs associated with inducible defense, we cultured S. obliquus along resource availability gradients in the presence or absence of infochemical cues from Daphnia, and measured the strength of defensive colony formation and fitness characters. Under the lowest phosphorous concentration, the expression of inducible defensive colony resulted in decreased growth rate, which provides direct evidence for physiological costs. Along the gradient reduction of phosphorous concentration or light intensity, inducible defense in S. obliquus showed a decreasing trend. However, the photosynthetic efficiency of S. obliquus was barely affected by its defense responses, suggesting that the negative correlations between resource availability and colony formation of this alga may be due to resource-based trade-offs in the allocation of limited resources. Thus, our results indicated that expression of inducible defense of S. obliquus was impaired under insufficient phosphorus or light. Furthermore, under severe phosphate deficiency, obvious physiological costs of inducible defense could be detected even though defensive colony formation also decreased significantly.

  20. Costs and trade-offs of grazer-induced defenses in Scenedesmus under deficient resource

    PubMed Central

    Zhu, Xuexia; Wang, Jun; Chen, Qinwen; Chen, Ge; Huang, Yuan; Yang, Zhou

    2016-01-01

    The green alga Scenedesmus obliquus can form inducible defensive morphs under grazing threat. Costs and trade-offs of inducible defense are expected to accompany the benefits of defensive morphs, but are hard to detect under nutrient-sufficient experimental conditions. To test the existence of costs associated with inducible defense, we cultured S. obliquus along resource availability gradients in the presence or absence of infochemical cues from Daphnia, and measured the strength of defensive colony formation and fitness characters. Under the lowest phosphorous concentration, the expression of inducible defensive colony resulted in decreased growth rate, which provides direct evidence for physiological costs. Along the gradient reduction of phosphorous concentration or light intensity, inducible defense in S. obliquus showed a decreasing trend. However, the photosynthetic efficiency of S. obliquus was barely affected by its defense responses, suggesting that the negative correlations between resource availability and colony formation of this alga may be due to resource-based trade-offs in the allocation of limited resources. Thus, our results indicated that expression of inducible defense of S. obliquus was impaired under insufficient phosphorus or light. Furthermore, under severe phosphate deficiency, obvious physiological costs of inducible defense could be detected even though defensive colony formation also decreased significantly. PMID:26932369

  1. CCR2 deficiency prevents neuronal dysfunction and cognitive impairments induced by cranial irradiation.

    PubMed

    Belarbi, Karim; Jopson, Timothy; Arellano, Carla; Fike, John R; Rosi, Susanna

    2013-02-01

    Cranial irradiation can lead to long-lasting cognitive impairments in patients receiving radiotherapy for the treatment of malignant brain tumors. Recent studies have suggested inflammation as a major contributor to these deficits; we determined if the chemokine (C-C motif) receptor 2 (CCR2) was a mediator of cognitive impairments induced by irradiation. Two-month-old male Ccr2 knockout (-/-) and wild-type mice received 10 Gy cranial irradiation or sham-treatment. One month after irradiation, bromodeoxyuridine was injected intraperitoneally for seven consecutive days to label newly generated cells. At two months postirradiation, cognitive function was assessed by novel object recognition and Morris water maze. Our results show that CCR2 deficiency prevented hippocampus-dependent spatial learning and memory impairments induced by cranial irradiation. Hippocampal gene expression analysis showed that irradiation induced CCR2 ligands such as CCL8 and CCR2 deficiency reduced this induction. Irradiation reduced the number of adult-born neurons in both wild-type and Ccr2(-/-) mice, but the distribution pattern of the adult-born neurons through the granule cell layer was only altered in wild-type mice. Importantly, CCR2 deficiency normalized the fraction of pyramidal neurons expressing the plasticity-related immediate early gene Arc. These data offer new insight into the mechanism(s) of radiation-injury and suggest that CCR2 is a critical mediator of hippocampal neuronal dysfunction and hippocampal cognitive impairments after irradiation. Targeting CCR2 signaling could conceivably provide an effective approach to reduce or prevent the incidence and severity of this serious side effect of ionizing irradiation.

  2. CCR2 deficiency prevents neuronal dysfunction and cognitive impairments induced by cranial irradiation

    PubMed Central

    Belarbi, Karim; Jopson, Timothy; Arellano, Carla; Fike, John R.; Rosi, Susanna

    2013-01-01

    Cranial irradiation can lead to long-lasting cognitive impairments in patients receiving radiotherapy for the treatment of malignant brain tumors. Recent studies have suggested inflammation as a major contributor to these deficits; we determined if the chemokine receptor 2 (CCR2) was a mediator of cognitive impairments induced by irradiation. Two-month-old male Ccr2 knockout (−/−) and wild-type (WT) mice received 10 Gy cranial irradiation or sham-treatment. One month after irradiation, bromodeoxyuridine was injected intraperitoneally for seven consecutive days to label newly generated cells. At two months post-irradiation, cognitive function was assessed by novel object recognition and Morris water maze. Our results demonstrate that CCR2 deficiency prevented hippocampus-dependent spatial learning and memory impairments induced by cranial irradiation. Hippocampal gene expression analysis showed that irradiation induced CCR2 ligands such as CCL8, and CCR2 deficiency reduced this induction. Irradiation reduced the number of adult-born neurons in both WT and Ccr2−/− mice, but the distribution pattern of the adult-born neurons through the granule cell layer was only altered in WT mice. Importantly, CCR2 deficiency normalized the fraction of pyramidal neurons expressing the plasticity-related immediate early gene Arc. These data offer new insight into the mechanism(s) of radiation-injury and suggest that CCR2 is a critical mediator hippocampal neuronal dysfunction and hippocampal cognitive impairments after irradiation. Targeting CCR2 signaling could conceivably provide an effective approach to reduce or prevent the incidence and severity of this serious side effect of ionizing irradiation. PMID:23243025

  3. Genetic deficiency of Syk protects mice from autoantibody-induced arthritis

    PubMed Central

    Jakus, Zoltán; Simon, Edina; Balázs, Bálint; Mócsai, Attila

    2010-01-01

    Objective The Syk tyrosine kinase plays an important role in diverse functions in hematopoietic lineage cells. Although previous in vitro and pharmacologic analyses suggested Syk to be a possible player in the development of autoimmune arthritis, no in vivo genetic studies addressing that issue have yet been reported. The aim of the present study was to test whether genetic deficiency of Syk affects autoantibody-induced experimental arthritis in the K/BxN serum–transfer model. Methods Syk−/− bone marrow chimeras carrying a Syk-deficient hematopoietic system were generated by transplanting Syk−/− fetal liver cells into lethally irradiated wild-type recipients. After complete repopulation of the hematopoietic compartment, autoantibody-mediated arthritis was induced by injection of arthritogenic K/BxN serum. Arthritis development was monitored by macroscopic and microscopic observation of the ankle joints, micro–computed tomography of bone morphology, as well as a joint function assay. Results Genetic deficiency of Syk in the hematopoietic compartment completely blocked the development of all macroscopic and microscopic signs of arthritis. The Syk−/− mutation also prevented the appearance of periarticular bone erosions. Finally, Syk−/− bone marrow chimeras were completely protected from arthritis-induced loss of articular function. Conclusion Our results indicate that Syk is critically involved in the development of all clinically relevant aspects of autoantibody-mediated K/BxN serum–transfer arthritis in experimental mice. These results provide the first in vivo genetic evidence of the role of Syk in the development of autoimmune arthritis. PMID:20201079

  4. Abolishment of TNBS-induced visceral hypersensitivity in mast cell deficient rats.

    PubMed

    Ohashi, Katsuyo; Sato, Yasushi; Kawai, Mitsuhisa; Kurebayashi, Yoichi

    2008-02-13

    Mucosal mast cells are implicated in visceral hypersensitivity associated with irritable bowel syndrome (IBS). In this study, we investigated the role of mast cells in the development of visceral hypersensitivity by using mast cell deficient (Ws/Ws) rats and their control (W+/W+). In W+/W+ rats, an injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the proximal colon produced a significant decrease in pain threshold of the distal colon. Severe mucosal necrosis and inflammatory cell infiltration with concomitant increase in tissue myeloperoxidase activity were observed in the proximal colon that was directly insulted by TNBS, whereas neither necrosis nor increased myeloperoxidase activity occurred in the distal colon, indicating that TNBS-induced hypersensitivity is not caused by the local tissue damage or inflammation in the region of the gut where distention stimuli were applied. On the other hand, TNBS failed to elicit visceral hypersensitivity in Ws/Ws rats. This finding indicates that mast cells are essential for development of TNBS-induced visceral hypersensitivity in rats. Since the severity of TNBS-induced proximal colon injury and MPO activity was not affected by mast cell deficiency, it is unlikely that abolishment of visceral hypersensitivity in mast cell deficient rats was a result of altered development of the primary injury in the proximal colon. There was no difference between sham-operated Ws/Ws and W+/W+ rats in colonic pain threshold to distention stimuli, indicating that mast cells play no modulatory roles in normal colonic nociception. The present results support the view that mucosal mast cells play key roles in the pathogenesis of IBS.

  5. MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment

    PubMed Central

    Van Hove, Inge; Lefevere, Evy; De Groef, Lies; Sergeys, Jurgen; Salinas-Navarro, Manuel; Libert, Claude; Vandenbroucke, Roosmarijn; Moons, Lieve

    2016-01-01

    Matrix metalloproteinase-3 (MMP-3) is known to mediate neuroinflammatory processes by activating microglia, disrupting blood–central nervous system barriers and supporting neutrophil influx into the brain. In addition, the posterior part of the eye, more specifically the retina, the retinal pigment epithelium (RPE) and the blood–retinal barrier, is affected upon neuroinflammation, but a role for MMP-3 during ocular inflammation remains elusive. We investigated whether MMP-3 contributes to acute inflammation in the eye using the endotoxin-induced uveitis (EIU) model. Systemic administration of lipopolysaccharide induced an increase in MMP-3 mRNA and protein expression level in the posterior part of the eye. MMP-3 deficiency or knockdown suppressed retinal leukocyte adhesion and leukocyte infiltration into the vitreous cavity in mice subjected to EIU. Moreover, retinal and RPE mRNA levels of intercellular adhesion molecule 1 (Icam1), interleukin 6 (Il6), cytokine-inducible nitrogen oxide synthase (Nos2) and tumor necrosis factor α (Tnfα), which are key molecules involved in EIU, were clearly reduced in MMP-3 deficient mice. In addition, loss of MMP-3 repressed the upregulation of the chemokines monocyte chemoattractant protein (MCP)-1 and (C-X-C motif) ligand 1 (CXCL1). These findings suggest a contribution of MMP-3 during EIU, and its potential use as a therapeutic drug target in reducing ocular inflammation. PMID:27809288

  6. Dual-specificity phosphatase 6 deficiency regulates gut microbiome and transcriptome response against diet-induced obesity in mice.

    PubMed

    Ruan, Jhen-Wei; Statt, Sarah; Huang, Chih-Ting; Tsai, Yi-Ting; Kuo, Cheng-Chin; Chan, Hong-Lin; Liao, Yu-Chieh; Tan, Tse-Hua; Kao, Cheng-Yuan

    2016-11-28

    The gut microbiota plays profound roles in host metabolism and the inflammatory response associated with the development of obesity. Dusp6-deficient mice have been shown to be resistant to diet-induced obesity, but the mechanism behind this remains unclear. 16S ribosomal RNA gene analysis demonstrated that dusp6-deficient mice harbour unique gut microbiota with resistance to diet-induced-obesity-mediated alteration of the gut microbiome. Using a germ-free mouse model, we found that faecal/gut microbiota derived from dusp6-deficient mice significantly increased energy expenditure and reduced weight gain in recipient wild-type mice fed on a high-fat diet. On analysis of the intestinal transcriptome of dusp6-deficient mice, we found that dusp6 deficiency mainly induced biological processes involved in metabolism and the extracellular matrix, particularly the peroxisome proliferator-activated receptor gamma (Pparγ) pathway and tight-junction genes. Furthermore, dusp6-deficient mice have a high-fat-diet-specific transcriptomic response to reverse the expression of genes associated with intestinal barrier functions and mucosal immunity involved in microbiome homeostasis. This study demonstrates that dusp6 deficiency is a strong genetic factor shaping gut microbiota, and that it confers obesity protection by ameliorating the gut microbiota response to diet-mediated stress.

  7. Nuclear factor-kappaB sensitizes to benzyl isothiocyanate-induced antiproliferation in p53-deficient colorectal cancer cells

    PubMed Central

    Abe, N; Hou, D-X; Munemasa, S; Murata, Y; Nakamura, Y

    2014-01-01

    Benzyl isothiocyanate (BITC), a dietary isothiocyanate derived from cruciferous vegetables, inhibits the proliferation of colorectal cancer cells, most of which overexpress β-catenin as a result of mutations in the genes for adenomatous polyposis coli or mutations in β-catenin itself. Because nuclear factor-κB (NF-κB) is a plausible target of BITC signaling in inflammatory cell models, we hypothesized that it is also involved in BITC-inhibited proliferation of colorectal cancer cells. siRNA-mediated knockdown of the NF-κB p65 subunit significantly decreased the BITC sensitivity of human colorectal cancer HT-29 cells with mutated p53 tumor suppressor protein. Treating HT-29 cells with BITC induced the phosphorylation of IκB kinase, IκB-α and p65, the degradation of IκB-α, the translocation of p65 to the nucleus and the upregulation of NF-κB transcriptional activity. BITC also decreased β-catenin binding to a positive cis element of the cyclin D1 promoter and thus inhibited β-catenin-dependent cyclin D1 transcription, possibly through a direct interaction between p65 and β-catenin. siRNA-mediated knockdown of p65 confirmed that p65 negatively affects cyclin D1 expression. On the other hand, when human colorectal cancer HCT-116 cells with wild-type p53 were treated with BITC, translocation of p65 to the nucleus was inhibited rather than enhanced. p53 knockout increased the BITC sensitivity of HCT-116 cells in a p65-dependent manner, suggesting that p53 negatively regulates p65-dependent effects. Together, these results identify BITC as a novel type of antiproliferative agent that regulates the NF-κB pathway in p53-deficient colorectal cancer cells. PMID:25412312

  8. ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes.

    PubMed

    Liu, Na; Stoica, George; Yan, Mingshan; Scofield, Virginia L; Qiang, Wenan; Lynn, William S; Wong, Paul K Y

    2005-12-01

    ATM kinase, the product of the ataxia telangiectasia mutated (Atm) gene, is activated by genomic damage. ATM plays a crucial role in cell growth and development. Here we report that primary astrocytes isolated from ATM-deficient mice grow slowly, become senescent, and die in culture. However, before reaching senescence, these primary Atm(-/-) astrocytes, like Atm(-/-) lymphocytes, show increased spontaneous DNA synthesis. These astrocytes also show markers of oxidative stress and endoplasmic reticulum (ER) stress, including increased levels of heat shock proteins (HSP70 and GRP78), malondialdehyde adducts, Cu/Zn superoxide dismutase, procaspase 12 cleavage, and redox-sensitive phosphorylation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). In addition, HSP70 and ERK1/2 phosphorylation are upregulated in the cerebella of ATM-deficient mice. This increase in ERK1/2 phosphorylation is seen primarily in cerebellar astrocytes, or Bergmann glia, near degenerating Purkinje cells. ERK1/2 activation and astrogliosis are also found in other parts of the brain, for example, the cortex. We conclude that ATM deficiency induces intrinsic growth defects, oxidative stress, ER stress, and ERKs activation in astrocytes.

  9. Prevalence of overweight in adolescents with intellectual deficiency. Differences in socio-educative context, physical activity and dietary habits.

    PubMed

    Mikulovic, Jacques; Marcellini, Anne; Compte, Roy; Duchateau, Guillaume; Vanhelst, Jérémy; Fardy, Paul S; Bui-Xuan, Gilles

    2011-04-01

    The study investigates the prevalence of overweight and obesity in a population of intellectually disabled (ID) adolescents. An observational study was conducted on a group of 410 ID children, living in France. Overweight and obesity, defined according to international standards, were analyzed and related to demographic and sociological parameters, educational care, physical activity and dietary habits. The study highlighted a high prevalence of overweight and obesity (19.0%) in ID adolescents and 22.5% in oldest teenagers, age 15-20 y. This observation was more likely in medico-educative institutes (25.1%) than in general schools (12.3%). Average time spent in physical activity was 4.5 h/week, compared with 3.5 h/week in obese subjects. Time spent in sedentary behavior was 26.6 h/week for the whole population, compared with 18.6 h/week in obese adolescents. Meals were ingested regularly, and adherence to eating breakfast was good. However, snacks and soft drinks were consumed between and during meals by 66.5% of subjects. Overweight in young ID appeared to be related to parental overweight. Even though ID adolescents receive a balanced diet and practice sport regularly, they exhibit a high prevalence for overweight and obesity. In subjects more than 15 years of age, enrollment in medico-educative institutes and parental overweight were contributory factors to poor weight status.

  10. Dietary resistant maltodextrin ameliorates testicular function and spermatogenesis in streptozotocin-nicotinamide-induced diabetic rats.

    PubMed

    Liu, C-Y; Hsu, Y-J; Chien, Y-W E; Cha, T-L; Tsao, C-W

    2016-05-01

    This study investigated the effect of resistant maltodextrin (RMD) on reproduction in streptozotocin (STZ)-nicotinamide-induced type 2 diabetic male rats. Forty male rats were induced with diabetes by a single intraperitoneal injection of STZ (50 mg kg(-1)) and nicotinamide (100 mg kg(-1)). Five groups were analysed in total: normal, diabetic rats without RMD, diabetic rats with RMD 1.2 g per 100 g diet (1×), with RMD 2.4 g per 100 g (2×), and with RMD 6.0 g per 100 g (5×). The groups of diabetic rats with the RMD supplement, compared to those without supplement, showed improved plasma glucose control, attenuated insulin resistance and recovery of testosterone level and spermatogenesis stage. The STZ-nicotinamide-induced diabetes mellitus (DM) caused a significant reduction in serum testosterone, testis androgen receptor (AR), steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) protein, but a statistical recovery in each of these was observed in the 5× group. TUNEL-positive cells were observed in the diabetic without RMD group, and RMD treatment reduced apoptotic germ cells. The expression of Bax/Bcl2 was induced in the diabetic group and also significantly reduced in the 5× group. Dietary RMD may improve metabolic control in STZ-nicotinamide-induced diabetic rats and attenuate hyperglycaemia-related impaired male reproduction and testicular function.

  11. Osteoprotective effect of cordycepin on estrogen deficiency-induced osteoporosis in vitro and in vivo.

    PubMed

    Zhang, Da-wei; Deng, Hualiang; Qi, Wei; Zhao, Guang-yue; Cao, Xiao-rui

    2015-01-01

    The purpose of this study was to verify the effect of cordycepin on ovariectomized osteopenic rats. Fifty Wistar female rats used were divided into 5 groups: (1) sham-operation rats (control), (2) ovariectomized (OVX) rats with osteopenia, and (3) OVX'd rats with osteopenia treated with cordycepin (5 mg, 10 mg, and 20 mg) for 8 weeks. After the rats were treated orally with cordycepin, serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), serum osteocalcin (OC), homocysteine (HCY) , C-terminal crosslinked telopeptides of collagen type I (CTX) level, and oxidative stress were examined, respectively. The femoral neck was used for mechanical compression testing. At the same time, we further investigated the effect of cordycepin in vitro assay. The beneficial effects of cordycepin on improvement of osteoporosis in rats were attributable mainly to decrease ALP activity, TRAP activity, and CTX level. At the same time, cordycepin also increases the OC level in ovariectomized osteopenic rats. The histological examination clearly showed that dietary cordycepin can prevent bone loss caused by estrogen deficiency. These experimental results suggest that complement cordycepin is protective after ovariectomized osteopenic in specific way.

  12. Osteoprotective Effect of Cordycepin on Estrogen Deficiency-Induced Osteoporosis In Vitro and In Vivo

    PubMed Central

    Zhang, Da-wei; Deng, Hualiang; Qi, Wei; Zhao, Guang-yue; Cao, Xiao-rui

    2015-01-01

    The purpose of this study was to verify the effect of cordycepin on ovariectomized osteopenic rats. Fifty Wistar female rats used were divided into 5 groups: (1) sham-operation rats (control), (2) ovariectomized (OVX) rats with osteopenia, and (3) OVX'd rats with osteopenia treated with cordycepin (5 mg, 10 mg, and 20 mg) for 8 weeks. After the rats were treated orally with cordycepin, serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), serum osteocalcin (OC), homocysteine (HCY) , C-terminal crosslinked telopeptides of collagen type I (CTX) level, and oxidative stress were examined, respectively. The femoral neck was used for mechanical compression testing. At the same time, we further investigated the effect of cordycepin in vitro assay. The beneficial effects of cordycepin on improvement of osteoporosis in rats were attributable mainly to decrease ALP activity, TRAP activity, and CTX level. At the same time, cordycepin also increases the OC level in ovariectomized osteopenic rats. The histological examination clearly showed that dietary cordycepin can prevent bone loss caused by estrogen deficiency. These experimental results suggest that complement cordycepin is protective after ovariectomized osteopenic in specific way. PMID:25874211

  13. Ischemia/reperfusion-induced Kidney Injury in Heterozygous PACAP-deficient Mice.

    PubMed

    Laszlo, E; Varga, A; Kovacs, K; Jancso, G; Kiss, P; Tamas, A; Szakaly, P; Fulop, B; Reglodi, D

    2015-09-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with very diverse distribution and functions. Among others, PACAP is a potent cytoprotective peptide due to its antiapoptotic, anti-inflammatory, and antioxidant actions. This also has been shown in different kidney pathologies, including ischemia/reperfusion-induced kidney injury. Similar protective effects of the endogenous PACAP are confirmed by the increased vulnerability of PACAP-deficient mice to different harmful stimuli. Kidneys of homozygous PACAP-deficient mice have more severe damages in renal ischemia/reperfusion and kidney cell cultures isolated from these mice show increased sensitivity to renal oxidative stress. In our present study we raised the question of whether the partial lack of the PACAP gene is also deleterious, i.e. whether heterozygous PACAP-deficient mice also display more severe damage after renal ischemia/reperfusion. Mice underwent 45 or 60 minutes of ischemia followed by 2 weeks reperfusion. Histological evaluation of the kidneys was performed and individual histopathological parameters were graded. Furthermore, we investigated apoptotic markers, cytokine expression, and the activity of superoxide dismutase (SOD) enzyme 24 hours after 60 minutes of renal ischemia/reperfusion. We found no difference between the intact kidneys of wild-type and heterozygous mice, but marked differences could be observed following ischemia/reperfusion. Heterozygous PACAP-deficient mice had more severe histological alterations, with significantly higher histopathological scores for most of the tested parameters. Higher level of the proapoptotic pp38 MAPK and of some proinflammatory cytokines, as well as lower activity of the antioxidant SOD could be found in these mice. In conclusion, the partial lack of the PACAP gene results in worse outcomes in cases of renal ischemia/reperfusion, confirming that PACAP functions as an endogenous protective factor in the kidney.

  14. Aging-associated formaldehyde-induced norepinephrine deficiency contributes to age-related memory decline.

    PubMed

    Mei, Yufei; Jiang, Chun; Wan, You; Lv, Jihui; Jia, Jianping; Wang, Xiaomin; Yang, Xu; Tong, Zhiqian

    2015-08-01

    A norepinephrine (NE) deficiency has been observed in aged rats and in patients with Alzheimer's disease and is thought to cause cognitive disorder. Which endogenous factor induces NE depletion, however, is largely unknown. In this study, we investigated the effects of aging-associated formaldehyde (FA) on the inactivation of NE in vitro and in vivo, and on memory behaviors in rodents. The results showed that age-related DNA demethylation led to hippocampal FA accumulation, and when this occurred, the hippocampal NE content was reduced in healthy male rats of different ages. Furthermore, biochemical analysis revealed that FA rapidly inactivated NE in vitro and that an intrahippocampal injection of FA markedly reduced hippocampal NE levels in healthy adult rats. Unexpectedly, an injection of FA (at a pathological level) or 6-hydroxydopamine (6-OHDA, a NE depletor) can mimic age-related NE deficiency, long-term potentiation (LTP) impairments, and spatial memory deficits in healthy adult rats. Conversely, an injection of NE reversed age-related deficits in both LTP and memory in aged rats. In agreement with the above results, the senescence-accelerated prone 8 (SAMP8) mice also exhibited a severe deficit in LTP and memory associated with a more severe NE deficiency and FA accumulation, when compared with the age-matched, senescence-resistant 1 (SAMR1) mice. Injection of resveratrol (a natural FA scavenger) or NE into SAMP8 mice reversed FA accumulation and NE deficiency and restored the magnitude of LTP and memory. Collectively, these findings suggest that accumulated FA is a critical endogenous factor for aging-associated NE depletion and cognitive decline.

  15. FOXO1 Mediates Vitamin D Deficiency-induced Insulin Resistance in Skeletal Muscle

    PubMed Central

    Chen, Songcang; Villalta, Armando; Agrawal, Devendra K.

    2015-01-01

    Prospective epidemiological studies have consistently shown a relationship between vitamin D deficiency, insulin resistance, and type 2 diabetes mellitus (DM2). This is supported by recent trials showing that vitamin D supplementation in prediabetic or insulin-resistant patients with inadequate vitamin D levels improves insulin sensitivity. However, the molecular mechanisms underlying vitamin D deficiency-induced insulin resistance and DM2 remain unknown. Skeletal muscle insulin resistance is a primary defect in the majority of patients with DM2. While sustained activation of forkhead box O1 (FOXO1) in skeletal muscle causes insulin resistance, a relationship between vitamin D deficiency and FOXO1 activation in muscle is unknown. We generated skeletal muscle-specific vitamin D receptor (VDR)-null mice and discovered that these mice developed insulin resistance and glucose intolerance accompanied by increased expression and activity of FOXO1. We also found sustained FOXO1 activation in the skeletal muscle of global VDR-null mice. Treatment of C2C12 muscle cells with 1,25-dihydroxyvitamin D (VD3) reduced FOXO1 expression, nuclear translocation, and activity. The VD3-dependent suppression of FOXO1 activation disappeared by knockdown of VDR, indicating that it is VDR-dependent. Taken together, these results suggest that FOXO1 is a critical target mediating VDR-null signaling in skeletal muscle. The novel findings provide the conceptual support that persistent FOXO1 activation may be responsible for insulin resistance and impaired glucose metabolism in vitamin D signaling-deficient mice, as well as evidence for the utility of vitamin D supplementation for intervention in DM2. PMID:26462119

  16. FOXO1 Mediates Vitamin D Deficiency-Induced Insulin Resistance in Skeletal Muscle.

    PubMed

    Chen, Songcang; Villalta, S Armando; Agrawal, Devendra K

    2016-03-01

    Prospective epidemiological studies have consistently shown a relationship between vitamin D deficiency, insulin resistance, and type 2 diabetes mellitus (DM2). This is supported by recent trials showing that vitamin D supplementation in prediabetic or insulin-resistant patients with inadequate vitamin D levels improves insulin sensitivity. However, the molecular mechanisms underlying vitamin D deficiency-induced insulin resistance and DM2 remain unknown. Skeletal muscle insulin resistance is a primary defect in the majority of patients with DM2. Although sustained activation of forkhead box O1 (FOXO1) in skeletal muscle causes insulin resistance, a relationship between vitamin D deficiency and FOXO1 activation in muscle is unknown. We generated skeletal muscle-specific vitamin D receptor (VDR)-null mice and discovered that these mice developed insulin resistance and glucose intolerance accompanied by increased expression and activity of FOXO1. We also found sustained FOXO1 activation in the skeletal muscle of global VDR-null mice. Treatment of C2C12 muscle cells with 1,25-dihydroxyvitamin D (VD3) reduced FOXO1 expression, nuclear translocation, and activity. The VD3-dependent suppression of FOXO1 activation disappeared by knockdown of VDR, indicating that it is VDR-dependent. Taken together, these results suggest that FOXO1 is a critical target mediating VDR-null signaling in skeletal muscle. The novel findings provide the conceptual support that persistent FOXO1 activation may be responsible for insulin resistance and impaired glucose metabolism in vitamin D signaling-deficient mice, as well as evidence for the utility of vitamin D supplementation for intervention in DM2.

