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  1. 5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

    PubMed Central

    Hohmann, Miriam S. N.; Cardoso, Renato D. R.; Pinho-Ribeiro, Felipe A.; Crespigio, Jefferson; Cunha, Thiago M.; Alves-Filho, José C.; da Silva, Rosiane V.; Pinge-Filho, Phileno; Ferreira, Sergio H.; Cunha, Fernando Q.; Casagrande, Rubia; Verri, Waldiceu A.

    2013-01-01

    5-Lipoxygenase (5-LO) converts arachidonic acid into leukotrienes (LTs) and is involved in inflammation. At present, the participation of 5-LO in acetaminophen (APAP)-induced hepatotoxicity and liver damage has not been addressed. 5-LO deficient (5-LO−/−) mice and background wild type mice were challenged with APAP (0.3–6 g/kg) or saline. The lethality, liver damage, neutrophil and macrophage recruitment, LTB4, cytokine production, and oxidative stress were assessed. APAP induced a dose-dependent mortality, and the dose of 3 g/kg was selected for next experiments. APAP induced LTB4 production in the liver, the primary target organ in APAP toxicity. Histopathological analysis revealed that 5-LO−/− mice presented reduced APAP-induced liver necrosis and inflammation compared with WT mice. APAP-induced lethality, increase of plasma levels of aspartate aminotransferase and alanine aminotransferase, liver cytokine (IL-1β, TNF-α, IFN-γ, and IL-10), superoxide anion, and thiobarbituric acid reactive substances production, myeloperoxidase and N-acetyl-β-D-glucosaminidase activity, Nrf2 and gp91phox mRNA expression, and decrease of reduced glutathione and antioxidant capacity measured by 2,2′-azinobis(3-ethylbenzothiazoline 6-sulfonate) assay were prevented in 5-LO−/− mice compared to WT mice. Therefore, 5-LO deficiency resulted in reduced mortality due to reduced liver inflammatory and oxidative damage, suggesting 5-LO is a promising target to reduce APAP-induced lethality and liver inflammatory/oxidative damage. PMID:24288682

  2. Effects of MK-886, a 5-lipoxygenase activating protein (FLAP) inhibitor, and 5-lipoxygenase deficiency on the forced swimming behavior of mice.

    PubMed

    Uz, Tolga; Dimitrijevic, Nikola; Imbesi, Marta; Manev, Hari; Manev, Radmila

    2008-05-01

    A common biological pathway may contribute to the comorbidity of atherosclerosis and depression. Increased activity of the enzymatic 5-lipoxygenase (5-LOX, 5LO) pathway is a contributing factor in atherosclerosis and a 5-LOX inhibitor, MK-886, is beneficial in animal models of atherosclerosis. In the brain, MK-886 increases phosphorylation of the glutamate receptor subunit GluR1, and the increased phosphorylation of this receptor has been associated with antidepressant treatment. In this work, we evaluated the behavioral effects of MK-886 in an automated assay of mouse forced swimming, which identifies antidepressant activity as increased climbing behavior and/or decreased rest time. Whereas a single injection of MK-886 (3 and 10 mg/kg) did not affect forced swimming behaviors assayed 30 min later, six daily injections of 3 mg/kg MK-886 slightly increased climbing and significantly reduced rest time in wild-type mice but not in 5-LOX-deficient mice. A diet delivery of MK-886, 4 micro/(100 mg(body-weight)day), required 3 weeks to affect forced swimming; it increased climbing behavior. Climbing behavior was also increased in naive 5-LOX-deficient mice compared to naive wild-type controls. These results suggest that 5-LOX inhibition and deficiency may be associated with antidepressant activity. Increased climbing in a forced swimming assay is a typical outcome of antidepressants that increase noradrenergic and dopaminergic activity. Interestingly, 5-LOX deficiency and MK-886 treatment have been shown to be capable of increasing the behavioral effects of a noradrenaline/dopamine-potentiating drug, cocaine. Future research is needed to evaluate the clinical relevance of our findings. PMID:18403121

  3. Repeated allergen exposure reduce early phase airway response and leukotriene release despite upregulation of 5-