  17. N-Nitrosocarbaryl-induced mutagenesis in Haemophilus influenzae strains deficient in repair and recombination.

    PubMed

    Beattie, K L

    1975-02-01

    Mutagenesis was studied in repair- and recombination-deficient strains of Haemophilus influenzae after treatment with N-nitrosocarbaryl (NC). Three different strains of H. influenzae carrying mutations affecting excision-repair of UV-induced pyrimidine dimers exhibited normal repair of premutational lesions (as detected by decreased mutation yield resulting from post-treatment DNA synthesis delay) and normal nonreplicative mutation fixation. This indicated that neither of these phenomena are caused by the smae repair mechanism that removes UV-induced pyrimidine dimers from the DNA. The recombination-deficient mutant recI is apparently deficient in the replication-dependent mode of NC-induced mutation fixation. This conclusion is based on the following results: (I) NC-induced mutagenesis is lower in the recI strain than in rec+ cells. (2) Repair of premutational lesions (which depends on the existence of replication-dependent mutation fixation for its detection) was not detected in the recI strain. (3) When nonreplicative mutation fixation and final mutation frequency were measured in the same experiment, about I/4 to I/3 of the final mutation yield could be accounted for by nonreplicative mutation fixation in the rec+ strain, whereas all of the mutation could be accounted for in the recI strain by the nonreplicative mutation fixation. (4) When mutation fixation in strain dna9 recI was followed at the permissive (36 degrees) and nonpermissive (41 degrees) temperatures, it became apparent that in the recI strain replication-dependent mutation fixation occurs at early times, but these newly fixed mutations are unstable and disappear at later times, leaving only the mutations fixed by the nonreplicative process. The recI strain exhibits normal repair of NC-induced single-strand breaks or alkali-labile bonds in the DNA labeled before treatment, but is slow in joining discontinuties present in DNA synthesized after treatment. The results are consistent with the idea that

  18. ANA deficiency enhances bone morphogenetic protein-induced ectopic bone formation via transcriptional events.

    PubMed

    Miyai, Kentaro; Yoneda, Mitsuhiro; Hasegawa, Urara; Toita, Sayaka; Izu, Yayoi; Hemmi, Hiroaki; Hayata, Tadayoshi; Ezura, Yoichi; Mizutani, Shuki; Miyazono, Kohei; Akiyoshi, Kazunari; Yamamoto, Tadashi; Noda, Masaki

    2009-04-17

    Ectopic bone formation after joint replacement or brain injury in humans is a serious complication that causes immobility of joints and severe pain. However, mechanisms underlying such ectopic bone formation are not fully understood. Bone morphogenetic protein (BMPs) are defined as inducers of ectopic bone formation, and they are regulated by several types of inhibitors. ANA is an antiproliferative molecule that belongs to Tob/BTG family, but its activity in bone metabolism has not been known. Here, we examined the role of ANA on ectopic bone formation activity of BMP. In ANA-deficient and wild-type mice, BMP2 was implanted to induce ectopic bone formation in muscle. ANA deficiency increased mass of newly formed bone in vivo compared with wild-type based on 3D-muCT analyses. ANA mRNA was expressed in bone in vivo as well as in osteoblastic cells in vitro. Such ANA mRNA levels were increased by BMP2 treatment in MC3T3-E1 osteoblastic cells. Overexpression of ANA suppressed BMP-induced expression of luciferase reporter gene linked to BMP response elements in these cells. Conversely, ANA mRNA knockdown by small interference RNA enhanced the BMP-dependent BMP response element reporter expression. It also enhanced BMP-induced osteoblastic differentiation in muscle-derived C2C12 cells. Immunoprecipitation assay indicated that ANA interacts with Smad8. Thus, ANA is a suppressor of ectopic bone formation induced by BMP, and this inhibitory ANA activity is a part of the negative feedback regulation of BMP function.

  19. Edge-induced narrowing of dietary diversity in leaf-cutting ants.

    PubMed

    Falcão, P F; Pinto, S R R; Wirth, R; Leal, I R

    2011-06-01

    Much of the ecological alteration faced by human-modified Neotropical forests can be assigned to edge effects, including the proliferation of some voracious herbivores such as leaf-cutting ants. However, the underlying mechanisms/impacts of tropical forest edge on herbivores performance and their foraging behaviour (e.g. dietary diversity) have rarely been investigated. The goal of this study was, therefore, to determine whether and how the annual diet (i.e. species richness, diversity and the relative proportion of pioneer versus non-pioneer species of plant materials) of Atta cephalotes colonies differs in the forest edge versus the interior zone of a large remnant of Atlantic forest in northeastern Brazil. Among the key results was a strong habitat effect on dietary diversity (explaining ca. 40-50% of the variation), which, in edge colonies, decreased approximately by one fourth compared to interior colonies (inverse of Simpson's index: 3.7±0.84 versus 4.99±0.95). There was a predominance of leaf fragments collected from pioneer species in the diet in both habitat (86% in edge and 80.4% in interior). Edge colonies collected proportionally more fragments from pioneer species than colonies located in the forest interior. Our results are the first to demonstrate an edge-mediated relaxation of dietary restrictions in leaf-cutting ants. These findings render robust support to previous evidence indicating the reduction of bottom-up forces as a key factor explaining both edge-induced hyper-abundance and increased herbivory of leaf-cutting ants in human-modified Neotropical landscapes.

  20. ZINC FINGER OF ARABIDOPSIS THALIANA12 (ZAT12) Interacts with FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT) Linking Iron Deficiency and Oxidative Stress Responses.

    PubMed

    Le, Cham Thi Tuyet; Brumbarova, Tzvetina; Ivanov, Rumen; Stoof, Claudia; Weber, Eva; Mohrbacher, Julia; Fink-Straube, Claudia; Bauer, Petra

    2016-01-01

    Plants grown under iron (Fe)-deficient conditions induce a set of genes that enhance the efficiency of Fe uptake by the roots. In Arabidopsis (Arabidopsis thaliana), the central regulator of this response is the basic helix-loop-helix transcription factor FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT). FIT activity is regulated by protein-protein interactions, which also serve to integrate external signals that stimulate and possibly inhibit Fe uptake. In the search of signaling components regulating FIT function, we identified ZINC FINGER OF ARABIDOPSIS THALIANA12 (ZAT12), an abiotic stress-induced transcription factor. ZAT12 interacted with FIT, dependent on the presence of the ethylene-responsive element-binding factor-associated amphiphilic repression motif. ZAT12 protein was found expressed in the root early differentiation zone, where its abundance was modulated in a root layer-specific manner. In the absence of ZAT12, FIT expression was upregulated, suggesting a negative effect of ZAT12 on Fe uptake. Consistently, zat12 loss-of-function mutants had higher Fe content than the wild type at sufficient Fe. We found that under Fe deficiency, hydrogen peroxide (H2O2) levels were enhanced in a FIT-dependent manner. FIT protein, in turn, was stabilized by H2O2 but only in the presence of ZAT12, showing that H2O2 serves as a signal for Fe deficiency responses. We propose that oxidative stress-induced ZAT12 functions as a negative regulator of Fe acquisition. A model where H2O2 mediates the negative regulation of plant responses to prolonged stress might be applicable to a variety of stress conditions.

  1. Dietary Omega-3 Fatty Acid Deficiency and High Fructose intake in the Development of Metabolic Syndrome Brain, Metabolic Abnormalities, and Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Simopoulos, Artemis P.

    2013-01-01

    Western diets are characterized by both dietary omega-3 fatty acid deficiency and increased fructose intake. The latter found in high amounts in added sugars such as sucrose and high fructose corn syrup (HFCS). Both a low intake of omega-3 fatty acids or a high fructose intake contribute to metabolic syndrome, liver steatosis or non-alcoholic fatty liver disease (NAFLD), promote brain insulin resistance, and increase the vulnerability to cognitive dysfunction. Insulin resistance is the core perturbation of metabolic syndrome. Multiple cognitive domains are affected by metabolic syndrome in adults and in obese adolescents, with volume losses in the hippocampus and frontal lobe, affecting executive function. Fish oil supplementation maintains proper insulin signaling in the brain, ameliorates NAFLD and decreases the risk to metabolic syndrome suggesting that adequate levels of omega-3 fatty acids in the diet can cope with the metabolic challenges imposed by high fructose intake in Western diets which is of major public health importance. This review presents the current status of the mechanisms involved in the development of the metabolic syndrome, brain insulin resistance, and NAFLD a most promising area of research in Nutrition for the prevention of these conditions, chronic diseases, and improvement of Public Health. PMID:23896654

  2. Responses of brown adipose tissue to diet-induced obesity, exercise, dietary restriction and ephedrine treatment.

    PubMed

    Slocum, Nikki; Durrant, Jessica R; Bailey, David; Yoon, Lawrence; Jordan, Holly; Barton, Joanna; Brown, Roger H; Clifton, Lisa; Milliken, Tula; Harrington, Wallace; Kimbrough, Carie; Faber, Catherine A; Cariello, Neal; Elangbam, Chandikumar S

    2013-07-01

    Drug-induced weight loss in humans has been associated with undesirable side effects not present in weight loss from lifestyle interventions (caloric restriction or exercise). To investigate the mechanistic differences of weight loss by drug-induced and lifestyle interventions, we examined the gene expression (mRNA) in brown adipose tissue (BAT) and conducted histopathologic assessments in diet-induced obese (DIO) mice given ephedrine (18 mg/kg/day orally), treadmill exercise (10 m/min, 1-h/day), and dietary restriction (DR: 26% dietary restriction) for 7 days. Exercise and DR mice lost more body weight than controls and both ephedrine and exercise reduced percent body fat. All treatments reduced BAT and liver lipid accumulation (i.e., cytoplasmic lipids in brown adipocytes and hepatocytes) and increased oxygen consumption (VO2 ml/kg/h) compared with controls. Mitochondrial biogenesis/function-related genes (TFAM, NRF1 and GABPA) were up-regulated in the BAT of all groups. UCP-1 was up-regulated in exercise and ephedrine groups, whereas MFSD2A was up-regulated in ephedrine and DR groups. PGC-1α up-regulation was observed in exercise and DR groups but not in ephedrine group. In all experimental groups, except for ephedrine, fatty acid transport and metabolism genes were up-regulated, but the magnitude of change was higher in the DR group. PRKAA1 was up-regulated in all groups but not significantly in the ephedrine group. ADRß3 was slightly up-regulated in the DR group only, whereas ESRRA remained unchanged in all groups. Although our data suggest a common pathway of BAT activation elicited by ephedrine treatment, exercise or DR, mRNA changes were indicative of additional nutrient-sensing pathways in exercise and DR.

  3. Recovery of bone strength in young pigs from an induced short-term dietary calcium deficit followed by a calcium replete diet.

    PubMed

    Aiyangar, Ameet K; Au, Anthony G; Crenshaw, Thomas D; Ploeg, Heidi-Lynn

    2010-12-01

    This study investigated whether the deficits in bone strength of pre-pubertal pigs, induced by short-term deficits in dietary calcium can be recovered if followed by a calcium-fortified diet. Young pigs were divided into two groups based on diet: a marginal Ca diet (70% of established Ca requirements) or an excess Ca diet (150% of established Ca requirements) for 4 weeks. Each group was then randomly sub-divided into two groups and fed diets with either marginal or excess dietary Ca for 6 weeks in a cross-over design, resulting in four treatment groups: H150-H150, H150-L70, L70-H150, and L70-L70. Animals were DXA scanned at 2-week intervals during the 10-week period to obtain whole body bone mineral content (BMC) and density (BMD). After animals were euthanized, right femurs were collected for this study. Traits such as bone mineral density, mass, volume, area moment of inertia (MI) and the section modulus (SM) were computed from computed tomography (CT) data and failure load was measured from four-point bending tests. DXA results showed significant reduction in BMC (61.6%) and BMD (37.5%) in the (L70-L70) group compared to the (H150-H150) group. DXA results additionally showed that deficiencies induced by the 4-week marginal Ca diet in the (L70-H150) group were not recovered with a subsequent excess Ca diet. While mechanical test results also showed significant reduction (75%) in strength in the L70-L70 group, compared to the H150-H150 group, they revealed no differences between the failure loads of the (L70-H150) group and the (H150-H150) group. Similar results were also found for bone mineral mass and volume, indicating that recovery from a short-term dietary Ca deficiency is possible at the pre-pubertal stage. Furthermore, bone mineral content and bone volume calculated from CT data correlated highly with failure load (R(2)=0.78 and 0.84, respectively), while density, MI and SM only showed weak-to-moderate correlations (R(2)=0.40-0.56), implying that bone

  4. Gestational magnesium deficiency is deleterious to fetal outcome.

    PubMed

    Almonte, R A; Heath, D L; Whitehall, J; Russell, M J; Patole, S; Vink, R

    1999-07-01

    A number of recent epidemiological findings have implicated magnesium as being essential to fetal well-being. Few studies, however, have examined the relationship between maternal requirements for dietary magnesium and subsequent mortality and morbidity in offspring. The present study uses a rodent model of dietary-induced hypomagnesemia to investigate the effects of magnesium deficiency prior to and during gestation on neonatal morbidity and mortality. Magnesium deficiency during gestation significantly increased neonatal mortality and morbidity. Such increases were associated with a reduced free magnesium concentration in both maternal and offspring blood and an increased incidence of periventricular hemorrhage and edema in newborn pups as observed by magnetic resonance imaging and histology. Animals fed a magnesium-deficient diet before mating but given magnesium supplementation during gestation did not demonstrate a significant change in neonatal mortality and morbidity when compared to control animals. The significant improvement in fetal outcome with dietary magnesium supports the concept of magnesium supplementation during pregnancy.

  5. Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial.

    PubMed

    Basaria, Shehzad; Travison, Thomas G; Alford, Daniel; Knapp, Philip E; Teeter, Kjersten; Cahalan, Christine; Eder, Richard; Lakshman, Kishore; Bachman, Eric; Mensing, George; Martel, Marc O; Le, Dillon; Stroh, Helene; Bhasin, Shalender; Wasan, Ajay D; Edwards, Robert R

    2015-02-01

    Symptomatic androgen deficiency is common in patients taking opioid analgesics, as these drugs potently suppress the hypothalamic-pituitary-gonadal axis. However, the efficacy of testosterone replacement in this setting remains unclear. The objective of this trial was to evaluate the efficacy of testosterone replacement on pain perception and other androgen-dependent outcomes in men with opioid-induced androgen deficiency. We conducted a randomized, double-blind, parallel placebo-controlled trial at an outpatient academic research center. Participants were men aged 18 to 64 years on opioid analgesics for chronic noncancer pain, and total testosterone levels were <350 ng/dL. Participants were randomly assigned to 14 weeks of daily transdermal gel that contained 5 g of testosterone or placebo. Primary outcomes were changes in self-reported clinical pain and objectively assessed pain sensitivity. Sexual function, quality of life, and body composition were also assessed. The mean age was 49 years. The median total and free testosterone levels at baseline were 243 ng/dL and 47 pg/mL and 251 ng/dL and 43 pg/mL in the testosterone and placebo arm, respectively. Of the 84 randomized participants, 65 had follow-up data on efficacy outcomes. Compared with men assigned to the placebo arm, those assigned to testosterone replacement experienced greater improvements in pressure and mechanical hyperalgesia, sexual desire, and role limitation due to emotional problems. Testosterone administration was also associated with an improvement in body composition. There were no between-group differences in changes in self-reported pain. In conclusion, in men with opioid-induced androgen deficiency, testosterone administration improved pain sensitivity, sexual desire, body composition, and aspects of quality of life.

  6. Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

    PubMed Central

    Spassieva, Stefka D.; Ji, Xiaojie; Liu, Ye; Gable, Kenneth; Bielawski, Jacek; Dunn, Teresa M.; Bieberich, Erhard; Zhao, Lihong

    2016-01-01

    Sphingolipids exhibit extreme functional and chemical diversity that is in part determined by their hydrophobic moiety, ceramide. In mammals, the fatty acyl chain length variation of ceramides is determined by six (dihydro)ceramide synthase (CerS) isoforms. Previously, we and others showed that mutations in the major neuron-specific CerS1, which synthesizes 18-carbon fatty acyl (C18) ceramide, cause elevation of long-chain base (LCB) substrates and decrease in C18 ceramide and derivatives in the brain, leading to neurodegeneration in mice and myoclonus epilepsy with dementia in humans. Whether LCB elevation or C18 ceramide reduction leads to neurodegeneration is unclear. Here, we ectopically expressed CerS2, a nonneuronal CerS producing C22–C24 ceramides, in neurons of Cers1-deficient mice. Surprisingly, the Cers1 mutant pathology was almost completely suppressed. Because CerS2 cannot replenish C18 ceramide, the rescue is likely a result of LCB reduction. Consistent with this hypothesis, we found that only LCBs, the substrates common for all of the CerS isoforms, but not ceramides and complex sphingolipids, were restored to the wild-type levels in the Cers2-rescued Cers1 mutant mouse brains. Furthermore, LCBs induced neurite fragmentation in cultured neurons at concentrations corresponding to the elevated levels in the CerS1-deficient brain. The strong association of LCB levels with neuronal survival both in vivo and in vitro suggests high-level accumulation of LCBs is a possible underlying cause of the CerS1 deficiency-induced neuronal death. PMID:27162368

  7. Beta-aminoisobutyric acid prevents diet-induced obesity in mice with partial leptin deficiency.

    PubMed

    Begriche, Karima; Massart, Julie; Abbey-Toby, Adjé; Igoudjil, Anissa; Lettéron, Philippe; Fromenty, Bernard

    2008-09-01

    Beta-Aminoisobutyric acid (BAIBA), a thymine catabolite, increases fatty acid oxidation (FAO) in liver and reduces the gain of body fat mass in Swiss (lean) mice fed a standard chow. We determined whether BAIBA could prevent obesity and related metabolic disorders in different murine models. To this end, BAIBA (100 or 500 mg/kg/day) was administered for 4 months in mice totally deficient in leptin (ob/ob). BAIBA (100 mg/kg/day) was also given for 4 months in wild-type (+/+) mice and mice partially deficient in leptin (ob/+) fed a high-calorie (HC) diet. BAIBA did not limit obesity and hepatic steatosis in ob/ob mice, but reduced liver cytolysis and inflammation. In ob/+ mice fed the HC diet, BAIBA fully prevented, or limited, the gain of body fat, steatosis and necroinflammation, glucose intolerance, and hypertriglyceridemia. Plasma beta-hydroxybutyrate was increased, whereas expression of carnitine palmitoyltransferase-1 was augmented in liver and white adipose tissue. Acetyl-CoA carboxylase was more phosphorylated, and de novo lipogenesis was less induced in liver. These favorable effects of BAIBA in ob/+ mice were associated with a restoration of plasma leptin levels. The reduction of body adiposity afforded by BAIBA was less marked in +/+ mice. Finally, BAIBA significantly stimulated the secretion of leptin in isolated ob/+ adipose cells, but not in +/+ cells. Thus, BAIBA could limit triglyceride accretion in tissues through a leptin-dependent stimulation of FAO. As partial leptin deficiency is not uncommon in the general population, supplementation with BAIBA may help to prevent diet-induced obesity and related metabolic disorders in low leptin secretors.

  8. Dietary polyunsaturated fatty acids in asthma- and exercise-induced bronchoconstriction.

    PubMed

    Mickleborough, T D; Rundell, K W

    2005-12-01

    Despite progress that has been made in the treatment of asthma, the prevalence and burden of this disease has continued to increase. While pharmacological treatment of asthma is usually highly effective, medications may have significant side effects or exhibit tachyphylaxis. Alternative therapies for treatment that reduce the dose requirements of pharmacological interventions would be beneficial, and could potentially reduce the public health burden of this disease. Ecological and temporal data suggest that dietary factors may have a role in recent increases in the prevalence of asthma. A possible contributing factor to the increased incidence of asthma in Western societies may be the consumption of a proinflammatory diet. In the typical Western diet, 20- to 25-fold more omega (n)-6 polyunsaturated fatty acids (PUFA) than n-3 PUFA are consumed, which promotes the release of proinflammatory arachidonic acid metabolites (leukotrienes and prostanoids). This review will analyze the evidence for the health effects of n-3 PUFA in asthma- and exercise-induced bronchoconstriction (EIB). While clinical data evaluating the effect of omega-3 fatty acid supplementation in asthma has been equivocal, it has recently been shown that fish oil supplementation, rich in n-3 PUFA, reduces airway narrowing, medication use, and proinflammatory mediator generation in nonatopic elite athletes with EIB. These findings are provocative and suggest that dietary fish oil supplementation may be a viable treatment modality and/or adjunct therapy in asthma and EIB.

  9. Diet-Induced Obesity and Reduced Skin Cancer Susceptibility in Matrix Metalloproteinase 19-Deficient Mice

    PubMed Central

    Pendás, Alberto M.; Folgueras, Alicia R.; Llano, Elena; Caterina, John; Frerard, Françoise; Rodríguez, Francisco; Astudillo, Aurora; Noël, Agnès; Birkedal-Hansen, Henning; López-Otín, Carlos

    2004-01-01

    Matrix metalloproteinase 19 (MMP-19) is a member of the MMP family of endopeptidases that, in contrast to most MMPs, is widely expressed in human tissues under normal quiescent conditions. MMP-19 has been found to be associated with ovulation and angiogenic processes and is deregulated in diverse pathological conditions such as rheumatoid arthritis and cancer. To gain further insights into the in vivo functions of this protease, we have generated mutant mice deficient in Mmp19. These mice are viable and fertile and do not display any obvious abnormalities. However, Mmp19-null mice develop a diet-induced obesity due to adipocyte hypertrophy and exhibit decreased susceptibility to skin tumors induced by chemical carcinogens. Based on these results, we suggest that this enzyme plays an in vivo role in some of the tissue remodeling events associated with adipogenesis, as well as in pathological processes such as tumor progression. PMID:15169894

  10. Vulnerability of conditional NCAM-deficient mice to develop stress-induced behavioral alterations.

    PubMed

    Bisaz, Reto; Sandi, Carmen

    2012-03-01

    Previous studies in rodents showed that chronic stress induces structural and functional alterations in several brain regions, including shrinkage of the hippocampus and the prefrontal cortex, which are accompanied by cognitive and emotional disturbances. Reduced expression of the neural cell adhesion molecule (NCAM) following chronic stress has been proposed to be crucially involved in neuronal retraction and behavioral alterations. Since NCAM gene polymorphisms and altered expression of alternatively spliced NCAM isoforms have been associated with bipolar depression and schizophrenia in humans, we hypothesized that reduced expression of NCAM renders individuals more vulnerable to the deleterious effects of stress on behavior. Here, we specifically questioned whether mice in which the NCAM gene is inactivated in the forebrain by cre-recombinase under the control of the calcium-calmodulin-dependent kinase II promoter (conditional NCAM-deficient mice), display increased vulnerability to stress. We assessed the evolving of depressive-like behaviors and spatial learning and memory impairments following a subchronic stress protocol (2 weeks) that does not result in behavioral dysfunction, nor in altered NCAM expression, in wild-type mice. Indeed, while no behavioral alterations were detected in wild-type littermates after subchronic stress, conditional NCAM-deficient mice showed increased immobility in the tail suspension test and deficits in reversal spatial learning in the water maze. These findings indicate that diminished NCAM expression might be a critical vulnerability factor for the development of behavioral alterations by stress and further support a functional involvement of NCAM in stress-induced cognitive and emotional disturbances.

  11. Growth hormone secretagogue receptor deficiency in mice protects against obesity‐induced hypertension

    PubMed Central

    Harris, Louise E.; Morgan, David G.; Balthasar, Nina

    2014-01-01

    Abstract Growth hormone secretagogue receptor (GHS‐R) signaling has been associated with growth hormone release, increases in food intake and pleiotropic cardiovascular effects. Recent data demonstrated that acute GHS‐R antagonism leads to increases in mean arterial pressure mediated by the sympathetic nervous system in rats; a highly undesirable effect if GHS‐R antagonism was to be used as a therapeutic approach to reducing food intake in an already obese, hypertensive patient population. However, our data in conscious, freely moving GHS‐R deficient mice demonstrate that chronic absence of GHS‐R signaling is protective against obesity‐induced hypertension. GHS‐R deficiency leads to reduced systolic blood pressure variability (SBPV); in response to acute high‐fat diet (HFD)‐feeding, increases in the sympathetic control of SBPV are suppressed in GHS‐R KO mice. Our data further suggest that GHS‐R signaling dampens the immediate HFD‐mediated increase in spontaneous baroreflex sensitivity. In diet‐induced obesity, absence of GHS‐R signaling leads to reductions in obesity‐mediated hypertension and tachycardia. Collectively, our findings thus suggest that chronic blockade of GHS‐R signaling may not result in adverse cardiovascular effects in obesity. PMID:24760503

  12. Gibberellin deficiency pleiotropically induces culm bending in sorghum: an insight into sorghum semi-dwarf breeding

    PubMed Central

    Ordonio, Reynante L.; Ito, Yusuke; Hatakeyama, Asako; Ohmae-Shinohara, Kozue; Kasuga, Shigemitsu; Tokunaga, Tsuyoshi; Mizuno, Hiroshi; Kitano, Hidemi; Matsuoka, Makoto; Sazuka, Takashi

    2014-01-01

    Regulation of symmetrical cell growth in the culm is important for proper culm development. So far, the involvement of gibberellin (GA) in this process has not yet been demonstrated in sorghum. Here, we show that GA deficiency resulting from any loss-of-function mutation in four genes (SbCPS1, SbKS1, SbKO1, SbKAO1) involved in the early steps of GA biosynthesis, not only results in severe dwarfism but also in abnormal culm bending. Histological analysis of the bent culm revealed that the intrinsic bending was due to an uneven cell proliferation between the lower and upper sides of culm internodes. GA treatment alleviated the bending and dwarfism in mutants, whereas the GA biosynthesis inhibitor, uniconazole, induced such phenotypes in wild-type plants— both in a concentration-dependent manner, indicating an important role of GA in controlling erectness of the sorghum culm. Finally, we propose that because of the tight relationship between GA deficiency-induced dwarfism and culm bending in sorghum, GA-related mutations have unlikely been selected in the history of sorghum breeding, as could be inferred from previous QTL and association studies on sorghum plant height that did not pinpoint GA-related genes. PMID:24924234

  13. NLRP3 Deficiency Improves Angiotensin II-Induced Hypertension But Not Fetal Growth Restriction During Pregnancy.

    PubMed

    Shirasuna, Koumei; Karasawa, Tadayoshi; Usui, Fumitake; Kobayashi, Motoi; Komada, Tadanori; Kimura, Hiroaki; Kawashima, Akira; Ohkuchi, Akihide; Taniguchi, Shun'ichiro; Takahashi, Masafumi

    2015-11-01

    Preeclampsia is a pregnancy-specific syndrome characterized by elevated blood pressure, proteinuria, and intrauterine growth restriction (IUGR). Although sterile inflammation appears to be involved, its pathogenesis remains unclear. Recent evidence indicates that sterile inflammation is mediated through the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. Here we investigated the role of the NLRP3 inflammasomes in the pathogenesis of preeclampsia using Nlrp3(-/-) and Asc(-/-) (Nlrp3 and Asc deficient) pregnant mice. During pregnancy in mice, continuous infusion of high-dose angiotensin II (AngII) induced hypertension, proteinuria, and IUGR, whereas infusion of low-dose AngII caused hypertension alone. AngII-induced hypertension was prevented in Nlrp3(-/-) mice but not in Asc(-/-), indicating that NLRP3 contributes to gestational hypertension independently of ASC-mediated inflammasomes. Although NLRP3 deficiency had no effect on IUGR, it restored the IL-6 up-regulation in the placenta and kidney of AngII-infused mice. Furthermore, treatment with hydralazine prevented the development of gestational hypertension but not IUGR or IL-6 expression in the placenta and kidney. These findings demonstrate that NLRP3 contributes to the development of gestational hypertension independently of the inflammasomes and that IUGR and kidney injury can occur independent of blood pressure elevation during pregnancy.

  14. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level.

    PubMed

    Brommer, Benedikt; Engel, Odilo; Kopp, Marcel A; Watzlawick, Ralf; Müller, Susanne; Prüss, Harald; Chen, Yuying; DeVivo, Michael J; Finkenstaedt, Felix W; Dirnagl, Ulrich; Liebscher, Thomas; Meisel, Andreas; Schwab, Jan M

    2016-03-01

    Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner.

  15. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level

    PubMed Central

    Brommer, Benedikt; Engel, Odilo; Kopp, Marcel A.; Watzlawick, Ralf; Müller, Susanne; Prüss, Harald; Chen, Yuying; DeVivo, Michael J.; Finkenstaedt, Felix W.; Dirnagl, Ulrich; Liebscher, Thomas; Meisel, Andreas

    2016-01-01

    Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient’s environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS (‘immune paralysis’), sufficient to propagate clinically relevant infection in an injury level dependent manner. PMID:26754788

  16. Resveratrol prevents rapamycin-induced upregulation of autophagy and selectively induces apoptosis in TSC2-deficient cells.

    PubMed

    Alayev, Anya; Sun, Yang; Snyder, Rose B; Berger, Sara Malka; Yu, Jane J; Holz, Marina K

    2014-01-01

    The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is hyperactivated in a variety of cancers and disorders, including lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC), which are characterized by mutations in tumor suppressors TSC1 or TSC2. The concern with the use of mTORC1 inhibitors, such as rapamycin or its analogs (rapalogs), is that they cause upregulation of autophagy and suppress the negative feedback loop to Akt, which promotes cell survival, causing the therapy to be only partially effective, and relapse occurs upon cessation of treatment. In this study, we investigate the use of rapamycin in combination with resveratrol, a naturally occurring polyphenol, in TSC2-deficient cells. We tested whether such combination would prevent rapamycin-induced upregulation of autophagy and shift the cell fate toward apoptosis. We found that this combination treatment blocked rapamycin-induced upregulation of autophagy and restored inhibition of Akt. Interestingly, the combination of rapamycin and resveratrol selectively promoted apoptosis of TSC2-deficient cells. Thus, the addition of resveratrol to rapamycin treatment may be a promising option for selective and targeted therapy for diseases with TSC loss and mTORC1 hyperactivation.

  17. Dietary fiber suppresses elevations of uric acid and allantoin in serum and urine induced by dietary RNA and increases its excretion to feces in rats.

    PubMed

    Koguchi, Takashi; Nakajima, Hisao; Wada, Masahiro; Yamamoto, Yuji; Innami, Satoshi; Maekawa, Akio; Tadokor, Tadahiro

    2002-06-01

    This study was performed to examine the effects of several kinds of dietary fibers (DF) with different physical properties on dietary RNA metabolism. Male Wistar strain rats, 4 wk old, were fed diets with or without a 3% yeast RNA and a 5% DF (cellulose, chitin, chitosan, inulin, and xanthan gum) for 20 d (Experiment 1) or 5 d (Experiment 2). Feeding DF tested lowered the serum uric acid and allantoin concentrations and the urinary excretions of their compounds and increased the amount of RNA excreted into the feces compared with fiber-free. The water-holding capacity and nucleotide adsorption of chitin and chitosan in acidic solutions were higher than those of cellulose. The digestion rate of RNA by RNase A in vitro was found to be lower in the DF tested than in fiber-free. The decrease was remarkable in chitosan and xanthan gum. The uptakes of 14C-labeled adenosine and adenosine 5'-monophosphate (5'-AMP) in the rat jejunum were markedly decreased in regard to chitosan and xanthan gum in comparison with the fiber-free. These phenomena suggest that DF with high viscosity is more strongly associated with the suppression of RNA digestion by RNase A and the depression of the uptake of purine compounds to jejunum. The present results reveal that the elevation of serum uric acid concentration induced by dietary RNA can be suppressed by DF in rats.

  18. Radiation-induced effects in the electron-beam irradiation of dietary flavonoids

    NASA Astrophysics Data System (ADS)

    Tamba, M.; Torreggiani, A.

    2004-09-01

    The harmful effects of oxidative processes in living organisms can be reduced by the dietary intake of flavonoids, a class of phenolic compounds ubiquitous in plants and widely found in a number of fruits, vegetables and beverages. Many fruits and vegetables are treated by irradiation to solve preservation problems and a radical-induced degradation of nutrients, including polyphenols, may occur. The free radical chemistry of two abundant flavonoids in food, catechin and quercetin, have been investigated by using pulse radiolysis technique. The central role of the phenoxyl-type radical and the strong influence of the state of protonation of the compounds on the pathway of formation and decay of the corresponding oxidized radicals has been evidenced from the spectral properties and chemical reactivity of the radicals derived from the attack of several oxidizing species ( ṡOH, N 3ṡ SO 4-ṡ).

  19. Increased dietary protein attenuates C-reactive protein and creatine kinase responses to exercise-induced energy deficit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We determined if dietary protein (P) modulates responses of C-reactive protein (CRP) and creatine kinase (CK), biomarkers of inflammation and muscle damage, during exercise-induced energy deficit (DEF). Thirteen healthy men (22 +/- 1 y, VO2peak 60 +/- 2 ml.kg-1.min-1) balanced energy expenditure (EE...

  20. Dietary inhibition of xanthine oxidase attenuates radiation-induced endothelial dysfunction in rat aorta.

    PubMed

    Soucy, Kevin G; Lim, Hyun Kyo; Attarzadeh, David O; Santhanam, Lakshmi; Kim, Jae Hyung; Bhunia, Anil K; Sevinc, Baris; Ryoo, Sungwoo; Vazquez, Marcelo E; Nyhan, Daniel; Shoukas, Artin A; Berkowitz, Dan E

    2010-05-01

    Radiation exposure is associated with the development of various cardiovascular diseases. Although irradiation is known to cause elevated oxidant stress and chronic inflammation, both of which are detrimental to vascular function, the molecular mechanisms remain incompletely understood. We previously demonstrated that radiation causes endothelial dysfunction and increased vascular stiffness by xanthine oxidase (XO) activation. In this study, we investigated whether dietary inhibition of XO protects against radiation-induced vascular injury. We exposed 4-mo-old rats to a single dose of 0 or 5 Gy gamma radiation. These rats received normal drinking water or water containing 1 mM oxypurinol, an XO inhibitor. We measured XO activity and superoxide production in rat aorta and demonstrated that both were significantly elevated 2 wk after radiation exposure. However, oxypurinol treatment in irradiated rats prevented aortic XO activation and superoxide elevation. We next investigated endothelial function through fluorescent measurement of nitric oxide (NO) and vascular tension dose responses. Radiation reduced endothelium-dependent NO production in rat aorta. Similarly, endothelium-dependent vasorelaxation in the aorta of irradiated rats was significantly attenuated compared with the control group. Dietary XO inhibition maintained NO production at control levels and prevented the development of endothelial dysfunction. Furthermore, pulse wave velocity, a measure of vascular stiffness, increased by 1 day postirradiation and remained elevated 2 wk after irradiation, despite unchanged blood pressures. In oxypurinol-treated rats, pulse wave velocities remained unchanged from baseline throughout the experiment, signifying preserved vascular health. These findings demonstrate that XO inhibition can offer protection from radiation-induced endothelial dysfunction and cardiovascular complications.

  1. Dietary flaxseed intake exacerbates acute colonic mucosal injury and inflammation induced by dextran sodium sulfate.

    PubMed

    Zarepoor, Leila; Lu, Jenifer T; Zhang, Claire; Wu, Wenqing; Lepp, Dion; Robinson, Lindsay; Wanasundara, Janitha; Cui, Steve; Villeneuve, Sébastien; Fofana, Bourlaye; Tsao, Rong; Wood, Geoffrey A; Power, Krista A

    2014-06-15

    Flaxseed (FS), a dietary oilseed, contains a variety of anti-inflammatory bioactives, including fermentable fiber, phenolic compounds (lignans), and the n-3 polyunsaturated fatty acid (PUFA) α-linolenic acid. The objective of this study was to determine the effects of FS and its n-3 PUFA-rich kernel or lignan- and soluble fiber-rich hull on colitis severity in a mouse model of acute colonic inflammation. C57BL/6 male mice were fed a basal diet (negative control) or a basal diet supplemented with 10% FS, 6% kernel, or 4% hull for 3 wk prior to and during colitis induction via 5 days of 2% (wt/vol) dextran sodium sulfate (DSS) in their drinking water (n = 12/group). An increase in anti-inflammatory metabolites (hepatic n-3 PUFAs, serum mammalian lignans, and cecal short-chain fatty acids) was associated with consumption of all FS-based diets, but not with anti-inflammatory effects in DSS-exposed mice. Dietary FS exacerbated DSS-induced acute colitis, as indicated by a heightened disease activity index and an increase in colonic injury and inflammatory biomarkers [histological damage, apoptosis, myeloperoxidase, inflammatory cytokines (IL-6 and IL-1β), and NF-κB signaling-related genes (Nfkb1, Ccl5, Bcl2a1a, Egfr, Relb, Birc3, and Atf1)]. Additionally, the adverse effect of the FS diet was extended systemically, as serum cytokines (IL-6, IFNγ, and IL-1β) and hepatic cholesterol levels were increased. The adverse effects of FS were not associated with alterations in fecal microbial load or systemic bacterial translocation (endotoxemia). Collectively, this study demonstrates that although consumption of a 10% FS diet enhanced the levels of n-3 PUFAs, short-chain polyunsaturated fatty acids, and lignans in mice, it exacerbated DSS-induced colonic injury and inflammation.

  2. Endothelial cell tetrahydrobiopterin deficiency attenuates LPS-induced vascular dysfunction and hypotension☆

    PubMed Central

    Chuaiphichai, Surawee; Starr, Anna; Nandi, Manasi; Channon, Keith M.; McNeill, Eileen

    2016-01-01

    Overproduction of nitric oxide (NO) is thought to be a key mediator of the vascular dysfunction and severe hypotension in patients with endotoxaemia and septic shock. The contribution of NO produced directly in the vasculature by endothelial cells to the hypotension seen in these conditions, vs. the broader systemic increase in NO, is unclear. To determine the specific role of endothelium derived NO in lipopolysaccharide (LPS)-induced vascular dysfunction we administered LPS to mice deficient in endothelial cell tetrahydrobiopterin (BH4), the essential co-factor for NO production by NOS enzymes. Mice deficient in endothelial BH4 production, through loss of the essential biosynthesis enzyme Gch1 (Gch1fl/flTie2cre mice) received a 24 hour challenge with LPS or saline control. In vivo LPS treatment increased vascular GTP cyclohydrolase and BH4 levels in aortas, lungs and hearts, but this increase was significantly attenuated in Gch1fl/flTie2cre mice, which were also partially protected from the LPS-induced hypotension. In isometric tension studies, in vivo LPS treatment reduced the vasoconstriction response and impaired endothelium-dependent and independent vasodilatations in mesenteric arteries from wild-type mice, but not in Gch1fl/flTie2cre mesenteric arteries. Ex vivo LPS treatment decreased vasoconstriction response to phenylephrine in aortic rings from wild-type and not in Gch1fl/flTie2cre mice, even in the context of significant eNOS and iNOS upregulation. These data provide direct evidence that endothelial cell NO has a significant contribution to LPS-induced vascular dysfunction and hypotension and may provide a novel therapeutic target for the treatment of systemic inflammation and patients with septic shock. PMID:26276526

  3. CD147 deficiency blocks IL-8 secretion and inhibits lung cancer-induced osteoclastogenesis

    SciTech Connect

    Wang, Hongkai; Zhuo, Yunyun; Hu, Xu; Shen, Weiwei; Zhang, Ying; Chu, Tongwei

    2015-03-06

    Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and poor prognosis; however, the molecular basis of this process is still unknown. This study investigated the role of extracellular matrix metalloproteinase inducer (also known as cluster of differentiation (CD)147) in osteoclastogenesis resulting from bone metastasis, based on the enrichment of this glycoprotein on the surface of many malignant bone tumors. RNA interference was used to silence CD147 expression in A549 human lung cancer cells. Compared with conditioned medium (CM) from control cells (A549-CM), CM from CD147-deficient cells (A549-si-CM) suppressed receptor activator of nuclear factor κB ligand-stimulated osteoclastogenesis in RAW 264.7 cells and bone marrow-derived macrophages. The mRNA levels of osteoclast-specific genes such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K were also reduced in the presence of A549-si-CM. CD147 knockdown in A549 cells decreased interleukin (IL)-8mRNA and protein expression. IL-8 is present in large amounts in A549-CM and mimicked its inductive effect on osteoclastogenesis; this was reversed by depletion of IL-8 from the medium. Taken together, these results indicate that CD147 promotes lung cancer-induced osteoclastogenesis by modulating IL-8 secretion, and suggest that CD147 is a potential therapeutic target for cancer-associated bone resorption in lung cancer patients. - Highlights: • Bone loss frequently results from lung cancer metastasis. • Cluster of differentiation (CD)147 was depleted in A549 lung adenocarcinoma cells. • RAW 264.7 cell osteoclastogenesis was blocked by medium from CD147-deficient cells. • Interleukin (IL)-8 level was reduced in the conditioned medium. • Osteoclastogenesis induced by lung tumor cells requires CD147-mediated IL-8 release.

  4. Endothelial cell tetrahydrobiopterin deficiency attenuates LPS-induced vascular dysfunction and hypotension.

    PubMed

    Chuaiphichai, Surawee; Starr, Anna; Nandi, Manasi; Channon, Keith M; McNeill, Eileen

    2016-02-01

    Overproduction of nitric oxide (NO) is thought to be a key mediator of the vascular dysfunction and severe hypotension in patients with endotoxaemia and septic shock. The contribution of NO produced directly in the vasculature by endothelial cells to the hypotension seen in these conditions, vs. the broader systemic increase in NO, is unclear. To determine the specific role of endothelium derived NO in lipopolysaccharide (LPS)-induced vascular dysfunction we administered LPS to mice deficient in endothelial cell tetrahydrobiopterin (BH4), the essential co-factor for NO production by NOS enzymes. Mice deficient in endothelial BH4 production, through loss of the essential biosynthesis enzyme Gch1 (Gch1(fl/fl)Tie2cre mice) received a 24hour challenge with LPS or saline control. In vivo LPS treatment increased vascular GTP cyclohydrolase and BH4 levels in aortas, lungs and hearts, but this increase was significantly attenuated in Gch1(fl/fl)Tie2cre mice, which were also partially protected from the LPS-induced hypotension. In isometric tension studies, in vivo LPS treatment reduced the vasoconstriction response and impaired endothelium-dependent and independent vasodilatations in mesenteric arteries from wild-type mice, but not in Gch1(fl/fl)Tie2cre mesenteric arteries. Ex vivo LPS treatment decreased vasoconstriction response to phenylephrine in aortic rings from wild-type and not in Gch1(fl/fl)Tie2cre mice, even in the context of significant eNOS and iNOS upregulation. These data provide direct evidence that endothelial cell NO has a significant contribution to LPS-induced vascular dysfunction and hypotension and may provide a novel therapeutic target for the treatment of systemic inflammation and patients with septic shock.

  5. Role of Hydrogen Sulfide on Autophagy in Liver Injuries Induced by Selenium Deficiency in Chickens.

    PubMed

    Wenzhong, Wang; Tong, Zhang; Hongjin, Lin; Ying, Chang; Jun, Xing

    2017-01-01

    Selenium (Se) is an indispensable trace mineral that was associated with liver injuries in animal models. Hydrogen sulfide (H2S) is involved in many liver diseases, and autophagy can maintain liver homeostasis with a stress stimulation. However, little is known about the correlation between H2S and autophagy in the liver injury chicken models induced by Se deficiency. In this study, we aimed to investigate the correlation between H2S and autophagy in the liver injury chicken models. We randomly divided 120 1-day-old chickens into two equal groups. The control group was fed with complete food with a Se content of 0.15 mg/kg, and the Se-deficiency group (lab group) was fed with a Se-deficient diet with a Se content of 0.033 mg/kg. When the time comes to 15, 25, and 35 days, the chickens were sacrificed (20 each). The liver tissues were gathered and examined for pathological observations, the mRNA and protein levels of H2S synthases (CSE, CBS, and 3-MST) and the mRNA and protein levels of autophagy-related genes. The results showed that the expression of CSE, CBS, and 3-MST and H2S production were higher in the lab group than in the control group. Swellings, fractures, and vacuolizations were visible in the mitochondria cristae in the livers of the lab group and autophagosomes were found as well. In addition, the expression of autophagy-related genes (ATG5, LC3-I, LC3-II, Beclin1, and Dynein) was higher in the lab group than in the control group (p < 0.05) while TOR decreased significantly in the lab group (p < 0.05). The results showed that H2S and autophagy were involved in the liver injury chicken models, and H2S was correlated with autophagy.

  6. Vitamin D deficiency exacerbates atypical antipsychotic-induced metabolic side effects in rats: involvement of the INSIG/SREBP pathway.

    PubMed

    Dang, Ruili; Jiang, Pei; Cai, Hualin; Li, Huande; Guo, Ren; Wu, Yanqin; Zhang, Lihong; Zhu, Wenye; He, Xin; Liu, Yiping; Xu, Ping

    2015-08-01

    Metabolic syndrome is a major concern in psychotic patients receiving atypical antipsychotics. Recent evidence suggests that sterol regulatory element-binding proteins (SREBPs) and insulin-induced genes (INSIGs) are implicated in the antipsychotic-induced metabolic side-effects. Vitamin D (VD) deficiency, a highly prevalent phenomenon among patients with psychosis, might also predispose individuals to metabolic syndrome Considering that VD has modulating effects on the INSIG/SREBP pathway, it is possible that VD may have a role in the antipsychotic-induced metabolic disturbances involving its effects on the INSIG/SREBP system. Thus, the present study aimed to evaluate the effects of VD deficiency and VD supplementation on antipsychotic-induced metabolic changes in rats. After 4-week administration, clozapine (10mg/kg/d) and risperidone (1mg/kg/d) both caused glucose intolerance and insulin resistance in VD deficient rats, but not in rats with sufficient VD status. Antipsychotic treatments, especially clozapine, elevated serum lipid levels, which were most apparent in VD deficient rats, but alleviated in VD-supplemented rats. Additionally, antipsychotic treatments down-regulated INSIGs and up-regulated SREBPs expression in VD deficient rats, and these effects were attenuated when VD status was more sufficient. Collectively, this study disclose the novel findings that antipsychotic-induced metabolic disturbances is exacerbated by VD deficiency and can be alleviated by VD supplementation, providing new evidence for the promising role of VD in prevention and treatment of metabolic disorders caused by antipsychotic medications. Furthermore, our data also suggest the involvement of INSIG/SREBP pathway in the antipsychotic-induced hyperlipidemia and beneficial effects of VD on lipid profile.

  7. Chronic Zinc Deficiency Alters Chick Gut Microbiota Composition and Function

    PubMed Central

    Reed, Spenser; Neuman, Hadar; Moscovich, Sharon; Glahn, Raymond P.; Koren, Omry; Tako, Elad

    2015-01-01

    Zinc (Zn) deficiency is a prevalent micronutrient insufficiency. Although the gut is a vital organ for Zn utilization, and Zn deficiency is associated with impaired intestinal permeability and a global decrease in gastrointestinal health, alterations in the gut microbial ecology of the host under conditions of Zn deficiency have yet to be studied. Using the broiler chicken (Gallus gallus) model, the aim of this study was to characterize distinct cecal microbiota shifts induced by chronic dietary Zn depletion. We demonstrate that Zn deficiency induces significant taxonomic alterations and decreases overall species richness and diversity, establishing a microbial profile resembling that of various other pathological states. Through metagenomic analysis, we show that predicted Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways responsible for macro- and micronutrient uptake are significantly depleted under Zn deficiency; along with concomitant decreases in beneficial short chain fatty acids, such depletions may further preclude optimal host Zn availability. We also identify several candidate microbes that may play a significant role in modulating the bioavailability and utilization of dietary Zn during prolonged deficiency. Our results are the first to characterize a unique and dysbiotic cecal microbiota during Zn deficiency, and provide evidence for such microbial perturbations as potential effectors of the Zn deficient phenotype. PMID:26633470

  8. Triplex structures induce DNA double strand breaks via replication fork collapse in NER deficient cells

    PubMed Central

    Kaushik Tiwari, Meetu; Adaku, Nneoma; Peart, Natoya; Rogers, Faye A.

    2016-01-01

    Structural alterations in DNA can serve as natural impediments to replication fork stability and progression, resulting in DNA damage and genomic instability. Naturally occurring polypurine mirror repeat sequences in the human genome can create endogenous triplex structures evoking a robust DNA damage response. Failures to recognize or adequately process these genomic lesions can result in loss of genomic integrity. Nucleotide excision repair (NER) proteins have been found to play a prominent role in the recognition and repair of triplex structures. We demonstrate using triplex-forming oligonucleotides that chromosomal triplexes perturb DNA replication fork progression, eventually resulting in fork collapse and the induction of double strand breaks (DSBs). We find that cells deficient in the NER damage recognition proteins, XPA and XPC, accumulate more DSBs in response to chromosomal triplex formation than NER-proficient cells. Furthermore, we demonstrate that XPC-deficient cells are particularly prone to replication-associated DSBs in the presence of triplexes. In the absence of XPA or XPC, deleterious consequences of triplex-induced genomic instability may be averted by activating apoptosis via dual phosphorylation of the H2AX protein. Our results reveal that damage recognition by XPC and XPA is critical to maintaining replication fork integrity and preventing replication fork collapse in the presence of triplex structures. PMID:27298253

  9. Inflammation and increased IDO in hippocampus contribute to depression-like behavior induced by estrogen deficiency.

    PubMed

    Xu, Yongjun; Sheng, Hui; Tang, Zhiping; Lu, Jianqiang; Ni, Xin

    2015-07-15

    Estrogen deficiency is involved in the development of depression. However, the mechanism underlying estrogen modulates depression-like behavior remains largely unknown. Inflammation and indoleamine-2,3-dioxygenase (IDO) have been shown to play pivotal roles in various depression models. The objective of the present study was to investigate whether estrogen deficiency-induced depression-like behavior is associated with inflammation and IDO activation in brain. The results showed that ovariectomy resulted in depression-like behavior in female rats and caused a decrease in 5-HT content and an increase in levels of IDO, IFN-γ, IL-6, toll like receptor (TLR)-4 and phosphorylated NF-κB (p65 subunit) in hippocampus but not in prefrontal cortex (PFC). 17β-Estradiol (E2) treatment ameliorated depression-like behavior and restored above neurochemical alternations in hippocampus in ovariectomized rats. Partial correlation analysis showed that the levels of phosphorylated p65, IFN-γ and IL-6 in hippocampus correlated to serum E2 level. Our study suggests that estrogen inhibits inflammation and activates of IDO and maintains 5-HT level in hippocampus, thereby ameliorating depression-like behavior.

  10. Induced polarized state in intentionally grown oxygen deficient KTaO{sub 3} thin films

    SciTech Connect

    Mota, D. A.; Romaguera-Barcelay, Y.; Tkach, A.; Agostinho Moreira, J.; Almeida, A.; Perez de la Cruz, J.; Vilarinho, P. M.; Tavares, P. B.

    2013-07-21

    Deliberately oxygen deficient potassium tantalate thin films were grown by RF magnetron sputtering on Si/SiO{sub 2}/Ti/Pt substrates. Once they were structurally characterized, the effect of oxygen vacancies on their electric properties was addressed by measuring leakage currents, dielectric constant, electric polarization, and thermally stimulated depolarization currents. By using K{sub 2}O rich KTaO{sub 3} targets and specific deposition conditions, KTaO{sub 3-{delta}} oxygen deficient thin films with a K/Ta = 1 ratio were obtained. Room temperature X-ray diffraction patterns show that KTaO{sub 3-{delta}} thin films are under a compressive strain of 2.3% relative to KTaO{sub 3} crystals. Leakage current results reveal the presence of a conductive mechanism, following the Poole-Frenkel formalism. Furthermore, dielectric, polarization, and depolarization current measurements yield the existence of a polarized state below T{sub pol} {approx} 367 Degree-Sign C. A Cole-Cole dipolar relaxation was also ascertained apparently due to oxygen vacancies induced dipoles. After thermal annealing the films in an oxygen atmosphere at a temperature above T{sub pol}, the aforementioned polarized state is suppressed, associated with a drastic oxygen vacancies reduction emerging from annealing process.

  11. Determinants of G quadruplex-induced epigenetic instability in REV1-deficient cells

    PubMed Central

    Schiavone, Davide; Guilbaud, Guillaume; Murat, Pierre; Papadopoulou, Charikleia; Sarkies, Peter; Prioleau, Marie-Noëlle; Balasubramanian, Shankar; Sale, Julian E

    2014-01-01

    REV1-deficient chicken DT40 cells are compromised in replicating G quadruplex (G4)-forming DNA. This results in localised, stochastic loss of parental chromatin marks and changes in gene expression. We previously proposed that this epigenetic instability arises from G4-induced replication fork stalls disrupting the accurate propagation of chromatin structure through replication. Here, we test this model by showing that a single G4 motif is responsible for the epigenetic instability of the BU-1 locus in REV1-deficient cells, despite its location 3.5 kb from the transcription start site (TSS). The effect of the G4 is dependent on it residing on the leading strand template, but is independent of its in vitro thermal stability. Moving the motif to more than 4 kb from the TSS stabilises expression of the gene. However, loss of histone modifications (H3K4me3 and H3K9/14ac) around the transcription start site correlates with the position of the G4 motif, expression being lost only when the promoter is affected. This supports the idea that processive replication is required to maintain the histone modification pattern and full transcription of this model locus. PMID:25190518

  12. Gpr177 deficiency impairs mammary development and prohibits Wnt-induced tumorigenesis.

    PubMed

    Maruyama, Eri Ohfuchi; Yu, H-M Ivy; Jiang, Ming; Fu, Jiang; Hsu, Wei

    2013-01-01

    Aberrant regulation of the Wnt pathway, essential for various developmental processes, is tightly linked to human breast cancers. By hijacking this evolutionary conserved signaling pathway, cancer cells acquire sustaining proliferation ability, leading to modification of physiologic properties necessary for tumor initiation and progression. An enormous wealth of knowledge on the importance of Wnt signaling in breast development and cancer has been obtained, but the cell types responsible for production of this proliferative signal operating within normal and malignant tissues remains poorly understood. Here we report that Wnt production mediated by Gpr177 is essential for mammary morphogenesis. The loss of Gpr177 interferes with mammary stem cells, leading to deficiencies in cell proliferation and differentiation. Genetic analysis further demonstrates an indispensable role of Gpr177 in Wnt-induced tumorigenesis. The Gpr177-deficiency mice are resistant to malignant transformation. This study not only demonstrates the necessity of Wnt in mammary organogenesis but also provides a proof-of-principle for targeting of Gpr177 as a potential new treatment for human diseases with aberrant Wnt stimulation.

  13. Characterization of the Xanthophyll Cycle and Other Photosynthetic Pigment Changes Induced by Iron Deficiency in Sugar Beet (Beta vulgaris L.).

    PubMed

    Morales, F; Abadía, A; Abadía, J

    1990-10-01

    In this work we characterize the changes induced by iron deficiency in the pigment composition of sugar beet (Beta vulgaris L.) leaves. When sugar beet plants were grown hydroponically under limited iron supply, neoxanthin and beta-carotene decreased concomitantly with chlorophyll a, whereas lutein and the carotenoids within the xanthophyll cycle were less affected. Iron deficiency caused major increases in the lutein/chlorophyll a and xanthophyll cycle pigments/chlorophyll a molar ratios. Xanthophyll cycle carotenoids in Fe-deficient plants underwent epoxidations and de-epoxidations in response to ambient light conditions. In dark adapted Fe-deficient plants most of the xanthophyll cycle pigment pool was in the epoxidated form violaxanthin. We show, both by HPLC and by in vivo 505 nanometers absorbance changes, that in Fe deficient plants and in response to light, the de-epoxidated forms antheraxanthin and zeaxanthin were rapidly formed at the expense of violaxanthin. Several hours after returning to dark, the xanthophyll cycle was shifted again toward violaxanthin. The ratio of variable to maximum chlorophyll fluorescence from intact leaves was decreased by iron deficiency. However, in iron deficient leaves this ratio was little affected by light conditions which displace the xanthophyll cycle toward epoxidation or de-epoxidation. This suggests that the functioning of the xanthophyll cycle is not necessarily linked to protection against excess light input.

  14. Adult Lysophosphatidic Acid Receptor 1-Deficient Rats with Hyperoxia-Induced Neonatal Chronic Lung Disease Are Protected against Lipopolysaccharide-Induced Acute Lung Injury

    PubMed Central

    Chen, Xueyu; Walther, Frans J.; Laghmani, El H.; Hoogeboom, Annemarie M.; Hogen-Esch, Anne C. B.; van Ark, Ingrid; Folkerts, Gert; Wagenaar, Gerry T. M.

    2017-01-01

    Aim: Survivors of neonatal chronic lung disease or bronchopulmonary dysplasia (BPD) suffer from compromised lung function and are at high risk for developing lung injury by multiple insults later in life. Because neonatal lysophosphatidic acid receptor-1 (LPAR1)-deficient rats are protected against hyperoxia-induced lung injury, we hypothesize that LPAR1-deficiency may protect adult survivors of BPD from a second hit response against lipopolysaccharides (LPS)-induced lung injury. Methods: Directly after birth, Wistar control and LPAR1-deficient rat pups were exposed to hyperoxia (90%) for 8 days followed by recovery in room air. After 7 weeks, male rats received either LPS (2 mg kg−1) or 0.9% NaCl by intraperitoneal injection. Alveolar development and lung inflammation were investigated by morphometric analysis, IL-6 production, and mRNA expression of cytokines, chemokines, coagulation factors, and an indicator of oxidative stress. Results: LPAR1-deficient and control rats developed hyperoxia-induced neonatal emphysema, which persisted into adulthood, as demonstrated by alveolar enlargement and decreased vessel density. LPAR1-deficiency protected against LPS-induced lung injury. Adult controls with BPD exhibited an exacerbated response toward LPS with an increased expression of pro-inflammatory mRNAs, whereas LPAR1-deficient rats with BPD were less sensitive to this “second hit” with a decreased pulmonary influx of macrophages and neutrophils, interleukin-6 (IL-6) production, and mRNA expression of IL-6, monocyte chemoattractant protein-1, cytokine-induced neutrophil chemoattractant 1, plasminogen activator inhibitor-1, and tissue factor. Conclusion: LPAR1-deficient rats have increased hyperoxia-induced BPD survival rates and, despite the presence of neonatal emphysema, are less sensitive to an aggravated “second hit” than Wistar controls with BPD. Intervening in LPA-LPAR1-dependent signaling may not only have therapeutic potential for neonatal chronic

  15. Therapeutic role of dietary fibre.

    PubMed Central

    Hunt, R.; Fedorak, R.; Frohlich, J.; McLennan, C.; Pavilanis, A.

    1993-01-01

    The current status of dietary fibre and fibre supplements in health and disease is reported, and the components of dietary fibre and its respective mechanical and metabolic effects with emphasis on its therapeutic potential are reviewed. Practical management guidelines are provided to help physicians encourage patients identified as having fibre deficiency to increase dietary fibre intake to the recommended level. PMID:8388284

  16. TrxR2 deficiencies promote chondrogenic differentiation and induce apoptosis of chondrocytes through mitochondrial reactive oxygen species.

    PubMed

    Yan, Jidong; Xu, Jing; Fei, Yao; Jiang, Congshan; Zhu, Wenhua; Han, Yan; Lu, Shemin

    2016-05-15

    Thioredoxin reductase 2 (TrxR2) is a selenium (Se) containing protein. Se deficiency is associated with an endemic osteoarthropathy characterized by impaired cartilage formation. It is unclear whether TrxR2 have roles in cartilage function. We examined the effects of TrxR2 on chondrogenic ATDC5 cells through shRNA-mediated gene silencing of TrxR2. We demonstrated TrxR2 deficiencies could enhance chondrogenic differentiation and apoptosis of ATDC5 cells. TrxR2 deficiencies increased accumulation of cartilage glycosaminoglycans (GAGs) and mineralization. TrxR2 deficiencies also stimulated expression of extracellular (ECM) gene including Collagen II and Aggrecan. The enhanced chondrogenic properties were further confirmed by activation of Akt signaling which are required for chondrogenesis. In addition, TrxR2 deficiencies promoted chondrocyte proliferation through acceleration of cell cycle progression by increase in both S and G2/M phase cell distribution accompanied with induction of parathyroid hormone-related protein (PTHrP). Moreover, TrxR2 deficiencies induced chondrocyte death via apoptosis and increased cell sensitivity to exogenous oxidative stress. Furthermore, TrxR2 deficiencies induced emission of mitochondrial reactive oxygen species (ROS) without alteration of mitochondrial membrane potential and intracellular ATP content. Finally, treatment of TrxR2 deficiency cells with N-acetylcysteine (NAC) inhibited mitochondrial ROS production and chondrocyte apoptosis. NAC also prevented chondrogenic differentiation of TrxR2 deficiency cells by suppression of ECM gene expression, GAGs accumulation and mineralization, as well as attenuation of Akt signaling. Thus, TrxR2-mediated mitochondrial integrity is indispensable for chondrogenic differentiation of ATDC5 cells. TrxR2 deficiency-induced impaired proliferation and death of chondrocytes may be the pathological mechanism of the osteoarthropathy due to Se deficiency. Notably, this study also uncover the roles of

  17. Rotation induced octupole correlations in the neutron-deficient 109Te nucleus

    NASA Astrophysics Data System (ADS)

    de Angelis, G.; Fahlander, C.; Gadea, A.; Farnea, E.; Bazzacco, D.; Belcari, N.; Blasi, N.; Bizzeti, P. G.; Bizzeti-Sona, A.; de Acuña, D.; de Poli, M.; Grawe, H.; Johnson, A.; Lo Bianco, G.; Lunardi, S.; Napoli, D. R.; Nyberg, J.; Pavan, P.; Persson, J.; Rossi Alvarez, C.; Rudolph, D.; Schubart, R.; Spolaore, P.; Wyss, R.; Xu, F.

    1998-10-01

    High spin states in the neutron deficient nucleus 109Te have been populated with the 58Ni+54Fe reaction at 220 MeV and investigated through γ-spectroscopy methods at the GASP spectrometer making use of reaction channel selection with the ISIS Si-ball. The level scheme has been extended up to an excitation energy of ~12.1 MeV. The spins and parities of the observed levels are assigned tentatively supporting the identification of two bands of opposite parity connected by strong dipole transitions inferred to be of E1 character. Octupole correlations in 109Te induced by rotation are suggested as the cause of this effect.

  18. Dietary fish oil blocks carcinogen-induced down-regulation of colonic protein kinase C isozymes.

    PubMed

    Jiang, Y H; Lupton, J R; Chapkin, R S

    1997-02-01

    In order to elucidate the influence of dietary constituents on colonic intracellular signal transduction, the effect of different fats on rat colonic epithelial protein kinase C (PKC) alpha (classical), delta (novel) and lambda-zeta (atypical) expression was determined in carcinogen-treated animals. Sprague-Dawley rats were provided with one of two fats (corn oil and fish oil); plus or minus the carcinogen azoxymethane (AOM) and killed at two time points (15 and 37 weeks) in a 2x2x2 factorial design. At 5 and 6 weeks of age, animals were injected s.c. with either AOM at a dose of 15 mg/kg body weight or saline once a week for 2 weeks and continued on the same diet until termination of the study. At 15 and 37 weeks after the second injection, 10 rats from each treatment group were killed. Colonic PKC alpha, delta and lambda-zeta steady-state protein and mRNA levels were determined using immunoblotting and relative quantitative polymerase chain reaction, respectively. Colonic mucosa from rats injected with AOM had significantly suppressed membrane and cytosolic PKC alpha and cytosolic lambda-zeta protein levels (P < 0.05) as compared to saline-injected control animals at both time points. In contrast, rats fed fish oil diets had significantly higher (P < 0.05) cytosolic PKC delta and lambda-zeta protein levels relative to animals fed corn oil diets. However, the effect of diet and AOM on the steady-state expression of PKC alpha, delta and zeta mRNA was not consistent with changes in the respective isozyme protein levels, suggesting regulation at the post-transcriptional level. These data demonstrate that dietary fish oil blocks the carcinogen-induced decrease in the steady-state levels of colonic mucosal PKC delta and lambda-zeta, which may in part explain why this fat source protects against colon cancer development.

  19. Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling

    PubMed Central

    Wang, Xiao-Dong; Chen, Yuncai; Wolf, Miriam; Wagner, Klaus V.; Liebl, Claudia; Scharf, Sebastian H.; Harbich, Daniela; Mayer, Bianca; Wurst, Wolfgang; Holsboer, Florian; Deussing, Jan M.; Baram, Tallie Z.; Müller, Marianne B.; Schmidt, Mathias V.

    2011-01-01

    Chronic stress evokes profound structural and molecular changes in the hippocampus, which may underlie spatial memory deficits. Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) mediate some of the rapid effects of stress on dendritic spine morphology and modulate learning and memory, thus providing a potential molecular basis for impaired synaptic plasticity and spatial memory by repeated stress exposure. Using adult male mice with CRHR1 conditionally inactivated in the forebrain regions, we investigated the role of CRH-CRHR1 signaling in the effects of chronic social defeat stress on spatial memory, the dendritic morphology of hippocampal CA3 pyramidal neurons, and the hippocampal expression of nectin-3, a synaptic cell adhesion molecule important in synaptic remodeling. In chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of CA3 neurons reduced. In contrast, stressed mice with forebrain CRHR1 deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory. Additionally, we showed that the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Moreover, forebrain CRHR1 deficiency prevented the down-regulation of hippocampal glucocorticoid receptor expression by chronic stress but induced increased body weight gain during persistent stress exposure. These findings underscore the important role of forebrain CRH-CRHR1 signaling in modulating chronic stress-induced cognitive, structural and molecular adaptations, with implications for stress-related psychiatric disorders. PMID:21296667

  20. Selenoprotein W redox-regulated Ca2+ channels correlate with selenium deficiency-induced muscles Ca2+ leak

    PubMed Central

    Zhao, Xia; Zhao, Wenchao; Liu, Wei; Yang, Jie; Sattar, Hamid; Zhao, Jinxin; Zhang, Ziwei; Xu, Shiwen

    2016-01-01

    Selenium (Se) deficiency induces Ca2+ leak and calcification in mammal skeletal muscles; however, the exact mechanism is still unclear. In the present study, both Se-deficient chicken muscle models and selenoprotein W (SelW) gene knockdown myoblast and embryo models were used to study the mechanism. The results showed that Se deficiency-induced typical muscular injuries accompanied with Ca2+ leak and oxidative stress (P < 0.05) injured the ultrastructure of the sarcoplasmic reticulum (SR) and mitochondria; decreased the levels of the Ca2+ channels, SERCA, SLC8A, CACNA1S, ORAI1, STIM1, TRPC1, and TRPC3 (P < 0.05); and increased the levels of Ca2+ channel PMCA (P < 0.05). Similarly, SelW knockdown also induced Ca2+ leak from the SR and cytoplasm; increased mitochondrial Ca2+ levels and oxidative stress; injured SR and mitochondrial ultrastructure; decreased levels of SLC8A, CACNA1S, ORA1, TRPC1, and TRPC3; and caused abnormal activities of Ca2+ channels in response to inhibitors in myoblasts and chicken embryos. Thus, both Se deficiency and SelW knockdown induced Ca2+ leak, oxidative stress, and Ca2+ channel reduction. In addition, Ca2+ levels and the expression of the Ca2+ channels, RyR1, SERCA, CACNA1S, TRPC1, and TRPC3 were recovered to normal levels by N-acetyl-L-cysteine (NAC) treatment compared with SelW knockdown cells. Thus, with regard to the decreased Ca2+ channels, SelW knockdown closely correlated Se deficiency with Ca2+ leak in muscles. The redox regulation role of SelW is crucial in Se deficiency-induced Ca2+ leak in muscles. PMID:27557522

  1. Bone Microenvironment Specific Roles of ITAM Adapter Signaling during Bone Remodeling Induced by Acute Estrogen-Deficiency

    PubMed Central

    Wu, Yalei; Torchia, James; Yao, Wei; Lane, Nancy E.; Lanier, Lewis L.; Nakamura, Mary C.; Humphrey, Mary Beth

    2007-01-01

    Immunoreceptor tyrosine-based activation motif (ITAM) signaling mediated by DAP12 or Fcε receptor Iγ chain (FcRγ) have been shown to be critical for osteoclast differentiation and maturation under normal physiological conditions. Their function in pathological conditions is unknown. We studied the role of ITAM signaling during rapid bone remodeling induced by acute estrogen-deficiency in wild-type (WT), DAP12-deficient (DAP12-/-), FcRγ-deficient (FcRγ-/-) and double-deficient (DAP12-/-FcRγ-/-) mice. Six weeks after ovariectomy (OVX), DAP12-/-FcRγ-/- mice showed resistance to lumbar vertebral body (LVB) trabecular bone loss, while WT, DAP12-/- and FcRγ-/- mice had significant LVB bone loss. In contrast, all ITAM adapter-deficient mice responded to OVX with bone loss in both femur and tibia of approximately 40%, relative to basal bone volumes. Only WT mice developed significant cortical bone loss after OVX. In vitro studies showed microenvironmental changes induced by OVX are indispensable for enhanced osteoclast formation and function. Cytokine changes, including TGFβ and TNFα, were able to induce osteoclastogenesis independent of RANKL in BMMs from WT but not DAP12-/- and DAP12-/-FcRγ-/- mice. FSH stimulated RANKL-induced osteoclast differentiation from BMMs in WT, but not DAP12-/- and DAP12-/-FcRγ-/- mice. Our study demonstrates that although ITAM adapter signaling is critical for normal bone remodeling, estrogen-deficiency induces an ITAM adapter-independent bypass mechanism allowing for enhanced osteoclastogenesis and activation in specific bony microenvironments. PMID:17611621

  2. Dietary cholesterol promotes AOM-induced colorectal cancer through activating the NLRP3 inflammasome.

    PubMed

    Du, Qianming; Wang, Qing; Fan, Huimin; Wang, Jianing; Liu, Xiuting; Wang, Hong; Wang, Yajing; Hu, Rong

    2016-04-01

    Prolonged ingestion of a cholesterol-enriched diet induces chronic, auto-inflammatory responses resulting in significant health problems including colorectal cancer. Inflammasomes are thought to mediate intestinal homeostasis, and their dysregulation contributes to inflammatory bowel diseases and colitis-associated cancer (CAC). However, in vitro and in vivo information regarding the inflammation-inducing and tumor-promoting effect of cholesterol is lacking. Here we show that the cholesterol promoted colon carcinogenesis in azoxymethane (AOM)-treated mice through activating the NLRP3 inflammasome. High cholesterol diet (HCD) significantly increased inflammatory responses and tumor burden. Cholesterol crystals, detected in the colon of mice fed with HCD, also promoted NLRP3 inflammasome activation in macrophages, as indicated by elevated expression of cleaved caspase-1, formation of NLRP3-ASC-caspase-1 complex assembly, and higher IL-1β secretion. Importantly, cholesterol was found to inhibit the activity of AMPKα in macrophages, leading to a significant production of mitochondrial ROS, which in turn activated the NLRP3 inflammasome. Moreover, crystal uptake and cathepsin B accounted for cholesterol crystal-induced inactivation of AMPKα. Finally, HCD-induced increase in IL-1β secretion, macrophage infiltration and tumor burden was diminished by the deletion of NLRP3 in AOM-treated mice. Taken together, our findings demonstrate that the pro-inflammatory and cancer-promoting effects of HCD are mediated by the activation of NLRP3 inflammasome. Our study extended our knowledge on how dietary choices can influence processes involved in chronic inflammatory disorders and colorectal cancer.

  3. Beef meat promotion of dimethylhydrazine-induced colorectal carcinogenesis biomarkers is suppressed by dietary calcium.

    PubMed

    Pierre, Fabrice; Santarelli, Raphaëlle; Taché, Sylviane; Guéraud, Françoise; Corpet, Denis E

    2008-05-01

    Red meat consumption is associated with increased risk of colorectal cancer. We have previously shown that haemin, Hb and red meat promote carcinogen-induced preneoplastic lesions: aberrant crypt foci (ACF) and mucin-depleted foci (MDF) in rats. We have also shown that dietary Ca, antioxidant mix and olive oil inhibit haemin-induced ACF promotion, and normalize faecal lipoperoxides and cytotoxicity. Here we tested if these strategies are effective also against red meat promotion in dimethylhydrazine-induced rats. Three diets with 60 % beef meat were supplemented with calcium phosphate (31 g/kg), antioxidant agents (rutin and butylated hydroxyanisole, 0.05 % each) and olive oil (5 %). ACF, MDF, faecal water cytotoxicity, thiobarbituric acid reactive substances (TBARS) and urinary 1,4-dihydroxynonane mercapturic acid (DHN-MA) were measured. Beef meat diet increased the number of ACF (+30 %) and MDF (+100 %) (P < 0.001), which confirms our previous findings. Promotion was associated with increased faecal water TBARs ( x 4) and cytotoxicity ( x 2), and urinary DHN-MA excretion ( x 15). Ca fully inhibited beef meat-induced ACF and MDF promotion, and normalized faecal TBARS and cytotoxicity, but did not reduce urinary DHN-MA. Unexpectedly, high-calcium control diet-fed rats had more MDF and ACF in the colon than low-Ca control diet-fed rats. Antioxidant mix and olive oil did not normalize beef meat promotion nor biochemical factors. The results confirm that haem causes promotion of colon carcinogenesis by red meat. They suggest that Ca can reduce colorectal cancer risk in meat-eaters. The results support the concept that toxicity associated with the excess of a useful nutrient may be prevented by another nutrient.

  4. CHOP deficiency prevents methylglyoxal-induced myocyte apoptosis and cardiac dysfunction.

    PubMed

    Nam, Dae-Hwan; Han, Jung-Hwa; Lee, Tae-Jin; Shishido, Tetsuro; Lim, Jae Hyang; Kim, Geun-Young; Woo, Chang-Hoon

    2015-08-01

    Epidemiological studies indicate that methylglyoxal (MGO) plasma levels are closely linked to diabetes and the exacerbation of diabetic cardiovascular complications. Recently, it was established that endoplasmic reticulum (ER) stress importantly contributes to the pathogenesis of diabetes and its cardiovascular complications. The objective of this study was to explore the mechanism by which diabetes instigates cardiomyocyte apoptosis and cardiac dysfunction via MGO-mediated myocyte apoptosis. Intriguingly, the MGO activated unfolded protein response pathway accompanying apoptotic events, such as cleavages of PARP-1 and caspase-3. In addition, Western blot analysis revealed that MGO-induced myocyte apoptosis was inhibited by depletion of CHOP with siRNA against Ddit3, the gene name for rat CHOP. To investigate the physiologic roles of CHOP in vivo, glucose tolerance and cardiac dysfunction were assessed in CHOP-deficient mice. No significant difference was observed between CHOP KO and littermate naïve controls in terms of the MGO-induced impairment of glucose tolerance. In contrast, myocyte apoptosis, inflammation, and cardiac dysfunction were significantly diminished in CHOP KO compared with littermate naïve controls. These results showed that CHOP is the key signal for myocyte apoptosis and cardiac dysfunction induced by MGO. These findings suggest a therapeutic potential of CHOP inhibition in the management of diabetic cardiovascular complications including diabetic cardiomyopathy.

  5. Deficiency of intestinal mucin-2 protects mice from diet-induced fatty liver disease and obesity

    PubMed Central

    Hartmann, Phillipp; Seebauer, Caroline T.; Mazagova, Magdalena; Horvath, Angela; Wang, Lirui; Llorente, Cristina; Varki, Nissi M.; Brandl, Katharina; Ho, Samuel B.

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) and obesity are characterized by altered gut microbiota, inflammation, and gut barrier dysfunction. Here, we investigated the role of mucin-2 (Muc2) as the major component of the intestinal mucus layer in the development of fatty liver disease and obesity. We studied experimental fatty liver disease and obesity induced by feeding wild-type and Muc2-knockout mice a high-fat diet (HFD) for 16 wk. Muc2 deficiency protected mice from HFD-induced fatty liver disease and obesity. Compared with wild-type mice, after a 16-wk HFD, Muc2-knockout mice exhibited better glucose homeostasis, reduced inflammation, and upregulated expression of genes involved in lipolysis and fatty acid β-oxidation in white adipose tissue. Compared with wild-type mice that were fed the HFD as well, Muc2-knockout mice also displayed higher intestinal and plasma levels of IL-22 and higher intestinal levels of the IL-22 target genes Reg3b and Reg3g. Our findings indicate that absence of the intestinal mucus layer activates the mucosal immune system. Higher IL-22 levels protect mice from diet-induced features of the metabolic syndrome. PMID:26702135

  6. Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis.

    PubMed

    Srinivasan, Gayathri; Aitken, Jesse D; Zhang, Benyue; Carvalho, Frederic A; Chassaing, Benoit; Shashidharamurthy, Rangaiah; Borregaard, Niels; Jones, Dean P; Gewirtz, Andrew T; Vijay-Kumar, Matam

    2012-08-15

    Various states of inflammation, including sepsis, are associated with hypoferremia, which limits iron availability to pathogens and reduces iron-mediated oxidative stress. Lipocalin 2 (Lcn2; siderocalin, 24p3) plays a central role in iron transport. Accordingly, Lcn2-deficient (Lcn2KO) mice exhibit elevated intracellular labile iron. In this study, we report that LPS induced systemic Lcn2 by 150-fold in wild-type mice at 24 h. Relative to wild-type littermates, Lcn2KO mice were markedly more sensitive to endotoxemia, exhibiting elevated indices of organ damage (transaminasemia, lactate dehydrogenase) and increased mortality. Such exacerbated endotoxemia was associated with substantially increased caspase-3 cleavage and concomitantly elevated immune cell apoptosis. Furthermore, cells from Lcn2KO mice were hyperresponsive to LPS ex vivo, exhibiting elevated cytokine secretion. Additionally, Lcn2KO mice exhibited delayed LPS-induced hypoferremia despite normal hepatic hepcidin expression and displayed decreased levels of the tissue redox state indicators cysteine and glutathione in liver and plasma. Desferroxamine, an iron chelator, significantly protects Lcn2KO mice from LPS-induced toxicity, including mortality, suggesting that Lcn2 may act as an antioxidant in vivo by regulating iron homeostasis. Thus, Lcn2-mediated regulation of labile iron protects the host against sepsis. Its small size and simple structure may make Lcn2 a deployable treatment for sepsis.

  7. dNTP deficiency induced by HU via inhibiting ribonucleotide reductase affects neural tube development.

    PubMed

    Guan, Zhen; Wang, Xiuwei; Dong, Yanting; Xu, Lin; Zhu, Zhiqiang; Wang, Jianhua; Zhang, Ting; Niu, Bo

    2015-02-03

    Exposure to environmental toxic chemicals in utero during the neural tube development period can cause developmental disorders. To evaluate the disruption of neural tube development programming, the murine neural tube defects (NTDs) model was induced by interrupting folate metabolism using methotrexate in our previous study. The present study aimed to examine the effects of dNTP deficiency induced by hydroxyurea (HU), a specific ribonucleotide reductase (RNR) inhibitor, during murine neural tube development. Pregnant C57BL/6J mice were intraperitoneally injected with various doses of HU on gestation day (GD) 7.5, and the embryos were checked on GD 11.5. RNR activity and deoxynucleoside triphosphate (dNTP) levels were measured in the optimal dose. Additionally, DNA damage was examined by comet analysis and terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling (TUNEL) assay. Cellular behaviors in NTDs embryos were evaluated with phosphorylation of histone H3 (PH-3) and caspase-3 using immunohistochemistry and western blot analysis. The results showed that NTDs were observed mostly with HU treatment at an optimal dose of 225 mg/kg b/w. RNR activity was inhibited and dNTP levels were decreased in HU-treated embryos with NTDs. Additionally, increased DNA damage, decreased proliferation, and increased caspase-3 were significant in NTDs embryos compared to the controls. Results indicated that HU induced murine NTDs model by disturbing dNTP metabolism and further led to the abnormal cell balance between proliferation and apoptosis.

  8. Deficiency of intestinal mucin-2 protects mice from diet-induced fatty liver disease and obesity.

    PubMed

    Hartmann, Phillipp; Seebauer, Caroline T; Mazagova, Magdalena; Horvath, Angela; Wang, Lirui; Llorente, Cristina; Varki, Nissi M; Brandl, Katharina; Ho, Samuel B; Schnabl, Bernd

    2016-03-01

    Nonalcoholic fatty liver disease (NAFLD) and obesity are characterized by altered gut microbiota, inflammation, and gut barrier dysfunction. Here, we investigated the role of mucin-2 (Muc2) as the major component of the intestinal mucus layer in the development of fatty liver disease and obesity. We studied experimental fatty liver disease and obesity induced by feeding wild-type and Muc2-knockout mice a high-fat diet (HFD) for 16 wk. Muc2 deficiency protected mice from HFD-induced fatty liver disease and obesity. Compared with wild-type mice, after a 16-wk HFD, Muc2-knockout mice exhibited better glucose homeostasis, reduced inflammation, and upregulated expression of genes involved in lipolysis and fatty acid β-oxidation in white adipose tissue. Compared with wild-type mice that were fed the HFD as well, Muc2-knockout mice also displayed higher intestinal and plasma levels of IL-22 and higher intestinal levels of the IL-22 target genes Reg3b and Reg3g. Our findings indicate that absence of the intestinal mucus layer activates the mucosal immune system. Higher IL-22 levels protect mice from diet-induced features of the metabolic syndrome.

  9. Soleus muscle in glycosylation-deficient muscular dystrophy is protected from contraction-induced injury.

    PubMed

    Gumerson, Jessica D; Kabaeva, Zhyldyz T; Davis, Carol S; Faulkner, John A; Michele, Daniel E

    2010-12-01

    The glycosylation of dystroglycan is required for its function as a high-affinity laminin receptor, and loss of dystroglycan glycosylation results in congenital muscular dystrophy. The purpose of this study was to investigate the functional defects in slow- and fast-twitch muscles of glycosylation-deficient Large(myd) mice. While a partial alteration in glycosylation of dystroglycan in heterozygous Large(myd/+) mice was not sufficient to alter muscle function, homozygous Large(myd/myd) mice demonstrated a marked reduction in specific force in both soleus and extensor digitorum longus (EDL) muscles. Although EDL muscles from Large(myd/myd) mice were highly susceptible to lengthening contraction-induced injury, Large(myd/myd) soleus muscles surprisingly showed no greater force deficit compared with wild-type soleus muscles even after five lengthening contractions. Despite no increased susceptibility to injury, Large(myd/myd) soleus muscles showed loss of dystroglycan glycosylation and laminin binding activity and dystrophic pathology. Interestingly, we show that soleus muscles have a markedly higher sarcolemma expression of β(1)-containing integrins compared with EDL and gastrocnemius muscles. Therefore, we conclude that β(1)-containing integrins play an important role as matrix receptors in protecting muscles containing slow-twitch fibers from contraction-induced injury in the absence of dystroglycan function, and that contraction-induced injury appears to be a separable phenotype from the dystrophic pathology of muscular dystrophy.

  10. Epigenetic Upregulation of Corticotrophin-Releasing Hormone Mediates Postnatal Maternal Separation-Induced Memory Deficiency

    PubMed Central

    Wang, Aiyun; Nie, Wenying; Li, Haixia; Hou, Yuhua; Yu, Zhen; Fan, Qing; Sun, Ruopeng

    2014-01-01

    Accumulating evidences demonstrated that early postnatal maternal separation induced remarkable social and memory defects in the adult rodents. Early-life stress induced long-lasting functional adaptation of neuroendocrine hypothalamic-pituitary-adrenal axis, including neuropeptide corticotrophin-releasing hormone (CRH) in the brain. In the present study, a significantly increased hippocampal CRH was observed in the adult rats with postnatal maternal separation, and blockade of CRHR1 signaling significantly attenuated the hippocampal synaptic dysfunction and memory defects in the modeled rats. Postnatal maternal separation enduringly increased histone H3 acetylation and decreased cytosine methylation in Crh promoter region, resulting from the functional adaptation of several transcriptional factors, in the hippocampal CA1 of the modeled rats. Enriched environment reversed the epigenetic upregulation of CRH, and ameliorated the hippocampal synaptic dysfunction and memory defects in the adult rats with postnatal maternal separation. This study provided novel insights into the epigenetic mechanism underlying postnatal maternal separation-induced memory deficiency, and suggested environment enrichment as a potential approach for the treatment of this disorder. PMID:24718660

  11. The Protective Effect of Yi Shen Juan Bi Pill in Arthritic Rats with Castration-Induced Kidney Deficiency

    PubMed Central

    Zhao, Hongyan; Li, Jian; He, Xiaojuan; Lu, Cheng; Xiao, Cheng; Niu, Xuyan; Zhao, Ning; Ju, Dahong; Lu, Aiping

    2012-01-01

    Androgens have been linked to the onset, severity, and progression of rheumatoid arthritis (RA). In traditional Chinese medicine (TCM), the most common pattern in RA is kidney deficiency, which partly corresponds to a low sex hormone state. In this study, TCM kidney deficiency was induced in male Sprague-Dawley rats with castration surgery, and a TCM preparation, Yi Shen Juan Bi Pill (YJB), was used to treat collagen induced arthritis (CIA) rats with castration. Metabolomic technique was used to evaluate the pharmacological mechanism in castrated CIA rats treated by YJB. The results showed that castration significantly increased the severity of the arthritis in rats but was ameliorated by YJB. Its pharmacological mechanism was partially associated with lipid metabolites involving free fatty acid (FFA) and lysophosphatidylcholine (LPC). In conclusion, the experimental results demonstrate the protective effect of YJB on the TCM kidney deficiency pattern induced by androgen deficiency in CIA rats and support that YJB should be used for the clinical treatment of RA with TCM kidney deficiency pattern. PMID:22550538

  12. Cysteine dietary supplementation reverses the decrease in mitochondrial ROS production at complex I induced by methionine restriction.

    PubMed

    Gomez, A; Gomez, J; Lopez Torres, M; Naudi, A; Mota-Martorell, N; Pamplona, R; Barja, G

    2015-06-01

    It has been described that dietary cysteine reverses many of the beneficial changes induced by methionine restriction in aging rodents. In this investigation male Wistar rats were subjected to diets low in methionine, supplemented with cysteine, or simultaneously low in methionine and supplemented with cysteine. The results obtained in liver showed that cysteine supplementation reverses the decrease in mitochondrial ROS generation induced by methionine restriction at complex I. Methionine restriction also decreased various markers of oxidative and non-oxidative stress on mitochondrial proteins which were not reversed by cysteine. Instead, cysteine supplementation also lowered protein damage in association with decreases in mTOR activation. The results of the present study add the decrease in mitochondrial ROS production to the various beneficial changes induced by methionine restriction that are reversed by cysteine dietary supplementation.

  13. Dietary protocatechuic acid ameliorates dextran sulphate sodium-induced ulcerative colitis and hepatotoxicity in rats.

    PubMed

    Farombi, Ebenezer O; Adedara, Isaac A; Awoyemi, Omolola V; Njoku, Chinonye R; Micah, Gabriel O; Esogwa, Cynthia U; Owumi, Solomon E; Olopade, James O

    2016-02-01

    The present study investigated the antioxidant and anti-inflammatory effects of dietary protocatechuic acid (PCA), a simple hydrophilic phenolic compound commonly found in many edible vegetables, on dextran sulphate sodium (DSS)-induced ulcerative colitis and its associated hepatotoxicity in rats. PCA was administered orally at 10 mg kg(-1) to dextran sulphate sodium exposed rats for five days. The result revealed that administration of PCA significantly (p < 0.05) prevented the incidence of diarrhea and bleeding, the decrease in the body weight gain, shortening of colon length and the increase in colon mass index in DSS-treated rats. Furthermore, PCA prevented the increase in the plasma levels of pro-inflammatory cytokines, markers of liver toxicity and markedly suppressed the DSS-mediated elevation in colonic nitric oxide concentration and myeloperoxidase activity in the treated rats. Administration of PCA significantly protected against colonic and hepatic oxidative damage by increasing the antioxidant status and concomitantly decreased hydrogen peroxide and lipid peroxidation levels in the DSS-treated rats. Moreover, histological examinations confirmed PCA chemoprotection against colon and liver damage. Immunohistochemical analysis showed that PCA significantly inhibited cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein expression in the colon of DSS-treated rats. In conclusion, the effective chemoprotective role of PCA in colitis and the associated hepatotoxicity is related to its intrinsic anti-inflammatory and anti-oxidative properties.

  14. Sphingosine Kinase 1 Deficiency Confers Protection against Hyperoxia-Induced Bronchopulmonary Dysplasia in a Murine Model

    PubMed Central

    Harijith, Anantha; Pendyala, Srikanth; Reddy, Narsa M.; Bai, Tao; Usatyuk, Peter V.; Berdyshev, Evgeny; Gorshkova, Irina; Huang, Long Shuang; Mohan, Vijay; Garzon, Steve; Kanteti, Prasad; Reddy, Sekhar P.; Raj, J. Usha; Natarajan, Viswanathan

    2014-01-01

    Bronchopulmonary dysplasia of the premature newborn is characterized by lung injury, resulting in alveolar simplification and reduced pulmonary function. Exposure of neonatal mice to hyperoxia enhanced sphingosine-1-phosphate (S1P) levels in lung tissues; however, the role of increased S1P in the pathobiological characteristics of bronchopulmonary dysplasia has not been investigated. We hypothesized that an altered S1P signaling axis, in part, is responsible for neonatal lung injury leading to bronchopulmonary dysplasia. To validate this hypothesis, newborn wild-type, sphingosine kinase1−/− (Sphk1−/−), sphingosine kinase 2−/− (Sphk2−/−), and S1P lyase+/− (Sgpl1+/−) mice were exposed to hyperoxia (75%) from postnatal day 1 to 7. Sphk1−/−, but not Sphk2−/− or Sgpl1+/−, mice offered protection against hyperoxia-induced lung injury, with improved alveolarization and alveolar integrity compared with wild type. Furthermore, SphK1 deficiency attenuated hyperoxia-induced accumulation of IL-6 in bronchoalveolar lavage fluids and NADPH oxidase (NOX) 2 and NOX4 protein expression in lung tissue. In vitro experiments using human lung microvascular endothelial cells showed that exogenous S1P stimulated intracellular reactive oxygen species (ROS) generation, whereas SphK1 siRNA, or inhibitor against SphK1, attenuated hyperoxia-induced S1P generation. Knockdown of NOX2 and NOX4, using specific siRNA, reduced both basal and S1P-induced ROS formation. These results suggest an important role for SphK1-mediated S1P signaling–regulated ROS in the development of hyperoxia-induced lung injury in a murine neonatal model of bronchopulmonary dysplasia. PMID:23933064

  15. Dietary restriction-induced life extension: a broadly based biological phenomenon.

    PubMed

    Masoro, Edward J

    2006-06-01

    It is concluded that dietary restriction will extend the life of all species in the Animalia Kingdom, including the human species. This conclusion is based on the fact that hormesis is a component of the life-extending action and the other anti-aging effects of dietary restriction. It is also concluded that given the currently available database, it is not possible to predict the quantitative effect of dietary restriction on the human life span.

  16. Preservation and promotion of bone formation in the mandible as a response to a novel calcium-phosphate based biomaterial in mineral deficiency induced low bone mass male versus female rats

    PubMed Central

    Srinivasan, Kritika; Naula, Diana P.; Mijares, Dindo Q.; Janal, Malvin N.; LeGeros, Raquel Z.; Zhang, Yu

    2016-01-01

    Calcium and other trace mineral supplements have previously demonstrated to safely improve bone quality. We hypothesize that our novel calcium-phosphate based biomaterial (SBM) preserves and promotes mandibular bone formation in male and female rats on mineral deficient diet (MD). Sixty Sprague-Dawley rats were randomly assigned to receive one of three diets (n = 10): basic diet (BD), MD or mineral deficient diet with 2% SBM. Rats were sacrificed after 6 months. Micro-Computed Tomography (μCT) was used to evaluate bone volume and 3D-microarchitecture while microradiography (Faxitron) was used to measure bone mineral density from different sections of the mandible. Results showed that bone quality varied with region, gender and diet. MD reduced bone mineral density (BMD) and volume and increased porosity. SBM preserved BMD and bone mineral content (BMC) in the alveolar bone and condyle in both genders. In the alveolar crest and mandibular body, while preserving more bone in males, SBM also significantly supplemented female bone. Results indicate that mineral deficiency leads to low bone mass in skeletally immature rats, comparatively more in males. Furthermore, SBM administered as a dietary supplement was effective in preventing mandibular bone loss in all subjects. This study suggests that the SBM preparation has potential use in minimizing low peak bone mass induced by mineral deficiency and related bone loss irrespective of gender. PMID:26914814

  17. Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype.

    PubMed

    Tarantini, Stefano; Valcarcel-Ares, Noa M; Yabluchanskiy, Andriy; Springo, Zsolt; Fulop, Gabor A; Ashpole, Nicole; Gautam, Tripti; Giles, Cory B; Wren, Jonathan D; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2017-03-14

    Clinical and experimental studies show that aging exacerbates hypertension-induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. There is growing evidence that aging promotes insulin-like growth factor 1 (IGF-1) deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF-1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with liver-specific knockdown of IGF-1 (Igf1(f/f)  + TBG-Cre-AAV8) and control mice by angiotensin II plus l-NAME treatment. In IGF-1-deficient mice, the same level of hypertension led to significantly earlier onset and increased incidence and neurological consequences of CMHs, as compared to control mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Previous studies showed that in aging, increased oxidative stress-mediated matrix metalloprotease (MMP) activation importantly contributes to the pathogenesis of CMHs. Thus, it is significant that hypertension-induced cerebrovascular oxidative stress and MMP activation were increased in IGF-1-deficient mice. We found that IGF-1 deficiency impaired hypertension-induced adaptive media hypertrophy and extracellular matrix remodeling, which together with the increased MMP activation likely also contributes to increased fragility of intracerebral arterioles. Collectively, IGF-1 deficiency promotes the pathogenesis of CMHs, mimicking the aging phenotype, which likely contribute to its deleterious effect on cognitive function. Therapeutic strategies that upregulate IGF-1 signaling in the cerebral vessels and/or reduce microvascular oxidative stress, and MMP activation may be useful for the prevention of CMHs, protecting cognitive function in high-risk elderly patients.

  18. Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors.

    PubMed

    Powell, Christine L; Bradford, Blair U; Craig, Christopher Patrick; Tsuchiya, Masato; Uehara, Takeki; O'Connell, Thomas M; Pogribny, Igor P; Melnyk, Stepan; Koop, Dennis R; Bleyle, Lisa; Threadgill, David W; Rusyn, Ivan

    2010-05-01

    Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a control high-fat diet or diet enriched in methyl donors with or without alcohol for 4 weeks using the enteral alcohol feeding model. As expected, attenuation of ALI and an increase in reduced glutathione:oxidized glutathione ratio were achieved with methyl donor supplementation. Interestingly, methyl donors led to a 35% increase in blood alcohol elimination rate, and while there was no effect on alcohol metabolism in the stomach, a profound effect on liver alcohol metabolism was observed. The catalase-dependent pathway of alcohol metabolism was induced, yet the increase in CYP2E1 activity by alcohol was blunted, which may be mitigating production of oxidants. Additional factors contributing to the protective effects of methyl donors in ALI were increased activity of low- and high-K(m) aldehyde dehydrogenases leading to lower hepatic acetaldehyde, maintenance of the efficient mitochondrial energy metabolism, and promotion of peroxisomal beta-oxidation. Profound changes in alcohol metabolism represent additional important mechanism of the protective effect of methyl donors in ALI.

  19. Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice

    PubMed Central

    Chen, Jayson X.; Li, Guangxun; Wang, Hong; Liu, Anna; Lee, Mao-Jung; Reuhl, Kenneth; Suh, Nanjoo; Bosland, Maarten C.; Yang, Chung S.

    2015-01-01

    Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), β-T, γ-T and δ-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer. PMID:26582657

  20. Dietary trans-10,cis-12 CLA reduces murine collagen-induced arthritis in a dose-dependent manner.

    PubMed

    Huebner, Shane M; Olson, Jake M; Campbell, James P; Bishop, Jeffrey W; Crump, Peter M; Cook, Mark E

    2014-02-01

    Dietary trans-10,cis-12 (t10c12) conjugated linoleic acid (CLA) has been shown to reduce inflammation in a murine collagen-induced arthritis (CA) model. To understand the anti-inflammatory potential of t10c12-CLA in the diet, the minimum dose of pure dietary t10c12-CLA capable of reducing CA was investigated. Because plasma inflammatory cytokines often do not reflect the progression of late-stage arthritis, inflamed tissue cytokine concentrations were also investigated in relation to increasing dietary t10c12-CLA amounts. Mice were randomly assigned to the following dietary treatments upon the establishment of arthritis: corn oil (CO) or 0.125%, 0.25%, 0.375%, or 0.5% t10c12-CLA (wt:wt) for 84 d. Sham mice (no arthritis) were fed CO and served as controls. Arthritic paw score, based on subjective assessment of arthritic severity, and paw thickness decreased linearly overall [16-65% (P < 0.001) and 0.5-12% (P < 0.001), respectively] as dietary t10c12-CLA increased (P < 0.001, R(2) < 0.81). Increasing dietary t10c12-CLA was associated with a decrease in plasma interleukin (IL)-1β at days 21 and 42 compared with CO-fed arthritic mice, such that mice fed ≥0.25% t10c12-CLA had IL-1β concentrations that were similar to sham mice. Plasma cytokines returned to sham mice concentrations by day 63 regardless of treatment; however, an arthritis-induced elevation in paw IL-1β decreased linearly as dietary t10c12-CLA concentrations increased at day 84 (P = 0.007, R(2) = 0.92). Similarly, increasing dietary t10c12-CLA linearly decreased paw tumor necrosis factor (TNF)-α (P = 0.05, R(2) = 0.70). In conclusion, ≥0.125% t10c12-CLA dose-dependently reduced inflammation in a murine CA model.

  1. The Pathogenesis of Ethanol versus Methionine and Choline Deficient Diet-Induced Liver Injury

    PubMed Central

    Gyamfi, Maxwell Afari; Damjanov, Ivan; French, Samuel; Wan, Yu-Jui Yvonne

    2008-01-01

    The differences and similarities of the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) were examined. Mice (6/group) received 1 of 4 Lieber-Decarli liquid diets for 6 weeks: (1) paired-fed control diet; (2) control diet with ethanol (ethanol); (3) paired-fed methionine/choline deficient (MCD) diet; and (4) MCD plus ethanol (combination). Hepatotoxicity, histology, and gene expression changes were examined. Both MCD and ethanol induced macrovesicular steatosis. However, the combination diet produced massive steatosis with minor necrosis and inflammation. MCD and combination diets, but not ethanol, induced serum ALT levels by 1.6- and 10-fold, respectively. MCD diet, but not ethanol, also induced serum alkaline phosphatase levels suggesting bile duct injury. Ethanol increased liver fatty acid binding protein (L-FABP) mRNA and protein levels. In contrast, the combination diet decreased L-FABP mRNA and protein levels and increased hepatic free fatty acid and lipid peroxide levels. Ethanol, but not MCD, reduced hepatic S-adenosylmethionine (SAM) and GSH levels. Hepatic TNFα protein levels were increased in all treatment groups, however, IL-6, a hepatoprotective cytokine which promotes liver regeneration was increased in ethanol-fed mice (2-fold), but decreased in the combination diet-treated mice. In addition, the combination diet reduced phosphorylated STAT3 and Bcl-2 levels. While MCD diet might cause bile duct injury and cholestasis, ethanol preferentially interferes with the SAM-GSH oxidative stress pathway. The exacerbated liver injury induced by the combination diet might be explained by reduced L-FABP, increased free fatty acids, oxidative stress, and decreased IL-6 protein levels. The combination diet is an efficient model of steatohepatitis. PMID:18036573

  2. Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer.

    PubMed

    Wang, Donghai; Peregrina, Karina; Dhima, Elena; Lin, Elaine Y; Mariadason, John M; Augenlicht, Leonard H

    2011-06-21

    Nutritional and genetic risk factors for intestinal tumors are additive on mouse tumor phenotype, establishing that diet and genetic factors impact risk by distinct combinatorial mechanisms. In a mouse model of dietary-induced sporadic small and large intestinal cancer in WT mice in which tumor etiology, lag, incidence, and frequency reflect >90% of intestinal cancer in Western societies, dietary-induced risk altered gene expression profiles predominantly in villus cells of the histologically normal mucosa, in contrast to targeting of crypt cells by inheritance of an Apc(1638N) allele or homozygous inactivation of p21(Waf1/cip1), and profiles induced by each risk factor were distinct at the gene or functional group level. The dietary-induced changes in villus cells encompassed ectopic expression of Paneth cell markers (a lineage normally confined to the bottom of small intestinal crypts), elevated expression of the Wnt receptor Fzd5 and of EphB2 (genes necessary for Paneth cell differentiation and localization to the crypt bottom), and increased Wnt signaling in villus cells. Ectopic elevation of these markers was also present in the colon crypts, which are also sites of sporadic tumors in the nutritional model. Elevating dietary vitamin D(3) and calcium, which prevents tumor development, abrogated these changes in the villus and colon cells. Thus, common intestinal cancer driven by diet involves mechanisms of tumor development distinct from those mechanisms that cause tumors induced by the rare inheritance of a mutant adenomatous polyposis coli (Apc) allele. This is fundamental for understanding how common sporadic tumors arise and in evaluating relative risk in the population.

  3. Kindling-induced learning deficiency and possible cellular and molecular involved mechanisms.

    PubMed

    Sherafat, Mohammad Amin; Ronaghi, Abdolaziz; Ahmad-Molaei, Leila; Nejadhoseynian, Mohammad; Ghasemi, Rasoul; Hosseini, Arman; Naderi, Nima; Motamedi, Fereshteh

    2013-06-01

    Hippocampus learning disturbance is a major symptom of patients with seizure, hence hippocampal dysfunction has essential role in worsening the disease. Hippocampal formation includes neurons and myelinated fibers that are necessary for acquisition and consolidation of memory, long-term potentiation and learning activity. The exact mechanism by which seizure can decrease memory and learning activity of hippocampus remains unknown. In the present study, electrical kindling-induced learning deficit in rats was evaluated by Morris water maze (MWM) test. The hippocampus was removed and changes in neurons and myelin sheaths around hippocampal fibers were investigated using histological and immunohistochemical methods. Demyelination was assessed by luxol fast blue staining, and immunohistological staining of myelin-binding protein (MBP). The TUNEL assay was used for evaluation of neuronal apoptosis and the glial fibriliary acetic protein (GFAP) was used for assessment of inflammatory reaction. The results indicated that electrical kindling of hippocampus could induce deficiency in spatial learning and memory as compared to control group. In addition, electrical kindling caused damage to the myelin sheath around hippocampal fibers and produced vast demyelination. Furthermore, an increase in the number of apoptotic cells in hippocampal slices was observed. In addition, inflammatory response was higher in kindled animals as compared to the control group. The results suggested that the decrease in learning and memory in kindled animals is likely due to demyelination and augmentation in apoptosis rate accompanied by inflammatory reaction in hippocampal neurons of kindled rats.

  4. CD147 deficiency blocks IL-8 secretion and inhibits lung cancer-induced osteoclastogenesis.

    PubMed

    Wang, Hongkai; Zhuo, Yunyun; Hu, Xu; Shen, Weiwei; Zhang, Ying; Chu, Tongwei

    2015-03-06

    Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and poor prognosis; however, the molecular basis of this process is still unknown. This study investigated the role of extracellular matrix metalloproteinase inducer (also known as cluster of differentiation (CD)147) in osteoclastogenesis resulting from bone metastasis, based on the enrichment of this glycoprotein on the surface of many malignant bone tumors. RNA interference was used to silence CD147 expression in A549 human lung cancer cells. Compared with conditioned medium (CM) from control cells (A549-CM), CM from CD147-deficient cells (A549-si-CM) suppressed receptor activator of nuclear factor κB ligand-stimulated osteoclastogenesis in RAW 264.7 cells and bone marrow-derived macrophages. The mRNA levels of osteoclast-specific genes such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K were also reduced in the presence of A549-si-CM. CD147 knockdown in A549 cells decreased interleukin (IL)-8mRNA and protein expression. IL-8 is present in large amounts in A549-CM and mimicked its inductive effect on osteoclastogenesis; this was reversed by depletion of IL-8 from the medium. Taken together, these results indicate that CD147 promotes lung cancer-induced osteoclastogenesis by modulating IL-8 secretion, and suggest that CD147 is a potential therapeutic target for cancer-associated bone resorption in lung cancer patients.

  5. Plasmid-deficient Chlamydia muridarum fail to induce immune pathology and protect against oviduct disease.

    PubMed

    O'Connell, Catherine M; Ingalls, Robin R; Andrews, Charles W; Scurlock, Amy M; Darville, Toni

    2007-09-15

    Chlamydia trachomatis is the most prevalent sexually transmitted bacterial infection in the world. In women, genital infection can cause endometritis and pelvic inflammatory disease with the severe sequelae of ectopic pregnancy or infertility. Chlamydia sp. do not damage tissues directly, but induce an injurious host inflammatory response at the infected site. In the murine model of genital disease with Chlamydia muridarum, TLR2 plays a role in both early production of inflammatory mediators and development of chronic oviduct pathology. We report the results of studies with plasmid-cured C. muridarum mutants that retain the ability to infect the murine genital tract, but fail to cause disease in the oviduct. These mutants do not stimulate TLR2-dependent cytokine production in mice, nor in innate immune cells or epithelial cells in vitro. They induce an effective Th1 immune response, with no evidence for Th1-immune-mediated collateral tissue damage. Furthermore, mice previously infected with the plasmid-deficient strains are protected against oviduct disease upon challenge with virulent C. muridarum. If plasmid-cured derivatives of human C. trachomatis biovars exhibit similar phenotypic characteristics, they have the potential to serve as vaccines to prevent human disease.

  6. Notch Downregulation and Extramedullary Erythrocytosis in Hypoxia-Inducible Factor Prolyl 4-Hydroxylase 2-Deficient Mice.

    PubMed

    Myllymäki, Mikko N M; Määttä, Jenni; Dimova, Elitsa Y; Izzi, Valerio; Väisänen, Timo; Myllyharju, Johanna; Koivunen, Peppi; Serpi, Raisa

    2017-01-15

    Erythrocytosis is driven mainly by erythropoietin, which is regulated by hypoxia-inducible factor (HIF). Mutations in HIF prolyl 4-hydroxylase 2 (HIF-P4H-2) (PHD2/EGLN1), the major downregulator of HIFα subunits, are found in familiar erythrocytosis, and large-spectrum conditional inactivation of HIF-P4H-2 in mice leads to severe erythrocytosis. Although bone marrow is the primary site for erythropoiesis, spleen remains capable of extramedullary erythropoiesis. We studied HIF-P4H-2-deficient (Hif-p4h-2(gt/gt)) mice, which show slightly induced erythropoiesis upon aging despite nonincreased erythropoietin levels, and identified spleen as the site of extramedullary erythropoiesis. Splenic hematopoietic stem cells (HSCs) of these mice exhibited increased erythroid burst-forming unit (BFU-E) growth, and the mice were protected against anemia. HIF-1α and HIF-2α were stabilized in the spleens, while the Notch ligand genes Jag1, Jag2, and Dll1 and target Hes1 became downregulated upon aging HIF-2α dependently. Inhibition of Notch signaling in wild-type spleen HSCs phenocopied the increased BFU-E growth. HIFα stabilization can thus mediate non-erythropoietin-driven splenic erythropoiesis via altered Notch signaling.

  7. Bile Duct Ligation Induces ATZ Globule Clearance In a Mouse Model of Alpha-1 Antitrypsin Deficiency

    PubMed Central

    Khan, Zahida; Yokota, Shinichiro; Ono, Yoshihiro; Bell, Aaron W.; Stolz, Donna B.; Michalopoulos, George K.

    2016-01-01

    Background Alpha-1 antitrypsin deficiency (A1ATD) can progress to cirrhosis and hepatocellular carcinoma; however, not all patients are susceptible to severe liver disease. In A1ATD, a toxic gain-of-function mutation generates insoluble ATZ “globules” in hepatocytes, overwhelming protein clearance mechanisms. The relationship between bile acids and hepatocytic autophagy is less clear, but may involve altered gene expression pathways. Based on previous findings that bile duct ligation (BDL) induces autophagy, we hypothesized that retained bile acids may have hepatoprotective effects in PiZZ transgenic mice, which model A1ATD. Methods We performed BDL and partial BDL (pBDL) in PiZZ mice, followed by analysis of liver tissues. Results PiZZ liver subjected to BDL showed up to 50% clearance of ATZ globules, with increased expression of autophagy proteins. Analysis of transcription factors revealed significant changes. Surprisingly nuclear TFEB, a master regulator of autophagy, remained unchanged. pBDL confirmed that ATZ globule clearance was induced by localized stimuli rather than diet or systemic effects. Several genes involved in bile metabolism were over-expressed in globule-devoid hepatocytes, compared to globule-containing cells. Conclusions Retained bile acids led to a dramatic reduction of ATZ globules, with enhanced hepatocyte regeneration and autophagy. These findings support investigation of synthetic bile acids as potential autophagy-enhancing agents. PMID:27938510

  8. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome.

    PubMed

    Macia, Laurence; Tan, Jian; Vieira, Angelica T; Leach, Katie; Stanley, Dragana; Luong, Suzanne; Maruya, Mikako; Ian McKenzie, Craig; Hijikata, Atsushi; Wong, Connie; Binge, Lauren; Thorburn, Alison N; Chevalier, Nina; Ang, Caroline; Marino, Eliana; Robert, Remy; Offermanns, Stefan; Teixeira, Mauro M; Moore, Robert J; Flavell, Richard A; Fagarasan, Sidonia; Mackay, Charles R

    2015-04-01

    Diet and the gut microbiota may underpin numerous human diseases. A major metabolic product of commensal bacteria are short-chain fatty acids (SCFAs) that derive from fermentation of dietary fibre. Here we show that diets deficient or low in fibre exacerbate colitis development, while very high intake of dietary fibre or the SCFA acetate protects against colitis. SCFAs binding to the 'metabolite-sensing' receptors GPR43 and GPR109A in non-haematopoietic cells mediate these protective effects. The inflammasome pathway has hitherto been reported as a principal pathway promoting gut epithelial integrity. SCFAs binding to GPR43 on colonic epithelial cells stimulates K(+) efflux and hyperpolarization, which lead to NLRP3 inflammasome activation. Dietary fibre also shapes gut bacterial ecology, resulting in bacterial species that are more effective for inflammasome activation. SCFAs and metabolite receptors thus explain health benefits of dietary fibre, and how metabolite signals feed through to a major pathway for gut homeostasis.

  9. Zinc deficiency alters host response and pathogen virulence in a mouse model of enteroaggregative Escherichia coli-induced diarrhea.

    PubMed

    Bolick, David T; Kolling, Glynis L; Moore, John H; de Oliveira, Luís Antônio; Tung, Kenneth; Philipson, Casandra; Viladomiu, Monica; Hontecillas, Raquel; Bassaganya-Riera, Josep; Guerrant, Richard L

    2014-01-01

    Enteroaggregative Escherichia coli (EAEC) is increasingly recognized as a major cause of diarrheal disease globally. In the current study, we investigated the impact of zinc deficiency on the host and pathogenesis of EAEC. Several outcomes of EAEC infection were investigated including weight loss, EAEC shedding and tissue burden, leukocyte recruitment, intestinal cytokine expression, and virulence expression of the pathogen in vivo. Mice fed a protein source defined zinc deficient diet (dZD) had an 80% reduction of serum zinc and a 50% reduction of zinc in luminal contents of the bowel compared to mice fed a protein source defined control diet (dC). When challenged with EAEC, dZD mice had significantly greater weight loss, stool shedding, mucus production, and, most notably, diarrhea compared to dC mice. Zinc deficient mice had reduced infiltration of leukocytes into the ileum in response to infection suggesting an impaired immune response. Interestingly, expression of several EAEC virulence factors were increased in luminal contents of dZD mice. These data show a dual effect of dietary zinc in benefitting the host while impairing virulence of the pathogen. The study demonstrates the critical importance of zinc and may help elucidate the benefits of zinc supplementation in cases of childhood diarrhea and malnutrition.

  10. The influence of experimentally induced copper deficiency on the fertility of rams. I. Semen parameters and peripheral plasma androgen concentration.

    PubMed

    Van Niekerk, F E; Van Niekerk, C H

    1989-03-01

    The influence of molybdenum and molybdenum plus sulphate-induced copper deficiencies on semen quality and peripheral plasma testosterone concentrations in South African Mutton Merino rams was investigated. All animals received an identical ration, supplemented with molybdenum in one group (M) and molybdenum plus sulphate in another (MS) while the control group (C) received additional copper supplementation. After almost a year on these rations, rams in Group MS produced ejaculates of lower volume, lower sperm concentration, poorer sperm motility and morphology than rams of the other 2 groups. The fructose concentration in the ejaculates of group MS rams was also lower than that of rams in the other groups. Peripheral plasma testosterone concentrations in Group MS were lower than in Groups C or M. Liver copper concentrations and clinical signs were consistent with a severe copper deficiency in Group MS and a mild deficiency in Group M. After the copper deficiency was reversed, the above parameters reverted to normal. It was concluded that an experimentally induced copper deficiency produced reversible impairment of testicular function in rams.

  11. A Small Amount of Dietary Carbohydrate Can Promote the HFD-Induced Insulin Resistance to a Maximal Level

    PubMed Central

    Guo, Huailan; Gu, Haihua; Zha, Longying; Cai, Junwei; Li, Xuefeng; Liu, Zhenqi; Bennett, Brian J.; He, Ling; Cao, Wenhong

    2014-01-01

    Both dietary fat and carbohydrates (Carbs) may play important roles in the development of insulin resistance. The main goal of this study was to further define the roles for fat and dietary carbs in insulin resistance. C57BL/6 mice were fed normal chow diet (CD) or HFD containing 0.1–25.5% carbs for 5 weeks, followed by evaluations of calorie consumption, body weight and fat gains, insulin sensitivity, intratissue insulin signaling, ectopic fat, and oxidative stress in liver and skeletal muscle. The role of hepatic gluconeogenesis in the HFD-induced insulin resistance was determined in mice. The role of fat in insulin resistance was also examined in cultured cells. HFD with little carbs (0.1%) induced severe insulin resistance. Addition of 5% carbs to HFD dramatically elevated insulin resistance and 10% carbs in HFD was sufficient to induce a maximal level of insulin resistance. HFD with little carbs induced ectopic fat accumulation and oxidative stress in liver and skeletal muscle and addition of carbs to HFD dramatically enhanced ectopic fat and oxidative stress. HFD increased hepatic expression of key gluconeogenic genes and the increase was most dramatic by HFD with little carbs, and inhibition of hepatic gluconeogenesis prevented the HFD-induced insulin resistance. In cultured cells, development of insulin resistance induced by a pathological level of insulin was prevented in the absence of fat. Together, fat is essential for development of insulin resistance and dietary carb is not necessary for HFD-induced insulin resistance due to the presence of hepatic gluconeogenesis but a very small amount of it can promote HFD-induced insulin resistance to a maximal level. PMID:25055153

  12. Enhanced seizures and hippocampal neurodegeneration following kainic acid-induced seizures in metallothionein-I + II-deficient mice.

    PubMed

    Carrasco, J; Penkowa, M; Hadberg, H; Molinero, A; Hidalgo, J

    2000-07-01

    Metallothioneins (MTs) are major zinc binding proteins in the CNS that could be involved in the control of zinc metabolism as well as in protection against oxidative stress. Mice lacking MT-I and MT-II (MT-I + II deficient) because of targeted gene inactivation were injected with kainic acid (KA), a potent convulsive agent, to examine the neurobiological importance of these MT isoforms. At 35 mg/kg KA, MT-I + II deficient male mice showed a higher number of convulsions and a longer convulsion time than control mice. Three days later, KA-injected mice showed gliosis and neuronal injury in the hippocampus. MT-I + II deficiency decreased both astrogliosis and microgliosis and potentiated neuronal injury and apoptosis as shown by terminal deoxynucleotidyl transferase-mediated in situ end labelling (TUNEL), detection of single stranded DNA (ssDNA) and by increased interleukin-1beta-converting enzyme (ICE) and caspase-3 levels. Histochemically reactive zinc in the hippocampus was increased by KA to a greater extent in MT-I + II-deficient compared with control mice. KA-induced seizures also caused increased oxidative stress, as suggested by the malondialdehyde (MDA) and protein tyrosine nitration (NITT) levels and by the expression of MT-I + II, nuclear factor-kappaB (NF-kappaB), and Cu/Zn-superoxide dismutase (Cu/Zn-SOD). MT-I + II deficiency potentiated the oxidative stress caused by KA. Both KA and MT-I + II deficiency significantly affected the expression of MT-III, granulocyte-macrophage colony stimulating factor (GM-CSF) and its receptor (GM-CSFr). The present results indicate MT-I + II as important for neuron survival during KA-induced seizures, and suggest that both impaired zinc regulation and compromised antioxidant activity contribute to the observed neuropathology of the MT-I + II-deficient mice.

  13. Hepatic Deficiency of Augmenter of Liver Regeneration Exacerbates Alcohol-Induced Liver Injury and Promotes Fibrosis in Mice

    PubMed Central

    Kumar, Sudhir; Wang, Jiang; Rani, Richa; Gandhi, Chandrashekhar R.

    2016-01-01

    Why only a subpopulation (about 15%) of humans develops liver cirrhosis due to alcohol is a critical as yet unanswered question. Liver-specific depletion of augmenter of liver regeneration (ALR) protein in mice causes robust steatosis and hepatocyte apoptosis by 2 weeks; these pathologies regress subsequently with return of ALR expression even at lower than control levels, but the mice develop modest steatohepatitis by 8 weeks. We aimed to investigate whether chronic alcohol ingestion promotes excessive hepatic fibrosis in these ALR-deficient mice. Liver-specific ALR-deficient and wild type (WT) female mice (8–10 weeks old) were placed on 4% alcohol-supplemented or isocaloric diet for 4 weeks. Liver sections were examined for histopathology, and parameters of steatosis and fibrosis were quantified. The mRNA expression of alcohol dehydrogenase-1, acetaldehyde dehydrogenase-1 and cytochrome P450-2E1 increased in WT mice but decreased in ALR-deficient mice upon alcohol ingestion. While alcohol induced steatosis and mild inflammation in WT mice, ALR-deficient mice showed minimal steatosis, strong hepatocellular injury and inflammation, prominent ductular proliferation, and robust fibrosis. Compared to the WT mice, alcohol feeding of ALR-deficient mice resulted in significantly greater increase in hepatic TNFα and TGFβ, and oxidative stress; there was also hepatic iron accumulation, robust lipid peroxidation and mitochondrial DNA damage. Importantly, similar to ALR-deficient mice, lower hepatic ALR levels in human alcoholic liver cirrhosis were associated with increased iron content, reduced expression of alcohol dehydrogenase and acetaldehyde dehydrogenase, and elevated fibrogenic markers. We conclude that ALR deficiency or anomaly can play a critical role in alcohol-induced hepatic fibrosis/cirrhosis, mechanisms of which may involve dysregulation of alcohol metabolism and iron homeostasis, mitochondrial damage and oxidative injury. PMID:26808690

  14. Loss of TLR2 Worsens Spontaneous Colitis in MDR1A Deficiency through Commensally Induced Pyroptosis

    PubMed Central

    Ey, Birgit; Eyking, Annette; Klepak, Magdalena; Salzman, Nita H.; Göthert, Joachim R.; Rünzi, Michael; Schmid, Kurt W.; Gerken, Guido; Podolsky, Daniel K.

    2013-01-01

    Variants of the multidrug resistance gene (MDR1/ABCB1) have been associated with increased susceptibility to severe ulcerative colitis (UC). In this study, we investigated the role of TLR/IL-1R signaling pathways including the common adaptor MyD88 in the pathogenesis of chronic colonic inflammation in MDR1A deficiency. Double- or triple-null mice lacking TLR2, MD-2, MyD88, and MDR1A were generated in the FVB/N background. Deletion of TLR2 in MDR1A deficiency resulted in fulminant pancolitis with early expansion of CD11b+ myeloid cells and rapid shift toward TH1-dominant immune responses in the lamina propria. Colitis exacerbation in TLR2/MDR1A double-knockout mice required the unaltered commensal microbiota and the LPS coreceptor MD-2. Blockade of IL-1β activity by treatment with IL-1R antagonist (IL-1Ra; Anakinra) inhibited colitis acceleration in TLR2/MDR1A double deficiency; intestinal CD11b+Ly6C+-derived IL-1β production and inflammation entirely depended on MyD88. TLR2/MDR1A double-knockout CD11b+ myeloid cells expressed MD-2/TLR4 and hyperresponded to nonpathogenic Escherichia coli or LPS with reactive oxygen species production and caspase-1 activation, leading to excessive cell death and release of proinflammatory IL-1β, consistent with pyroptosis. Inhibition of reactive oxygen species–mediated lysosome degradation suppressed LPS hyperresponsiveness. Finally, active UC in patients carrying the TLR2-R753Q and MDR1-C3435T polymorphisms was associated with increased nuclear expression of caspase-1 protein and cell death in areas of acute inflammation, compared with active UC patients without these variants. In conclusion, we show that the combined defect of two UC susceptibility genes, MDR1A and TLR2, sets the stage for spontaneous and uncontrolled colitis progression through MD-2 and IL-1R signaling via MyD88, and we identify commensally induced pyroptosis as a potential innate immune effector in severe UC pathogenesis. PMID:23636052

  15. Influence of Corticosteroids and Vitamin E Deficiency on Onset and Cytopathology of Radiation-Induced Cataract

    NASA Astrophysics Data System (ADS)

    Junk, A. K.; Worgul, B. V.

    Cataracts characteristic of those arising from radiation exposure have been reported among the astronaut and cosmonaut corps. This being the case it is critical to appreciate how radiogenic cataracts relate to those arising from other exogenous causes such as therapeutics, which may, one day, have to be administered on an extended mission. Because they produce precisely the same clinical picture, corticosteroids are examples of a class of drugs that potentially can exacerbate damage to the lens from radiation. On the other hand, Vitamin E, a free radical scavenger, has been shown to ameliorate oxidative damage as caused by ionizing radiation and evidence is accumulating that it may constitute protection from radiogenic damage. An experimental study was conducted to understand if corticosteroids with and in the absence of Vitamin E deficiency modulate the onset of cataract induced by ionizing radiation. The right eyes of 72 28-day-old Brown-Norway rats were irradiated with 6 Gy of 240 kV X-rays, the shielded left eyes served as controls. Half of the animals were maintained on a Vitamin E free diet after irradiation, the others were kept on regular chow. In each nutritional group 18 rats additionally received dexamethasone. The initial daily dose of 10 mg/kg body weight injected subcutaneously was reduced to 0.5 mg/kg over the course of 6 months. Cataract onset and development were followed by weekly slit-lamp exam. After 6 month the lenses were harvested for microscopic analyses. Irradiated eyes in all treatment subgroups showed early cataract onset [5 wks versus 11 wks in controls (p<0.0001)]. Corticosteroids accounted for accelerated cataract development in both irradiated (p<0.0005) and non-irradiated eyes (p<0.0001) relative to respective control eyes. Vitamin E deficiency did not affect cataract incidence in combination with radiation or steroids alone. Unexpectedly, when compared to irradiated controls, cataract development was inhibited in the group that

  16. Influence of corticosteroids and vitamin E deficiency on onset of radiation-induced cataract

    NASA Astrophysics Data System (ADS)

    Junk, A. K.; Worgul, B. W.

    Cataracts characteristic of those arising from radiation exposure have been reported among the astronaut and cosmonaut corps. This being the case it is critical to appreciate how radiogenic cataracts relate to those arising from other exogenous causes such as therapeutics, which may, one day, have to be administered on an extended mission. Because they produce precisely the same clinical picture, corticosteroids are examples of a class of drugs that potentially can exacerbate damage to the lens from radiation. On the other hand, Vitamin E, a free radical scavenger, has been shown to ameliorate oxidative damage as caused by ionizing radiation and evidence is accumulating that it may constitute protection from radiogenic damage. An experimental study was conducted to understand if corticosteroids with, and in the absence of Vitamin E deficiency modulate the onset of cataract induced by ionizing radiation. The right eyes of seventy-two 28-day-old Brown-Norway rats were irradiated with 6 Gy of 240 kV X-rays, the shielded left eyes served as controls. Half of the animals were maintained on a Vitamin E free diet after irradiation, the others were kept on standard chow. Fifty per cent of the animals in each nutritional group received dexamethasone. The initial daily dose of 10 mg/kg body weight injected subcutaneously was reduced to 0.5 mg/kg over the course of six months. Cataract onset and development were followed by weekly slit-lamp exam. After six month the lenses were harvested for microscopic analyses. Irradiated eyes in all treatment subgroups showed early cataract onset [5 wks vs. 11 wks in controls ( p < 0.0001)]. Corticosteroids accounted for accelerated cataract development in both irradiated ( p < 0.0005) and non-irradiated eyes ( p < 0.0001) relative to respective control eyes. Vitamin E deficiency did not affect cataract incidence in combination with radiation or steroids alone. Unexpectedly, when compared to irradiated controls, cataract development was

  17. High dietary calcium intake does not counteract disuse-induced bone loss

    NASA Astrophysics Data System (ADS)

    Baecker, N.; Boese, A.; Smith, S. M.; Heer, M.

    Reduction of mechanical stress on bone inhibits osteoblast-mediated bone formation, increases osteoclast-mediated bone resorption, and leads to what has been called disuse osteoporosis. Prolonged therapeutic bed rest, immobilization and space flight are common causes of disuse osteoporosis. There are sufficient data supporting the use of calcium in combination with vitamin D in the prevention and treatment of postmenopausal osteoporosis. In our study we examined the potential of high dietary calcium intake as a nutrition therapy for disuse-induced bone loss during head-down bed rest in healthy young men. In 2 identical metabolic ward, head-down bed rest (HDBR) experiments (crossover design), we studied the effect of high dietary calcium intake (2000 mg/d) in comparison to the recommended calcium intake of 1000 mg/d on markers of bone turnover. Experiment A (EA) was a 6-day randomized, controlled HDBR study. Experiment B (EB) was a 14-day randomized, controlled HDBR study. In both experiments, the test subjects stayed under well-controlled environmental conditions in our metabolic ward. Subjects' diets in the relevant study phases (HDBR versus Ambulatory Control) of EA and EB were identical except for the calcium intake. The subjects obtained 2000 mg/d Calcium in EA and 2000 mg/d in EB. Blood was drawn at baseline, before entering the relevant intervention period, on day 5 in study EA, and on days 6, 11 and 14 in study EB. Serum calcium, bone formation markers - Procollagen-I-C-Propeptide (PICP) and bone alkaline phosphatase (bAP) were analyzed in serum. 24h-urine was collected throughout the studies for determination of the excretion of calcium (UCaV) and a bone resorption marker, C-terminal telopeptide of collagen type I (UCTX). In both studies, serum calcium levels were unchanged. PICP tended to decrease in EA (p=0.08). In EB PICP decreased significantly over time (p=0.003) in both the control and HDBR periods, and tended to further decrease in the HDBR period (p

  18. Cyclooxygenase-2 deficiency exacerbates bleomycin-induced lung dysfunction but not fibrosis.

    PubMed

    Card, Jeffrey W; Voltz, James W; Carey, Michelle A; Bradbury, J Alyce; Degraff, Laura M; Lih, Fred B; Bonner, James C; Morgan, Daniel L; Flake, Gordon P; Zeldin, Darryl C

    2007-09-01

    Cyclooxygenase (COX)-derived eicosanoids have been implicated in the pathogenesis of pulmonary fibrosis. Uncertainty regarding the influence of COX-2 on experimental pulmonary fibrosis prompted us to clarify the fibrotic and functional effects of intratracheal bleomycin administration in mice genetically deficient in COX-2. Further, the effects of airway-specific COX-1 overexpression on fibrotic and functional outcomes in wild-type and COX-2 knockout mice were assessed. Equivalent increases in airway cell influx, lung collagen content, and histopathologic evidence of fibrosis were observed in wild-type and COX-2 knockout mice 21 d after bleomycin treatment, suggesting that COX-2 deficiency did not alter the extent or severity of fibrosis in this model. However, bleomycin-induced alterations in respiratory mechanics were more severe in COX-2 knockout mice than in wild-type mice, as illustrated by a greater decrease in static compliance compared with genotype-matched, saline-treated control mice (26 +/- 3% versus 11 +/- 4% decreases for COX-2 knockout and wild-type mice, respectively; P < 0.05). The influence of COX-1 overexpression in airway Clara cells was also examined. Whereas the fibrotic effects of bleomycin were not altered in wild-type or COX-2 knockout mice overexpressing COX-1, the exaggerated lung function decrement in bleomycin-treated COX-2 knockout mice was prevented by COX-1 overexpression and coincided with decreased airway cysteinyl leukotriene levels. Collectively, these data suggest an important regulatory role for COX-2 in the maintenance of lung function in the setting of lung fibrosis, but not in the progression of the fibrotic process per se.

  19. Nitric Oxide Induction of Parkin Translocation in PTEN-induced Putative Kinase 1 (PINK1) Deficiency

    PubMed Central

    Han, Ji-Young; Kang, Min-Ji; Kim, Kyung-Hee; Han, Pyung-Lim; Kim, Hyun-Seok; Ha, Ji-Young; Son, Jin H.

    2015-01-01

    The failure to trigger mitophagy is implicated in the pathogenesis of familial Parkinson disease that is caused by PINK1 or Parkin mutations. According to the prevailing PINK1-Parkin signaling model, mitophagy is promoted by the mitochondrial translocation of Parkin, an essential PINK1-dependent step that occurs via a previously unknown mechanism. Here we determined that critical concentrations of NO was sufficient to induce the mitochondrial translocation of Parkin even in PINK1 deficiency, with apparent increased interaction of full-length PINK1 accumulated during mitophagy, with neuronal nitric oxide synthase (nNOS). Specifically, optimum levels of NO enabled PINK1-null dopaminergic neuronal cells to regain the mitochondrial translocation of Parkin, which appeared to be significantly suppressed by nNOS-null mutation. Moreover, nNOS-null mutation resulted in the same mitochondrial electron transport chain (ETC) enzyme deficits as PINK1-null mutation. The involvement of mitochondrial nNOS activation in mitophagy was further confirmed by the greatly increased interactions of full-length PINK1 with nNOS, accompanied by mitochondrial accumulation of phospho-nNOS (Ser1412) during mitophagy. Of great interest is that the L347P PINK1 mutant failed to bind to nNOS. The loss of nNOS phosphorylation and Parkin accumulation on PINK1-deficient mitochondria could be reversed in a PINK1-dependent manner. Finally, non-toxic levels of NO treatment aided in the recovery of PINK1-null dopaminergic neuronal cells from mitochondrial ETC enzyme deficits. In summary, we demonstrated the full-length PINK1-dependent recruitment of nNOS, its activation in the induction of Parkin translocation, and the feasibility of NO-based pharmacotherapy for defective mitophagy and ETC enzyme deficits in Parkinson disease. PMID:25716315

  20. ADAMTS13 deficiency promotes microthrombosis in a murine model of diet-induced liver steatosis.

    PubMed

    Geys, Lotte; Bauters, Dries; Roose, Elien; Tersteeg, Claudia; Vanhoorelbeke, Karen; Hoylaerts, Marc F; Lijnen, Roger H; Scroyen, Ilse

    2017-01-05

    ADAMTS13 cleaves ultralarge multimeric von Willebrand Factor (VWF), thereby preventing formation of platelet-rich microthrombi. ADAMTS13 is mainly produced by hepatic stellate cells, and numerous studies have suggested a functional role of ADAMTS13 in the pathogenesis of liver diseases. The aim of our study was to investigate a potential role of ADAMTS13 in formation of hepatic microthrombi and development of non-alcoholic steatohepatitis (NASH), and furthermore to evaluate whether plasmin can compensate for the absence of ADAMTS13 in removal of thrombi. Therefore, we used a model of high-fat diet-induced steatosis in Adamts13 deficient (Adamts13(-/-)) and wild-type (WT) control mice. Microthrombi were more abundant in the liver of obese Adamts13(-/-) as compared to obese WT or to lean Adamts13(-/-) mice. Obese Adamts13(-/-) mice displayed lower platelet counts and higher prevalence of ultra-large VWF multimers. Hepatic plasmin-α2-antiplasmin complex levels were comparable for obese WT and Adamts13(-/-) mice and were lower for lean Adamts13(-/-) than WT mice, not supporting marked activation of the fibrinolytic system. High fat diet feeding, as compared to normal chow, resulted in enhanced liver triglyceride levels for both genotypes (p < 0.0001) and steatosis (p < 0.0001 for WT mice, p = 0.002 for Adamts13(-/-) mice) without differences between the genotypes. Expression of markers of inflammation, oxidative stress, steatosis and fibrosis was affected by diet, but not by genotype. Thus, our data confirm that obesity promotes NASH, but do not support a detrimental role of ADAMTS13 in its development. However, Adamts13 deficiency in obese mice promotes hepatic microthrombosis, whereas a compensatory role of plasmin in removal of microthrombi in the absence of ADAMTS13 could not be demonstrated.

  1. Strigolactones are required for nitric oxide to induce root elongation in response to nitrogen and phosphate deficiencies in rice.

    PubMed

    Sun, Huwei; Bi, Yang; Tao, Jinyuan; Huang, Shuangjie; Hou, Mengmeng; Xue, Ren; Liang, Zhihao; Gu, Pengyuan; Yoneyama, Koichi; Xie, Xiaonan; Shen, Qirong; Xu, Guohua; Zhang, Yali

    2016-07-01

    The response of the root system architecture to nutrient deficiencies is critical for sustainable agriculture. Nitric oxide (NO) is considered a key regulator of root growth, although the mechanisms remain unknown. Phenotypic, cellular and genetic analyses were undertaken in rice to explore the role of NO in regulating root growth and strigolactone (SL) signalling under nitrogen-deficient and phosphate-deficient conditions (LN and LP). LN-induced and LP-induced seminal root elongation paralleled NO production in root tips. NO played an important role in a shared pathway of LN-induced and LP-induced root elongation via increased meristem activity. Interestingly, no responses of root elongation were observed in SL d mutants compared with wild-type plants, although similar NO accumulation was induced by sodium nitroprusside (SNP) application. Application of abamine (the SL inhibitor) reduced seminal root length and pCYCB1;1::GUS expression induced by SNP application in wild type; furthermore, comparison with wild type showed lower SL-signalling genes in nia2 mutants under control and LN treatments and similar under SNP application. Western blot analysis revealed that NO, similar to SL, triggered proteasome-mediated degradation of D53 protein levels. Therefore, we presented a novel signalling pathway in which NO-activated seminal root elongation under LN and LP conditions, with the involvement of SLs.

  2. Folate deficiency-induced oxidative stress contributes to neuropathy in young and aged zebrafish--implication in neural tube defects and Alzheimer's diseases.

    PubMed

    Kao, Tseng-Ting; Chu, Chia-Yi; Lee, Gang-Hui; Hsiao, Tsun-Hsien; Cheng, Nai-Wei; Chang, Nan-Shan; Chen, Bing-Hung; Fu, Tzu-Fun

    2014-11-01

    Folate is a nutrient essential for the development, function and regeneration of nervous systems. Folate deficiency has been linked to many neurological disorders including neural tube defects in fetus and Alzheimer's diseases in the elderly. However, the etiology underlying these folate deficiency-associated diseases is not completely understood. In this study, zebrafish transgenic lines with timing and duration-controllable folate deficiency were developed by ectopically overexpressing a recombinant EGFP-γ-glutamyl hydrolase (γGH). Impeded neural crest cell migration was observed in the transgenic embryos when folate deficiency was induced in early stages, leading to defective neural tube closure and hematopoiesis. Adding reduced folate or N-acetylcysteine reversed the phenotypic anomalies, supporting the causal link between the increased oxidative stress and the folate deficiency-induced abnormalities. When folate deficiency was induced in aged fish accumulation of beta-amyloid and phosphorylated Tau protein were found in the fish brain cryo-sections. Increased autophagy and accumulation of acidic autolysosome were apparent in folate deficient neuroblastoma cells, which were reversed by reduced folate or N-acetylcysteine supplementation. Decreased expression of cathepsin B, a lysosomal protease, was also observed in cells and tissue with folate deficiency. We concluded that folate deficiency-induced oxidative stress contributed to the folate deficiency-associated neuropathogenesis in both early and late stages of life.

  3. Flesh Quality Loss in Response to Dietary Isoleucine Deficiency and Excess in Fish: A Link to Impaired Nrf2-Dependent Antioxidant Defense in Muscle

    PubMed Central

    Gan, Lu; Jiang, Wei-Dan; Wu, Pei; Liu, Yang; Jiang, Jun; Li, Shu-Hong; Tang, Ling; Kuang, Sheng-Yao; Feng, Lin; Zhou, Xiao-Qiu

    2014-01-01

    The present study explored the impact of dietary isoleucine (Ile) on fish growth and flesh quality and revealed a possible role of muscle antioxidant defense in flesh quality in relation to dietary Ile. Grass carp (weighing 256.8±3.5 g) were fed diets containing six graded levels of Ile (3.8, 6.6, 9.3, 12.5, 15.2 and 18.5 g/kg) for eight weeks. The results indicated that compared with Ile deficiency (3.8 g/kg diets) and excess (18.5 g/kg diets) groups, 9.3–15.2 g Ile/kg diet supplementations promoted fish growth and muscle fat deposition, whereas 6.6–15.2 g Ile/kg diets supplementation enhanced muscle nutrients (protein and total EAAs) deposition. Furthermore, muscle shear force, pH value, and hydroxyproline concentration were improved by 9.3–12.5, 9.3 and 9.3 g Ile/kg diet supplementations, respectively. However, muscle cooking loss, lactate content, and activities of cathepsin B and L were decreased by 6.6–15.2, 9.3–12.5, 9.3–12.5 and 9.3–15.2 g Ile/kg diet supplementations, respectively. Additionally, 6.6–15.2 and 6.6–12.5 g Ile/kg diet supplementations attenuated malondialdehyde and protein carbonyl contents, respectively. The activities of copper/zinc superoxide dismutase (Cu/Zn-SOD) and glutathione peroxidase (GPx), and glutathione content were enhanced by 6.6–9.3, 6.6–12.5 and 6.6–15.2 g Ile/kg diet supplementations, respectively. Moreover, the relative mRNA expressions of antioxidant enzymes, including Cu/Zn-SOD (6.6–12.5 g/kg diets) and GPx (12.5 g/kg diets), as well as antioxidant-related signaling molecules, including NF-E2-related factor 2 (Nrf2) (6.6–12.5 g/kg diets), target of rapamycin (6.6–12.5 g/kg diets), ribosomal S6 protein kinase 1 (9.3–12.5 g/kg diets) and casein kinase 2 (6.6–12.5 g/kg diets), were up-regulated when Ile diet supplementations were administered at these levels, respectively, whereas the relative mRNA expression of Kelch-like ECH-associated protein 1 was down-regulated with 9.3 g Ile/kg diet

  4. Methionine sulfoxide reductase B1 deficiency does not increase high-fat diet-induced insulin resistance in mice.

    PubMed

    Heo, Jung-Yoon; Cha, Hye-Na; Kim, Ki Young; Lee, Eujin; Kim, Suk-Jeong; Kim, Yong-Woon; Kim, Jong-Yeon; Lee, In-Kyu; Gladyshev, Vadim N; Kim, Hwa-Young; Park, So-Young

    2017-01-01

    Methionine-S-sulfoxide reductase (MsrA) protects against high-fat diet-induced insulin resistance due to its antioxidant effects. To determine whether its counterpart, methionine-R-sulfoxide reductase (MsrB) has similar effects, we compared MsrB1 knockout and wild-type mice using a hyperinsulinemic-euglycemic clamp technique. High-fat feeding for eight weeks increased body weights, fat masses, and plasma levels of glucose, insulin, and triglycerides to similar extents in wild-type and MsrB1 knockout mice. Intraperitoneal glucose tolerance test showed no difference in blood glucose levels between the two genotypes after eight weeks on the high-fat diet. The hyperglycemic-euglycemic clamp study showed that glucose infusion rates and whole body glucose uptakes were decreased to similar extents by the high-fat diet in both wild-type and MsrB1 knockout mice. Hepatic glucose production and glucose uptake of skeletal muscle were unaffected by MsrB1 deficiency. The high-fat diet-induced oxidative stress in skeletal muscle and liver was not aggravated in MsrB1-deficient mice. Interestingly, whereas MsrB1 deficiency reduced JNK protein levels to a great extent in skeletal muscle and liver, it markedly elevated phosphorylation of JNK, suggesting the involvement of MsrB1 in JNK protein activation. However, this JNK phosphorylation based on a p-JNK/JNK level did not positively correlate with insulin resistance in MsrB1-deficient mice. Taken together, our results show that, in contrast to MsrA deficiency, MsrB1 deficiency does not increase high-fat diet-induced insulin resistance in mice.

  5. The Vacuolar Manganese Transporter MTP8 Determines Tolerance to Iron Deficiency-Induced Chlorosis in Arabidopsis1[OPEN

    PubMed Central

    2016-01-01

    Iron (Fe) deficiency is a widespread nutritional disorder on calcareous soils. To identify genes involved in the Fe deficiency response, Arabidopsis (Arabidopsis thaliana) transfer DNA insertion lines were screened on a high-pH medium with low Fe availability. This approach identified METAL TOLERANCE PROTEIN8 (MTP8), a member of the Cation Diffusion Facilitator family, as a critical determinant for the tolerance to Fe deficiency-induced chlorosis, also on soil substrate. Subcellular localization to the tonoplast, complementation of a manganese (Mn)-sensitive Saccharomyces cerevisiae yeast strain, and Mn sensitivity of mtp8 knockout mutants characterized the protein as a vacuolar Mn transporter suitable to prevent plant cells from Mn toxicity. MTP8 expression was strongly induced on low-Fe as well as high-Mn medium, which were both strictly dependent on the transcription factor FIT, indicating that high-Mn stress induces Fe deficiency. mtp8 mutants were only hypersensitive to Fe deficiency when Mn was present in the medium, which further suggested an Mn-specific role of MTP8 during Fe limitation. Under those conditions, mtp8 mutants not only translocated more Mn to the shoot than did wild-type plants but suffered in particular from critically low Fe concentrations and, hence, Fe chlorosis, although the transcriptional Fe deficiency response was up-regulated more strongly in mtp8. The diminished uptake of Fe from Mn-containing low-Fe medium by mtp8 mutants was caused by an impaired ability to boost the ferric chelate reductase activity, which is an essential process in Fe acquisition. These findings provide a mechanistic explanation for the long-known interference of Mn in Fe nutrition and define the molecular processes by which plants alleviate this antagonism. PMID:26668333

  6. Choline dietary supplementation improves LiCl-induced context aversion retention in adult rats.

    PubMed

    Moreno, Hayarelis C; Gil, Marta; Carias, Diamela; Gallo, Milagros; de Brugada, Isabel

    2012-06-25

    Previous studies have demonstrated that choline is an essential nutrient during prenatal and early postnatal developmental periods. Thus, the availability of choline during these periods produces some beneficial effects on hippocampal-dependent learning and memory in rats. However, research on the effect of adult choline supplementation on learning and memory abilities is scarce. In the present study, 3-4 month-old male Wistar rats receiving a 7-week choline-supplemented diet (4.5 fold that of a standard diet) and control rats receiving a standard diet were trained in a LiCl-induced contextual aversion task. Short and long-term context aversion retention was assessed by recording the consumption of a flavoured solution in the aversive and safe contexts over two subsequent tests. Statistical analysis showed that the supplemented group exhibited greater intake suppression in the aversive context than in the safe context when two retention tests were applied 3 and 15 days after conditioning. These results suggest that increasing dietary choline availability during adulthood may favour the retention of a context aversion.

  7. Inhibitory effects of dietary soyasaponin on 2,4-dinitrofluorobenzene-induced contact hypersensitivity in mice.

    PubMed

    Nagano, Takao; Katase, Mitsuru; Tsumura, Kazunobu; Saito, Mineki; Matsuda, Tsukasa

    2017-03-01

    Soyasaponins (SSs) abundant in soybean have anti-inflammatory activities; however, their therapeutic effects on allergic contact dermatitis (ACD) remain unknown. To assess the effects of SS-enriched diets on ACD, we used a mouse model of contact hypersensitivity (CHS). Mice were fed low-dose or high-dose SS-containing diets for 3 weeks prior to CHS induction with 2,4-dinitrofluorobenzene (DNFB). The low-dose SS diet attenuated DNFB-induced ear swelling and tissue oedema, and reduced the number of infiltrating Gr-1-positive myeloid cells. Low-dose, but not high-dose, SSs decreased chemokine (C-X-C motif) ligand 2 (CXCL2) and triggering receptor expressed on myeloid cells (TREM)-1 production in ear tissues, compared to a control. Taxonomic 16S rRNA analysis revealed significant alterations in faecal microbiota caused by CHS, which were reversed by low-dose SSs. The low-dose SS and non-CHS groups clustered together, while the high-dose SS group split between CHS and non-CHS clusters. Our results demonstrated that low-dose SSs alleviated CHS symptoms by attenuating inflammation and improving the intestinal microbiota composition, suggesting that dietary SSs may have beneficial effects on ACD.

  8. Adaptive parotid gland hypertrophy induced by dietary treatment of GSE in rats.

    PubMed

    Inoue, Kaoru; Morikawa, Tomomi; Matsuo, Saori; Tamura, Kei; Takahashi, Miwa; Yoshida, Midori

    2014-08-01

    In a 13-week feeding toxicity study of grape skin extract (GSE) performed previously, 5.0% GSE showed diffuse hypertrophy and basophilia in rat parotid glands. To clarify whether the change in the parotid glands was an adverse effect of GSE, 6-week-old male F344 rats were fed a diet containing 5.0% GSE or were administered a dose corresponding to the dietary concentration via gavage for 4 weeks, and the treatment was stopped for 2 weeks. To ascertain the effect of astringency, other animals were fed a diet containing 5.0% tannic acid (TA) using the same protocol as the GSE feed group. Control groups were fed a basal diet or were administered sterilized distilled water by gavage. In the GSE and TA feed groups, diffuse severe hypertrophy and basophilia in the parotid glandular epithelial cells were observed. Macroscopic, microscopic, and ultrastructural characteristics consistent with cellular hypertrophy was less apparent after the recovery period in both feed groups. In contrast, no changes were observed in the parotid glands of the gavage GSE and control groups at week 4. Based on these findings of parotid hypertrophy without cytotoxicity, the data from this and previous studies suggest that hypertrophy of the parotid glands induced by feeding treatment with GSE is an adaptive non-adverse effect that is reversible upon removal of the sialotrophic agent.

  9. Preventive effects of taurine on development of hepatic steatosis induced by a high-fat/cholesterol dietary habit.

    PubMed

    Chang, Yuan-Yen; Chou, Chung-Hsi; Chiu, Chih-Hsien; Yang, Kuo-Tai; Lin, Yi-Ling; Weng, Wei-Lien; Chen, Yi-Chen

    2011-01-12

    Nonalcoholic fatty liver (NAFL) is also called hepatic steatosis and has become an emergent liver disease in developed and developing nations. This study was to exam the preventive effects of taurine (Tau) on the development of hepatic steatosis via a hamster model. Although hepatic steatosis of hamsters was induced by feeding a high-fat/cholesterol diet, drinking water containing 0.35 and 0.7% Tau improved (p < 0.05) the serum lipid profile. Meanwhile, the smaller (p < 0.05) liver sizes and lower (p < 0.05) hepatic lipids in high-fat/cholesterol dietary hamsters drinking Tau may be partially due to higher (p < 0.05) fecal cholesterol, triacylglycerol, and bile acid outputs. In the regulation of lipid homeostasis, drinking a Tau solution upregulated (p < 0.05) low-density lipoprotein receptor and CYP7A1 gene expressions in high-fat/cholesterol dietary hamsters, which result in increased fecal cholesterol and bile acid outputs. Drinking a Tau solution also upregulated (p < 0.05) peroxisome proliferator-activated receptor-α (PPAR-α) and uncoupling protein 2 (UPC2) gene expressions in high-fat/cholesterol dietary hamsters, thus increasing energy expenditure. Besides, Tau also enhanced (p < 0.05) liver antioxidant capacities (GSH, TEAC, SOD, and CAT) and decreased (p < 0.05) lipid peroxidation (MDA), which alleviated liver damage in the high-fat/cholesterol dietary hamsters. Therefore, Tau shows preventive effects on the development of hepatic steatosis induced by a high-fat/cholesterol dietary habit.

  10. Abrogation of hybrid resistance to bone marrow engraftment by graft versus host induced immune deficiency

    SciTech Connect

    Hakim, F.T.; Shearer, G.M.

    1986-03-01

    Lethally irradiated F/sub 1/ mice, heterozygous at the hematopoietic histocompatibility (Hh) locus at H-2D/sup b/, reject bone marrow grafts from homozygous H-2/sup b/ parents. This hybrid resistance (HR) is reduced by prior injection of H-2/sup b/ parental spleen cells. Since injection of parental spleen cells produces a profound suppression of F/sub 1/ immune functions, the authors investigated whether parental-induced abrogation of HR was due to graft-vs-host induced immune deficiency (GVHID). HR was assessed by quantifying engraftment in irradiated mice using /sup 125/I-IUdR spleen uptake; GVHID by measuring generation of cytotoxic T lymphocytes (CTL) from unirradiated mice. They observed correlation in time course, spleen dose dependence and T cell dependence between GVHID and loss of HR. The injection of B10 recombinant congenic spleens into (B10 x B10.A) F/sub 1/ mice, prior to grafting with B10 marrow, demonstrated that only those disparities in major histocompatibility antigens which generated GVHID would result in loss of HR. Spleens from (B10 x B10.A(2R))F/sub 1/ mice (Class I disparity only) did not induce GVHID or affect HR, while (B10 x B10.A(5R)F/sub 1/ spleens (Class I and II disparity) abrogated CTL generation and HR completely. GVHID produced by a Class II only disparity, as in (B10 x B10.A(5R))F/sub 1/ spleens injected into (B6/sup bm12 x B10.A(5R))F/sub 1/ mice, was also sufficient to markedly reduce HR to B10 bone marrow. Modulation of hematopoietic graft rejection by GVHID may affect marrow engraftment in man.

  11. RMI1 deficiency in mice protects from diet and genetic-induced obesity.

    PubMed

    Suwa, Akira; Yoshino, Masayasu; Yamazaki, Chihiro; Naitou, Masanori; Fujikawa, Rie; Matsumoto, Shun-Ichiro; Kurama, Takeshi; Shimokawa, Teruhiko; Aramori, Ichiro

    2010-02-01

    The aim of this study is to discover and characterize novel energy homeostasis-related molecules. We screened stock mouse embryonic stem cells established using the exchangeable gene trap method, and examined the effects of deficiency of the target gene on diet and genetic-induced obesity. The mutant strain 0283, which has an insertion at the recQ-mediated genome instability 1 (RMI1) locus, possesses a number of striking features that allow it to resist metabolic abnormalities. Reduced RMI1 expression, lower fasting-blood glucose and a reduced body weight (normal diet) were observed in the mutant mice. When fed a high-fat diet, the mutant mice were resistant to obesity, and also showed improved glucose intolerance and reduced abdominal fat tissue mass and food intake. In addition, the mutants were also resistant to obesity induced by the lethal yellow agouti (A(y)) gene. Endogenous RMI1 genes were found to be up-regulated in the liver and adipose tissue of KK-A(y) mice. RMI1 is a component of the Bloom's syndrome gene helicase complex that maintains genome integrity and activates cell-cycle checkpoint machinery. Interestingly, diet-induced expression of E2F8 mRNA, which is an important cell cycle-related molecule, was suppressed in the mutant mice. These results suggest that the regulation of energy balance by RMI1 is attributable to the regulation of food intake and E2F8 expression in adipose tissue. Taken together, these findings demonstrate that RMI1 is a novel molecule that regulates energy homeostasis.

  12. p-Coumaric acid, a common dietary polyphenol, protects cadmium chloride-induced nephrotoxicity in rats.

    PubMed

    Navaneethan, Dhanalakshmi; Rasool, Mahaboobkhan

    2014-03-01

    The present study was conducted to elucidate the protective role of p-coumaric acid, a common dietary polyphenol against cadmium induced nephrotoxicity in rats. For the purpose of comparison, a standard reference drug silymarin (50 mg/kg b. wt) was used. In this experiment, the animals were divided into four groups, with each consisting of six animals. The animals in Group I animals received saline and served as a control group and those in Group II received cadmium chloride (3 mg/kg b. wt) subcutaneously once daily for 3 weeks, but Group III and IV animals received cadmium chloride followed by p-coumaric acid (100 mg/kg b. wt, oral) and silymarin (50 mg/kg b. wt, oral), respectively, daily for 3 weeks. At the end of the treatment, the animals were sacrificed, and the blood and kidney samples were collected. The results obtained in this study revealed the fact that the levels of lipid peroxidation, lysosomal enzymes, glycoprotein, cadmium and metallothionein were increased in the cadmium chloride alone treated rats and antioxidant status was found to be decreased, when compared to the control group. The levels of kidney functional markers (urea, uric acid and creatinine) were also found to be abnormal in serum and urine of cadmium chloride alone treated rats. On the other hand, the administration of p-coumaric acid along with cadmium chloride significantly protected the biochemical alterations as observed in the cadmium chloride alone treated rats as evidenced by histopathology. Thus, the oral administration of p-coumaric acid significantly protected the cadmium-induced nephrotoxicity in rats.

  13. Attenuation of gentamycin-induced nephrotoxicity in rats by dietary inclusion of ginger (Zingiber officinale) and turmeric (Curcuma longa) rhizomes.

    PubMed

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Ogunsuyi, Opeyemi B; Akinyemi, Ayodele J

    2012-10-01

    This study sought to investigate the modulatory effects of dietary inclusion of ginger (Zingiber officinale) and turmeric (Curcuma longa) rhizomes on antioxidant status and renal damage induced by gentamycin in rats. Renal damage was induced in albino rats pretreated with dietary inclusion of ginger and turmeric (2% and 4%) by intraperitoneal (i.p.) administration of gentamycin (100 mg/kg body weight) for three days. Assays for renal damage biomarkers (plasma creatinine, plasma urea, blood urea nitrogen and plasma uric acid), malondialdehyde (MDA) content and reduced glutathione (GSH) content as well as renal antioxidant enzymes (catalase, glutathione-S-transferase (GST), glutathione peroxidase (GPx) and superoxide dismutase (SOD)) were carried out. The study revealed significant (p < 0.05) increases in renal damage biomarkers following gentamycin administration with severe alteration in kidney antioxidant status. However, pretreatment with ginger and turmeric rhizome (2% and 4%) prior to gentamycin administration significantly (p < 0.05) protected the kidney and attenuated oxidative stress by modulating renal damage and antioxidant indices. This finding therefore suggests that dietary inclusion of ginger and turmeric rhizomes may protect against gentamycin-induced nephrotoxicity and oxidative stress.

  14. Resistance of essential fatty acid-deficient rats to endotoxin-induced increases in vascular permeability

    SciTech Connect

    Li, E.J.; Cook, J.A.; Spicer, K.M.; Wise, W.C.; Rokach, J.; Halushka, P.V. )

    1990-06-01

    Resistance to endotoxin in essential fatty acid-deficient (EFAD) rats is associated with reduced synthesis of certain arachidonic acid metabolites. It was hypothesized that EFAD rats would manifest decreased vascular permeability changes during endotoxemia as a consequence of reduced arachidonic acid metabolism. To test this hypothesis, changes in hematocrit (HCT) and mesenteric localization rate of technetium-labeled human serum albumin (99mTc-HSA) and red blood cells (99mTc-RBC) were assessed in EFAD and normal rats using gamma-camera imaging. Thirty minutes after Salmonella enteritidis endotoxin, EFAD rats exhibited less hemoconcentration as determined by % HCT than normal rats. Endotoxin caused a less severe change in permeability index in the splanchnic region in EFAD rats than in normal rats (1.2 +/- 0.6 x 10(-3)min-1 vs. 4.9 +/- 1.7 x 10(-3)min-1 respectively, P less than 0.05). In contrast to 99mTc-HSA, mesenteric localization of 99mTc-RBC was not changed by endotoxin in control or EFAD rats. Supplementation with ethyl-arachidonic acid did not enhance susceptibility of EFAD rats to endotoxin-induced splanchnic permeability to 99mTc-HSA. Leukotrienes have been implicated as mediators of increased vascular permeability in endotoxin shock. Since LTC3 formation has been reported to be increased in EFA deficiency, we hypothesized that LTC3 may be less potent than LTC4. Thus the effect of LTC3 on mean arterial pressure and permeability was compared to LTC4 in normal rats. LTC3-induced increases in peak mean arterial pressure were less than LTC4 at 10 micrograms/kg (39 +/- 5 mm Hg vs. 58 +/- 4 mm Hg respectively, P less than 0.05) and at 20 micrograms/kg (56 +/- 4 mm Hg vs. 75 +/- 2 mm Hg respectively, P less than 0.05). LY171883 (30 mg/kg), an LTD4/E4 receptor antagonist, attenuated the pressor effect of LTC4, LTD4, and LTC3.

  15. The effect of dietary zinc - and polyphenols intake on DMBA-induced mammary tumorigenesis in rats

    PubMed Central

    2012-01-01

    Background The aim of the study was to investigate the effect of dietary supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein, on the effectiveness of chemically induced mammary cancer and the changes in the content of selected elements (Zn, Cu, Mg, Fe, Ca) in tumors as compared with normal tissue of the mammary gland. Methods Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet and DMBA (7,12-dimethyl-1,2- benz[a]anthracene), were treated with zinc ions (Zn) or zinc ions + resveratrol (Zn + resveratrol) or zinc ions + genistein (Zn + genistein) via gavage for a period from 40 days until 20 weeks of age. The ICP-OES (inductively coupled plasma optical emission spectrometry) technique was used to analyze the following elements: magnesium, iron, zinc and calcium. Copper content in samples was estimated in an atomic absorption spectrophotometer. Results Regardless of the diet (standard; Zn; Zn + resveratrol; Zn + genistein), DMBA-induced breast carcinogenesis was not inhibited. On the contrary, in the Zn + resveratrol supplemented group, tumorigenesis developed at a considerably faster rate. On the basis of quantitative analysis of selected elements we found - irrespectively of the diet applied - great accumulation of copper and iron, which are strongly prooxidative, with a simultaneous considerable decrease of the magnesium content in DMBA-induced mammary tumors. The combination of zinc supplementation with resveratrol resulted in particularly large differences in the amount of the investigated elements in tumors as compared with their content in normal tissue. Conclusions Diet supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein had no effect on the decreased copper level in tumor tissue and inhibited mammary carcinogenesis in the rat. Irrespectively of the applied diet, the development of the neoplastic process in rats resulted in changes of the iron and magnesium

  16. Resistant starch prevents colonic DNA damage induced by high dietary cooked red meat or casein in rats.

    PubMed

    Toden, Shusuke; Bird, Anthony R; Topping, David L; Conlon, Michael A

    2006-03-01

    In a previous study we have shown that high levels of dietary protein (as casein) result in increased levels of colonic DNA damage, measured by the comet assay, and thinning of the colonic mucus layer in rats when dietary resistant starch (RS) is negligible. Feeding RS abolishes these effects. This study aimed to establish whether a diet high in protein as cooked red meat would have similar effects and whether RS was protective. Rats were fed a diet containing 15% or 25% casein or 25% cooked lean red beef, each with or without the addition of 48% high amylose maize starch (a rich source of RS) for four weeks. As expected, high dietary casein caused a 2-fold increase in colonic DNA damage compared with a low casein diet and reduced the thickness of the colonic mucus layer by 41%. High levels of cooked meat caused 26% greater DNA damage than the high casein diet but reduced mucus thickness to a similar degree to casein. Addition of RS to the diet abolished the increase in DNA damage and the loss of colonic mucus thickness induced by either high protein diet. Cecal and fecal short chain fatty acid pools were also increased by inclusion of RS in the diet. Because DNA damage is an early step in the initiation of cancer, these findings suggest that increased DNA damage due to high dietary protein as cooked red meat or casein could increase colorectal cancer risk but inclusion of resistant starch in the diet could significantly reduce that risk.

  17. Thymidine Kinase 2 Deficiency-Induced Mitochondrial DNA Depletion Causes Abnormal Development of Adipose Tissues and Adipokine Levels in Mice

    PubMed Central

    Villarroya, Joan; Dorado, Beatriz; Vilà, Maya R.; Garcia-Arumí, Elena; Domingo, Pere; Giralt, Marta; Hirano, Michio; Villarroya, Francesc

    2011-01-01

    Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues. PMID:22216345

  18. Isolated pregnancy-induced anti-thrombin deficiency in a woman with twin pregnancy.

    PubMed

    Kawabata, Kosuke; Morikawa, Mamoru; Yamada, Takahiro; Minakami, Hisanori

    2016-06-01

    A woman with twin pregnancy had a gradual decline in anti-thrombin (AT) activity from 72% at gestational week (GW) 29(-3/7) , to 53% at GW31(-2/7) , and to 41% at GW32(-2/7) , at which time hypertension (148/90 mmHg) and proteinuria (protein-to-creatinine ratio [P/Cr], 0.79 mg/mg) developed in the presence of normal platelet count (159 × 10(9) /L) and serum aspartate aminotransferase/lactate dehydrogenase (22/164 IU/L). AT product was given three times to maintain AT activity >50% and blood pressure was maintained below 155/95 mmHg with no treatment, but generalized edema with a weekly weight gain of 4.9 kg and increased proteinuria (to P/Cr, 7.6 mg/mg) required cesarean section at GW33(-3/7) . This case highlights the occurrence of pregnancy-induced AT deficiency alone in the absence of any other abnormality, including hypertension, proteinuria, or thrombocytopenia. Measurement of AT activity was considered helpful for determination of the appropriate time for delivery in this patient.

  19. Stat5-deficient hematopoiesis is permissive for Myc-induced B-cell leukemogenesis.

    PubMed

    Wang, Zhengqi; Medrzycki, Magdalena; Bunting, Silvia T; Bunting, Kevin D

    2015-10-06

    Despite being an attractive molecular target for both lymphoid and myeloid leukemias characterized by activated tyrosine kinases, the molecular and physiological consequences of reduced signal transducer and activator of transcription-5 (Stat5) during leukemogenesis are not well known. Stat5 is a critical regulator of mouse hematopoietic stem cell (HSC) self-renewal and is essential for normal lymphocyte development. We report that pan-hematopoietic deletion in viable adult Vav1-Cre conditional knockout mice as well as Stat5ab(null/null) fetal liver transplant chimeras generated HSCs with reduced expression of quiescence regulating genes (Tie2, Mpl, Slamf1, Spi1, Cited2) and increased expression of B-cell development genes (Satb1, Dntt, Btla, Flk2). Using a classical murine B-cell acute lymphoblastic leukemia (B-ALL) model, we demonstrate that these HSCs were also poised to produce a burst of B-cell precursors upon expression of Bcl-2 combined with oncogenic Myc. This strong selective advantage for leukemic transformation in the background of Stat5 deficient hematopoiesis was permissive for faster initiation of Myc-induced transformation to B-ALL. However, once established, the B-ALL progression in secondary transplant recipients was Stat5-independent. Overall, these studies suggest that Stat5 can play multiple important roles that not only preserve the HSC compartment but can limit accumulation of potential pre-leukemic lymphoid populations.

  20. Mice Deficient in CD38 Develop an Attenuated Form of Collagen Type II-Induced Arthritis

    PubMed Central

    Postigo, Jorge; Iglesias, Marcos; Cerezo-Wallis, Daniela; Rosal-Vela, Antonio; García-Rodríguez, Sonia; Zubiaur, Mercedes; Sancho, Jaime

    2012-01-01

    CD38, a type II transmembrane glycoprotein expressed in many cells of the immune system, is involved in cell signaling, migration and differentiation. Studies in CD38 deficient mice (CD38 KO mice) indicate that this molecule controls inflammatory immune responses, although its involvement in these responses depends on the disease model analyzed. Here, we explored the role of CD38 in the control of autoimmune responses using chicken collagen type II (col II) immunized C57BL/6-CD38 KO mice as a model of collagen-induced arthritis (CIA). We demonstrate that CD38 KO mice develop an attenuated CIA that is accompanied by a limited joint induction of IL-1β and IL-6 expression, by the lack of induction of IFNγ expression in the joints and by a reduction in the percentages of invariant NKT (iNKT) cells in the spleen. Immunized CD38 KO mice produce high levels of circulating IgG1 and low of IgG2a anti-col II antibodies in association with reduced percentages of Th1 cells in the draining lymph nodes. Altogether, our results show that CD38 participates in the pathogenesis of CIA controlling the number of iNKT cells and promoting Th1 inflammatory responses. PMID:22438945

  1. Dose dependency of time of onset of radiation-induced growth hormone deficiency

    SciTech Connect

    Clayton, P.E.; Shalet, S.M. )

    1991-02-01

    Growth hormone (GH) secretion during insulin-induced hypoglycemia was assessed on 133 occasions in 82 survivors of childhood malignant disease. All had received cranial irradiation with a dose range to the hypothalamic-pituitary axis of 27 to 47.5 Gy (estimated by a schedule of 16 fractions over 3 weeks) and had been tested on one or more occasions between 0.2 and 18.9 years after treatment. Results of one third of the GH tests were defined as normal (GH peak response, greater than 15 mU/L) within the first 5 years, in comparison with 16% after 5 years. Stepwise multiple linear regression analysis showed that dose (p = 0.007) and time from irradiation (p = 0.03), but not age at therapy, had a significant influence on peak GH responses. The late incidence of GH deficiency was similar over the whole dose range (4 of 26 GH test results normal for less than 30 Gy and 4 of 25 normal for greater than or equal to 30 Gy after 5 years), but the speed of onset over the first years was dependent on dose. We conclude that the requirement for GH replacement therapy and the timing of its introduction will be influenced by the dose of irradiation received by the hypothalamic-pituitary axis.

  2. Anti-diabetic activity of recombinant irisin in STZ-induced insulin-deficient diabetic mice.

    PubMed

    Duan, Huikun; Ma, Baicheng; Ma, Xiaofeng; Wang, Haisong; Ni, Zaizhong; Wang, Bin; Li, Xiaodan; Jiang, Pingzhe; Umar, Muhammad; Li, Minggang

    2016-03-01

    In order to investigate the hypoglycemic effects and potential mechanism of recombinant irisin on diabetes, STZ-induced diabetic mice were established and treated with irisin. The results showed that daily water and food intake, and blood glucose significantly decreased after various concentrations of recombinant irisin treatment by intraperitoneal injection, of which 1.0 mg/kg was the optimal dose for lowering blood glucose. However, the body weight exhibited no significant difference during the treatment within groups, although the 0.9% NaCl treated group showed a trend of decreased body weight and the irisin treated groups showed a tendency of increasing weight. The oral glucose tolerance was improved, and serum insulin and circulating irisin content were significantly elevated in diabetic mice after 1.0 mg/kg irisin-injection treatment, compared to diabetic mice treated with 0.9% NaCl. 1.0 mg/kg irisin-injection also significantly increased the expression of energy and metabolism-related genes. In addition, oral administration of irisin lowered the blood glucose in diabetic mice. Our data suggested that irisin could lower blood glucose in insulin-deficient diabetic mice, to some extent, through irisin-mediated induction of energy and metabolic genes expression. These observations laid a foundation for the development of irisin-based therapy.

  3. Acid Sphingomyelinase Deficiency Prevents Diet-induced Hepatic Triacylglycerol Accumulation and Hyperglycemia in Mice*

    PubMed Central

    Deevska, Gergana M.; Rozenova, Krassimira A.; Giltiay, Natalia V.; Chambers, Melissa A.; White, James; Boyanovsky, Boris B.; Wei, Jia; Daugherty, Alan; Smart, Eric J.; Reid, Michael B.; Merrill, Alfred H.; Nikolova-Karakashian, Mariana

    2009-01-01

    Acid sphingomyelinase plays important roles in ceramide homeostasis, which has been proposed to be linked to insulin resistance. To test this association in vivo, acid sphingomyelinase deletion (asm–/–) was transferred to mice lacking the low density lipoprotein receptor (ldlr–/–), and then offsprings were placed on control or modified (enriched in saturated fat and cholesterol) diets for 10 weeks. The modified diet caused hypercholesterolemia in all genotypes; however, in contrast to asm+/+/ldlr–/–, the acid sphingomyelinase-deficient littermates did not display hepatic triacylglyceride accumulation, although sphingomyelin and other sphingolipids were substantially elevated, and the liver was enlarged. asm–/–/ldlr–/– mice on a modified diet did not accumulate body fat and were protected against diet-induced hyperglycemia and insulin resistance. Experiments with hepatocytes revealed that acid sphingomyelinase regulates the partitioning of the major fatty acid in the modified diet, palmitate, into two competitive and inversely related pools, triacylglycerides and sphingolipids, apparently via modulation of serine palmitoyltransferase, a rate-limiting enzyme in de novo sphingolipid synthesis. These studies provide evidence that acid sphingomyelinase activity plays an essential role in the regulation of glucose metabolism by regulating the hepatic accumulation of triacylglycerides and sphingolipids during consumption of a diet rich in saturated fats. PMID:19074137

  4. Compromised virus-induced gene silencing in RDR6-deficient plants.

    PubMed

    Vaistij, Fabián E; Jones, Louise

    2009-03-01

    RNA silencing in plants serves as a potent antiviral defense mechanism through the action of small interfering RNAs (siRNAs), which direct RNA degradation. siRNAs can be derived directly from the viral genome or via the action of host-encoded RNA-dependent RNA polymerases (RDRs). Plant genomes encode multiple RDRs, and it has been demonstrated that plants defective for RDR6 hyperaccumulate several classes of virus. In this study, we compared the effectiveness of virus-induced gene silencing (VIGS) and RNA-directed DNA methylation (RdDM) in wild-type and RDR6-deficient Nicotiana benthamiana plants. For the potexvirus Potato virus X (PVX) and the potyvirus Plum pox virus (PPV), the efficiency of both VIGS and RdDM were compromised in RDR6-defective plants despite accumulating high levels of viral siRNAs similar to infection of wild-type plants. The reduced efficiency of VIGS and RdDM was unrelated to the size class of siRNA produced and, at least for PVX, was not dependent on the presence of the virus-encoded silencing suppressor protein, 25K. We suggest that primary siRNAs produced from PVX and PPV in the absence of RDR6 may not be good effectors of silencing and that RDR6 is required to produce secondary siRNAs that drive a more effective antiviral response.

  5. Syndecan-1 deficiency promotes tumor growth in a murine model of colitis-induced colon carcinoma

    PubMed Central

    Binder Gallimidi, Adi; Nussbaum, Gabriel; Hermano, Esther; Weizman, Barak; Meirovitz, Amichay; Vlodavsky, Israel; Götte, Martin; Elkin, Michael

    2017-01-01

    Syndecan-1 (Sdc1) is an important member of the cell surface heparan sulfate proteoglycan family, highly expressed by epithelial cells in adult organisms. Sdc1 is involved in the regulation of cell migration, cell-cell and cell-matrix interactions, growth-factor, chemokine and integrin activity, and implicated in inflammatory responses and tumorigenesis. Gastrointestinal tract represents an important anatomic site where loss of Sdc1 expression was reported both in inflammation and malignancy. However, the biological significance of Sdc1 in chronic colitis-associated tumorigenesis has not been elucidated. To the best of our knowledge, this study is the first to test the effects of Sdc1 loss on colorectal tumor development in inflammation-driven colon tumorigenesis. Utilizing a mouse model of colitis-related colon carcinoma induced by the carcinogen azoxymethane (AOM), followed by the inflammatory agent dextran sodium sulfate (DSS), we found that Sdc1 deficiency results in increased susceptibility to colitis-associated tumorigenesis. Importantly, colitis-associated tumors developed in Sdc1-defficient mice were characterized by increased local production of IL-6, activation of STAT3, as well as induction of several STAT3 target genes that act as important effectors of colonic tumorigenesis. Altogether, our results highlight a previously unknown effect of Sdc1 loss in progression of inflammation-associated cancer and suggest that decreased levels of Sdc1 may serve as an indicator of colon carcinoma progression in the setting of chronic inflammation. PMID:28350804

  6. Pulmonary lesions induced by Pasteurella haemolytica in neutrophil sufficient and neutrophil deficient calves.

    PubMed Central

    Breider, M A; Walker, R D; Hopkins, F M; Schultz, T W; Bowersock, T L

    1988-01-01

    The role of neutrophils in the development of peracute lung lesions of bovine pneumonic pasteurellosis was investigated. Eight calves were divided into two groups of four calves each. Group I was treated with intravenous phosphate-buffered saline and served as the neutrophil sufficient calves. Group II was treated with intravenous hydroxyurea which produced a state of neutropenia. When peripheral blood neutrophil numbers dropped below 300 cells/microL in group II, all calves were challenged with an intrabronchial bolus of Pasteurella haemolytica in the log phase of growth. An acute inflammatory process occurred in both groups of calves indicated by a rise in body temperature. While pulmonary lesions occurred in both groups by six hours postinoculation, they varied in pathological characteristics. Pulmonary lesions in the neutrophil sufficient calves consisted of fibrinopurulent alveolitis-bronchiolitis with associated alveolar septal necrosis, interlobular edema, and intravascular thrombi. The neutrophil deficient calves had extensive intra-alveolar edema, interlobular edema, intraalveolar hemorrhage, atelectasis, and focal areas of alveolar septal necrosis. These results show that P. haemolytica can induce severe pulmonary tissue damage through both neutrophil dependent and neutrophil independent mechanisms. Images Fig. 1. Fig. 2. PMID:3370555

  7. Lead phytotoxicity in soils and nutrient solutions is related to lead induced phosphorus deficiency.

    PubMed

    Cheyns, Karlien; Peeters, Sofie; Delcourt, Dorien; Smolders, Erik

    2012-05-01

    This study was set up to relate lead (Pb) bioavailability with its toxicity to plants in soils. Tomato and barley seedlings were grown in six different PbCl(2) spiked soils (pH: 4.7-7.4; eCEC: 4.2-41.7 cmol(c)/kg). Soils were leached and pH corrected after spiking to exclude confounding factors. Plant growth was halved at 1600-6500 mg Pb/kg soil for tomato and at 1900-8300 mg Pb/kg soil for barley. These soil Pb threshold were unrelated to soil pH, organic carbon, texture or eCEC and neither soil solution Pb nor Pb(2+) ion activity adequately explained Pb toxicity among soils. Shoot phosphorus (P) concentrations significantly decreased with increasing soil Pb concentrations. Tomato grown in hydroponics at either varying P supply or at increasing Pb (equal initial P) illustrated that shoot P explained growth response in both scenarios. The results suggest that Pb toxicity is partially related to Pb induced P deficiency, likely due to lead phosphate precipitation.

  8. An Arabidopsis ABC Transporter Mediates Phosphate Deficiency-Induced Remodeling of Root Architecture by Modulating Iron Homeostasis in Roots.

    PubMed

    Dong, Jinsong; Piñeros, Miguel A; Li, Xiaoxuan; Yang, Haibing; Liu, Yu; Murphy, Angus S; Kochian, Leon V; Liu, Dong

    2017-02-13

    The remodeling of root architecture is a major developmental response of plants to phosphate (Pi) deficiency and is thought to enhance a plant's ability to forage for the available Pi in topsoil. The underlying mechanism controlling this response, however, is poorly understood. In this study, we identified an Arabidopsis mutant, hps10 (hypersensitive to Pi starvation 10), which is morphologically normal under Pi sufficient condition but shows increased inhibition of primary root growth and enhanced production of lateral roots under Pi deficiency. hps10 is a previously identified allele (als3-3) of the ALUMINUM SENSITIVE3 (ALS3) gene, which is involved in plant tolerance to aluminum toxicity. Our results show that ALS3 and its interacting protein AtSTAR1 form an ABC transporter complex in the tonoplast. This protein complex mediates a highly electrogenic transport in Xenopus oocytes. Under Pi deficiency, als3 accumulates higher levels of Fe(3+) in its roots than the wild type does. In Arabidopsis, LPR1 (LOW PHOSPHATE ROOT1) and LPR2 encode ferroxidases, which when mutated, reduce Fe(3+) accumulation in roots and cause root growth to be insensitive to Pi deficiency. Here, we provide compelling evidence showing that ALS3 cooperates with LPR1/2 to regulate Pi deficiency-induced remodeling of root architecture by modulating Fe homeostasis in roots.

  9. Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice

    PubMed Central

    Willecke, Florian; Yuan, Chujun; Oka, Kazuhiro; Chan, Lawrence; Hu, Yunying; Barnhart, Shelley; Bornfeldt, Karin E.; Goldberg, Ira J.; Fisher, Edward A.

    2015-01-01

    We tested whether a high fat diet (HFD) containing the inflammatory dietary fatty acid palmitate or insulin deficient diabetes altered the remodeling of atherosclerotic plaques in LDL receptor knockout (Ldlr-/-) mice. Cholesterol reduction was achieved by using a helper-dependent adenovirus (HDAd) carrying the gene for the low-density lipoprotein receptor (Ldlr; HDAd-LDLR). After injection of the HDAd-LDLR, mice consuming either HFD, which led to insulin resistance but not hyperglycemia, or low fat diet (LFD), showed regression compared to baseline. However there was no difference between the two groups in terms of atherosclerotic lesion size, or CD68+ cell and lipid content. Because of the lack of effects of these two diets, we then tested whether viral-mediated cholesterol reduction would lead to defective regression in mice with greater hyperglycemia. In both normoglycemic and streptozotocin (STZ)-treated hyperglycemic mice, HDAd-LDLR significantly reduced plasma cholesterol levels, decreased atherosclerotic lesion size, reduced macrophage area and lipid content, and increased collagen content of plaque in the aortic sinus. However, reductions in anti-inflammatory and ER stress-related genes were less pronounced in STZ-diabetic mice compared to non-diabetic mice. In conclusion, HDAd-mediated Ldlr gene therapy is an effective and simple method to induce atherosclerosis regression in Ldlr-/- mice in different metabolic states. PMID:26046657

  10. Ascorbate Alleviates Fe Deficiency-Induced Stress in Cotton (Gossypium hirsutum) by Modulating ABA Levels.

    PubMed

    Guo, Kai; Tu, Lili; Wang, Pengcheng; Du, Xueqiong; Ye, Shue; Luo, Ming; Zhang, Xianlong

    2016-01-01

    Fe deficiency causes significant losses to crop productivity and quality. To understand better the mechanisms of plant responses to Fe deficiency, we used an in vitro cotton ovule culture system. We found that Fe deficiency suppressed the development of ovules and fibers, and led to tissue browning. RNA-seq analysis showed that the myo-inositol and galacturonic acid pathways were activated and cytosolic APX (ascorbate peroxidase) was suppressed in Fe-deficient treated fibers, which increased ASC (ascorbate) concentrations to prevent tissue browning. Suppression of cytosolic APX by RNAi in cotton increased ASC contents and delayed tissue browning by maintaining ferric reduction activity under Fe-deficient conditions. Meanwhile, APX RNAi line also exhibited the activation of expression of iron-regulated transporter (IRT1) and ferric reductase-oxidase2 (FRO2) to adapt to Fe deficiency. Abscisic acid (ABA) levels were significantly decreased in Fe-deficient treated ovules and fibers, while the upregulated expression of ABA biosynthesis genes and suppression of ABA degradation genes in Fe-deficient ovules slowed down the decreased of ABA in cytosolic APX suppressed lines to delay the tissue browning. Moreover, the application of ABA in Fe-deficient medium suppressed the development of tissue browning and completely restored the ferric reduction activity. In addition, ABA 8'-hydroxylase gene (GhABAH1) overexpressed cotton has a decreased level of ABA and shows more sensitivity to Fe deficiency. Based on the results, we speculate that ASC could improve the tolerance to Fe deficiency through activating Fe uptake and maintaining ABA levels in cotton ovules and fibers, which in turn reduces symptom formation.

  11. Ascorbate Alleviates Fe Deficiency-Induced Stress in Cotton (Gossypium hirsutum) by Modulating ABA Levels

    PubMed Central

    Guo, Kai; Tu, Lili; Wang, Pengcheng; Du, Xueqiong; Ye, Shue; Luo, Ming; Zhang, Xianlong

    2017-01-01

    Fe deficiency causes significant losses to crop productivity and quality. To understand better the mechanisms of plant responses to Fe deficiency, we used an in vitro cotton ovule culture system. We found that Fe deficiency suppressed the development of ovules and fibers, and led to tissue browning. RNA-seq analysis showed that the myo-inositol and galacturonic acid pathways were activated and cytosolic APX (ascorbate peroxidase) was suppressed in Fe-deficient treated fibers, which increased ASC (ascorbate) concentrations to prevent tissue browning. Suppression of cytosolic APX by RNAi in cotton increased ASC contents and delayed tissue browning by maintaining ferric reduction activity under Fe-deficient conditions. Meanwhile, APX RNAi line also exhibited the activation of expression of iron-regulated transporter (IRT1) and ferric reductase–oxidase2 (FRO2) to adapt to Fe deficiency. Abscisic acid (ABA) levels were significantly decreased in Fe-deficient treated ovules and fibers, while the upregulated expression of ABA biosynthesis genes and suppression of ABA degradation genes in Fe-deficient ovules slowed down the decreased of ABA in cytosolic APX suppressed lines to delay the tissue browning. Moreover, the application of ABA in Fe-deficient medium suppressed the development of tissue browning and completely restored the ferric reduction activity. In addition, ABA 8′-hydroxylase gene (GhABAH1) overexpressed cotton has a decreased level of ABA and shows more sensitivity to Fe deficiency. Based on the results, we speculate that ASC could improve the tolerance to Fe deficiency through activating Fe uptake and maintaining ABA levels in cotton ovules and fibers, which in turn reduces symptom formation. PMID:28101095

  12. Endothelial Nitric Oxide Synthase Deficient Mice Are Protected from Lipopolysaccharide Induced Acute Lung Injury

    PubMed Central

    Gross, Christine M.; Rafikov, Ruslan; Kumar, Sanjiv; Aggarwal, Saurabh; Ham III, P. Benson; Meadows, Mary Louise; Cherian-Shaw, Mary; Kangath, Archana; Sridhar, Supriya; Lucas, Rudolf; Black, Stephen M.

    2015-01-01

    Lipopolysaccharide (LPS) derived from the outer membrane of gram-negative bacteria induces acute lung injury (ALI) in mice. This injury is associated with lung edema, inflammation, diffuse alveolar damage, and severe respiratory insufficiency. We have previously reported that LPS-mediated nitric oxide synthase (NOS) uncoupling, through increases in asymmetric dimethylarginine (ADMA), plays an important role in the development of ALI through the generation of reactive oxygen and nitrogen species. Therefore, the focus of this study was to determine whether mice deficient in endothelial NOS (eNOS-/-) are protected against ALI. In both wild-type and eNOS-/- mice, ALI was induced by the intratracheal instillation of LPS (2 mg/kg). After 24 hours, we found that eNOS-/-mice were protected against the LPS mediated increase in inflammatory cell infiltration, inflammatory cytokine production, and lung injury. In addition, LPS exposed eNOS-/- mice had increased oxygen saturation and improved lung mechanics. The protection in eNOS-/- mice was associated with an attenuated production of NO, NOS derived superoxide, and peroxynitrite. Furthermore, we found that eNOS-/- mice had less RhoA activation that correlated with a reduction in RhoA nitration at Tyr34. Finally, we found that the reduction in NOS uncoupling in eNOS-/- mice was due to a preservation of dimethylarginine dimethylaminohydrolase (DDAH) activity that prevented the LPS-mediated increase in ADMA. Together our data suggest that eNOS derived reactive species play an important role in the development of LPS-mediated lung injury. PMID:25786132

  13. Abscisic acid-deficient sit tomato mutant responses to cadmium-induced stress.

    PubMed

    Pompeu, Georgia B; Vilhena, Milca B; Gratão, Priscila L; Carvalho, Rogério F; Rossi, Mônica L; Martinelli, Adriana P; Azevedo, Ricardo A

    2017-03-01

    There is a very effective cross-talk between signals triggered by reactive oxygen species and hormonal responses in plants, activating proteins/enzymes likely to be involved in stress tolerance. Abscisic acid (ABA) is known as a stress hormone that takes part in the integration of signals. This work aimed to characterize the biochemical response and ultrastructural changes induced by cadmium (Cd) in the Micro-Tom (MT) sitiens ABA-deficient mutant (sit) and its wild-type (MT) counterpart. MT and sit plants were grown over a 96-h period in the presence of Cd (0, 10, and 100 μM CdCl2). The overall results indicated increases in lipid peroxidation, hydrogen peroxide content and in the activities of the key antioxidant enzymes such as catalase, glutathione reductase, and ascorbate peroxidase in both genotypes. On the other hand, no alteration was observed in chlorophyll content, while the activity of another antioxidant enzyme, superoxide dismutase, remained constant or even decreased in the presence of Cd. Roots and shoots of the sit mutant and MT were analyzed by light and transmission electron microscopy in order to characterize the structural changes caused by the exposure to this metal. Cd caused a decrease in intercellular spaces in shoots and a decrease in cell size in roots of both genotypes. In leaves, Cd affected organelle shape and internal organization of the thylakoid membranes, whereas noticeable increase in the number of mitochondria and vacuoles in MT and sit roots were observed. These results add new information that should help unravel the relative importance of ABA in regulating the cell responses to stressful conditions induced by Cd apart from providing the first characterization of this mutant to oxidative stress.

  14. Glutamic acid ameliorates estrogen deficiency-induced menopausal-like symptoms in ovariectomized mice.

    PubMed

    Han, Na-Ra; Kim, Hee-Yun; Yang, Woong Mo; Jeong, Hyun-Ja; Kim, Hyung-Min

    2015-09-01

    Some amino acids are considered alternative therapies for improving menopausal symptoms. Glutamic acid (GA), which is abundant in meats, fish, and protein-rich plant foods, is known to be a neurotransmitter or precursor of γ-aminobutyric acid. Although it is unclear if GA functions in menopausal symptoms, we hypothesized that GA would attenuate estrogen deficiency-induced menopausal symptoms. The objective to test our hypothesis was to examine an estrogenic effect of GA in ovariectomized (OVX) mice, estrogen receptor (ER)-positive human osteoblast-like MG-63 cells, and ER-positive human breast cancer MCF-7 cells. The results demonstrated that administration with GA to mice suppressed body weight gain and vaginal atrophy when compared with the OVX mice. A microcomputed tomographic analysis of the trabecular bone showed increases in bone mineral density, trabecular number, and connectivity density as well as a significant decrease in total porosity of the OVX mice treated with GA. In addition, GA increased serum levels of alkaline phosphatase and estrogen compared with the OVX mice. Furthermore, GA induced proliferation and increased ER-β messenger RNA (mRNA) expression, estrogen response element (ERE) activity, extracellular signal-regulated kinase phosphorylation, and alkaline phosphatase activity in MG-63 cells. In MCF-7 cells, GA also increased proliferation, Ki-67 mRNA expression, ER-β mRNA expression, and ERE activity. Estrogen response element activity increased by GA was inhibited by an estrogen antagonist. Taken together, our data demonstrated that GA has estrogenic and osteogenic activities in OVX mice, MG-63 cells, and MCF-7 cells.

  15. High-fat diet induces leptin resistance in leptin-deficient mice.

    PubMed

    Koch, C E; Lowe, C; Pretz, D; Steger, J; Williams, L M; Tups, A

    2014-02-01

    The occurrence of type II diabetes is highly correlated with obesity, although the mechanisms linking the two conditions are incompletely understood. Leptin is a potent insulin sensitiser and, in leptin-deficient, insulin insensitive, Lep(ob/ob) mice, leptin improves glucose tolerance, indicating that leptin resistance may link obesity to insulin insensitivity. Leptin resistance occurs in response to a high-fat diet (HFD) and both hyperleptinaemia and inflammation have been proposed as causative mechanisms. Scrutinising the role of hyperleptinaemia in this process, central hyperleptinaemia in Lep(ob/ob) mice was induced by chronic i.c.v. infusion of leptin (4.2 μg/day) over 10 days. This treatment led to a dramatic decline in body weight and food intake, as well as an improvement in glucose tolerance. Transfer to HFD for 4 days markedly arrested the beneficial effects of leptin on these parameters. Because Lep(ob/ob) mice are exquisitely sensitive to leptin, the possibility that leptin could reverse HFD-induced glucose intolerance in these animals was investigated. HFD led to increased body weight and glucose intolerance compared to a low-fat diet (LFD). Older and heavier Lep(ob/ob) mice were used as body weight-matched controls. Mice in each group received either i.p. leptin (1.25 mg/kg) or vehicle, and glucose tolerance, food intake and the number of phosphorylated signal transducer and activator of transcription (pSTAT)3 immunoreactive cells in the arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) were analysed. Leptin improved glucose tolerance (P = 0. 019) and reduced food intake in Lep(ob/ob) mice on LFD (P ≤ 0.001) but was ineffective in mice on HFD. Furthermore, when leptin was administered centrally, the glucose tolerance of Lep(ob/ob) mice on HFD was significantly impaired (P = 0.007). Although leptin induced the number of pSTAT3 immunoreactive cells in the ARC and VMH of Lep(ob/ob) mice on LFD, HFD was associated with elevated pSTAT3

  16. Promotion of bone growth by dietary soy protein isolate: Comparision with dietary casein, whey hydrolysate and rice protein isolate in growing female rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effects of different dietary protein sources(casein (CAS), soy protein isolate (SPI), whey protein hydrolysate (WPH) and rice protein isolate (RPI)) on bone were studied in intact growing female rats and in ovarectomized (OVX) rats showing sex steroid deficiency-induced bone loss. In addition, S...

  17. NLRP3 Deficiency Reduces Macrophage Interleukin-10 Production and Enhances the Susceptibility to Doxorubicin-induced Cardiotoxicity

    PubMed Central

    Kobayashi, Motoi; Usui, Fumitake; Karasawa, Tadayoshi; Kawashima, Akira; Kimura, Hiroaki; Mizushina, Yoshiko; Shirasuna, Koumei; Mizukami, Hiroaki; Kasahara, Tadashi; Hasebe, Naoyuki; Takahashi, Masafumi

    2016-01-01

    NLRP3 inflammasomes recognize non-microbial danger signals and induce release of proinflammatory cytokine interleukin (IL)-1β, leading to sterile inflammation in cardiovascular disease. Because sterile inflammation is involved in doxorubicin (Dox)-induced cardiotoxicity, we investigated the role of NLRP3 inflammasomes in Dox-induced cardiotoxicity. Cardiac dysfunction and injury were induced by low-dose Dox (15 mg/kg) administration in NLRP3-deficient (NLRP3−/−) mice but not in wild-type (WT) and IL-1β−/− mice, indicating that NLRP3 deficiency enhanced the susceptibility to Dox-induced cardiotoxicity independent of IL-1β. Although the hearts of WT and NLRP3−/− mice showed no significant difference in inflammatory cell infiltration, macrophages were the predominant inflammatory cells in the hearts, and cardiac IL-10 production was decreased in Dox-treated NLRP3−/− mice. Bone marrow transplantation experiments showed that bone marrow-derived cells contributed to the exacerbation of Dox-induced cardiotoxicity in NLRP3−/− mice. In vitro experiments revealed that NLRP3 deficiency decreased IL-10 production in macrophages. Furthermore, adeno-associated virus-mediated IL-10 overexpression restored the exacerbation of cardiotoxicity in the NLRP3−/− mice. These results demonstrated that NLRP3 regulates macrophage IL-10 production and contributes to the pathophysiology of Dox-induced cardiotoxicity, which is independent of IL-1β. Our findings identify a novel role of NLRP3 and provided new insights into the mechanisms underlying Dox-induced cardiotoxicity. PMID:27225830

  18. Elevated Slit2 Activity Impairs VEGF-induced Angiogenesis and Tumor Neovascularization in EphA2-deficient Endothelium

    PubMed Central

    Youngblood, Victoria; Wang, Shan; Song, Wenqiang; Walter, Debra; Hwang, Yoonha; Chen, Jin; Brantley-Sieders, Dana M.

    2015-01-01

    Angiogenic remodeling during embryonic development and in adult tissue homeostasis is orchestrated by cooperative signaling between several distinct molecular pathways, which are often exploited by tumors. Indeed, tumors upregulate pro-angiogenic molecules while simultaneously suppressing angiostatic pathways in order to recruit blood vessels for growth, survival, and metastatic spread. Understanding how cancers exploit pro- and anti-angiogenic signals is a key step in developing new, molecularly targeted anti-angiogenic therapies. While EphA2, a receptor tyrosine kinase (RTK), is required for vascular endothelial growth factor (VEGF)-induced angiogenesis, the mechanism through which these pathways intersect remains unclear. Slit2 expression is elevated in EphA2-deficient endothelium, and here it is reported that inhibiting Slit activity rescues VEGF-induced angiogenesis in cell culture and in vivo, as well as VEGF-dependent tumor angiogenesis, in EphA2-deficient endothelial cells and animals. Moreover, blocking Slit activity or Slit2 expression in EphA2-deficient endothelial cells restores VEGF-induced activation of Src and Rac, both of which are required for VEGF-mediated angiogenesis. These data suggest that EphA2 suppression of Slit2 expression and Slit angiostatic activity enables VEGF-induced angiogenesis in vitro and in vivo, providing a plausible mechanism for impaired endothelial responses to VEGF in the absence of EphA2 function. PMID:25504371

  19. ARYL HYDROCARBON RECEPTOR DEFICIENCY PROTECTS MICE FROM DIET-INDUCED ADIPOSITY AND METABOLIC DISORDERS THROUGH INCREASED ENERGY EXPENDITURE

    PubMed Central

    Zhang, Zhi-Ming; Jaeger, Cassie D.; Krager, Stacey L.; Bottum, Kathleen M.; Liu, Jianghua; Liao, Duan-Fang; Tischkau, Shelley A.

    2015-01-01

    BACKGROUND/OBJECTIVES Epidemics of obesity and diabetes are escalating. High-calorie/high-fat food is a major cause for these global health issues, but molecular mechanisms underlying high-fat, diet-induced obesity are still not well understood. The aryl hydrocarbon receptor (AhR), a transcription factor that acts as a xenobiotic sensor, mediates environmental toxicant-induced obesity, insulin resistance and development of diabetes. AhR also influences lipid metabolism and diet-induced obesity. The effects of AhR deficiency on diet-induced obesity, hepatic steatosis and insulin resistance were examined. METHODS : Male wild type (WT), AhR null (AhR−/−) and AhR heterozygote (AhR+/−) mice were fed a normal chow diet (NCD, 10% kcal from fat) or a high-fat diet (HFD, 60% kcal from fat) for up to 14 weeks. Adiposity, adipose and liver morphology, insulin signaling, metabolic parameters and gene profiles were assessed. RESULTS AhR deficiency protected against HFD-induced obesity, hepatic steatosis, insulin resistance and inflammation. Moreover, AhR deficiency preserved insulin signaling in major metabolic tissues. These protective effects result from a higher energy expenditure in AhR-deficient mice compared to WT. Levels of transcript for both the thermogenic gene, uncoupling protein 1 (Ucp1), in brown adipose tissue and mitochondrial β-oxidation genes in muscle were significantly higher in AhR−/− and AhR+/− mice compared to WT. CONCLUSIONS This work documents a physiologically relevant function for AhR in regulation of body weight, hepatic fat deposition, insulin sensitivity and energy expenditure under HFD exposure, suggesting that AhR signaling may be developed as a potential therapeutic target for treatment of obesity and metabolic disorders. PMID:25907315

  20. Developmental vitamin D (DVD) deficiency alters pup-retrieval but not isolation-induced pup ultrasonic vocalizations in the rat.

    PubMed

    Burne, Thomas H J; O'Loan, Jonathan; Splatt, Karisha; Alexander, Suzanne; McGrath, John J; Eyles, Darryl W

    2011-02-01

    Evidence from animal experiments now demonstrates that prenatal vitamin D levels influence brain development. The aims of this study were to examine isolation-induced pup ultrasonic vocalizations and maternal-infant interactions using a pup-retrieval test in developmental vitamin D (DVD) deficient and control rats. Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. In two separate experiments we recorded ultrasonic vocalizations at 46KHz in isolated pups and we performed a pup-retrieval test on the day of birth. There was no significant effect of maternal diet on the calling rate of isolation-induced ultrasonic vocalizations by pups. We found that DVD-deficient dams retrieved their pups sooner than control dams and engaged in more pup directed activities (sniffing and carrying pups) and had a longer latency for self-grooming and rearing than control dams. We also assessed vitamin D related measures from a terminal blood sample immediately after the pup-retrieval test and found that DVD-deficient dams and pups had significantly lower levels of 25 OH D₃, 1,25 (OH)₂D₃ and phosphate, elevated levels of parathyroid hormone (PTH) but there was no significant effect of maternal diet on calcium levels. We speculate that the altered maternal-pup interactions identified in the DVD model may impact on early periods of brain development and behaviour.

  1. Photoprotection by dietary phenolics against melanogenesis induced by UVA through Nrf2-dependent antioxidant responses.

    PubMed

    Chaiprasongsuk, Anyamanee; Onkoksoong, Tasanee; Pluemsamran, Thanyawan; Limsaengurai, Saowalak; Panich, Uraiwan

    2016-08-01

    Dietary phenolics may play a protective role in UV-mediated skin pigmentation through their antioxidant and UV-absorbing actions. In this study, we investigated whether genetic silencing of Nrf2, regulating the transcription of antioxidant genes, affected melanogenesis in primary human epidermal melanocytes (HEMn) and B16F10 melanoma cells subjected to UVA (8J/cm(2)) exposure. Then, we explored the antimelanogenic actions of phenolics; caffeic acid (CA) and ferulic acid (FA) providing partial UVA protection; quercetin (QU) and rutin (RU) providing strong UVA protection and; avobenzone (AV), an efficient UVA filter, in association with modulation of Nrf2-mediated antioxidant defenses in response to UVA insults in B16F10 cells. Upon oxidative insults, Nrf2 silencing promoted melanogenesis in both HEMn and B16F10 cells irradiated with UVA. Stimulation of melanogenesis by UVA correlated with increased ROS and oxidative DNA damage (8-OHdG), GSH depletion as well as a transient downregulation of Nrf2 nuclear translocation and of Nrf2-ARE signaling in B16F10 cells. All test compounds exerted antimelanogenic effects with respect to their abilities to reverse UVA-mediated oxidative damage as well as downregulation of Nrf2 activity and its target antioxidants (GCLC, GST and NQO1) in B16F10 cells. In conclusion, defective Nrf2 may promote melanogenesis under UVA irradiation through oxidative stress mechanisms. Compounds with antioxidant and/or UVA absorption properties could protect against UVA-induced melanogenesis through indirect regulatory effect on Nrf2-ARE pathway.

  2. Photoprotection by dietary phenolics against melanogenesis induced by UVA through Nrf2-dependent antioxidant responses

    PubMed Central

    Chaiprasongsuk, Anyamanee; Onkoksoong, Tasanee; Pluemsamran, Thanyawan; Limsaengurai, Saowalak; Panich, Uraiwan

    2015-01-01

    Dietary phenolics may play a protective role in UV-mediated skin pigmentation through their antioxidant and UV-absorbing actions. In this study, we investigated whether genetic silencing of Nrf2, regulating the transcription of antioxidant genes, affected melanogenesis in primary human epidermal melanocytes (HEMn) and B16F10 melanoma cells subjected to UVA (8 J/cm2) exposure. Then, we explored the antimelanogenic actions of phenolics; caffeic acid (CA) and ferulic acid (FA) providing partial UVA protection; quercetin (QU) and rutin (RU) providing strong UVA protection and; avobenzone (AV), an efficient UVA filter, in association with modulation of Nrf2-mediated antioxidant defenses in response to UVA insults in B16F10 cells. Upon oxidative insults, Nrf2 silencing promoted melanogenesis in both HEMn and B16F10 cells irradiated with UVA. Stimulation of melanogenesis by UVA correlated with increased ROS and oxidative DNA damage (8-OHdG), GSH depletion as well as a transient downregulation of Nrf2 nuclear translocation and of Nrf2-ARE signaling in B16F10 cells. All test compounds exerted antimelanogenic effects with respect to their abilities to reverse UVA-mediated oxidative damage as well as downregulation of Nrf2 activity and its target antioxidants (GCLC, GST and NQO1) in B16F10 cells. In conclusion, defective Nrf2 may promote melanogenesis under UVA irradiation through oxidative stress mechanisms. Compounds with antioxidant and/or UVA absorption properties could protect against UVA-induced melanogenesis through indirect regulatory effect on Nrf2-ARE pathway. PMID:26765101

  3. Chronic dietary exposure to environmental organochlorine contaminants induces thyroid gland lesions in Arctic foxes (Vulpes lagopus).

    PubMed

    Sonne, Christian; Wolkers, Hans; Leifsson, Pall S; Iburg, Tine; Jenssen, Bjørn Munro; Fuglei, Eva; Ahlstrøm, Oystein; Dietz, Rune; Kirkegaard, Maja; Muir, Derek C G; Jørgensen, Even H

    2009-08-01

    The impact of dietary organochlorine (OC) exposure on thyroid gland pathology was studied in farmed male Arctic foxes (Vulpes lagopus). The exposed group (n=16) was fed a diet based on wild minke whale (Balaenoptera acutorostrata) blubber as a main fat source in order to mimic the exposure to OC cocktails in the Artic environment. This resulted in an exposure of approximately 17 microg Sigma OC/kg day and a Sigma OC residue adipose tissue and liver concentration of 1700 and 4470 ng/gl.w., respectively, after 16 months of exposure. Control foxes (n=13) were fed a diet with pork (Sus scrofa) fat as a main fat source containing significantly low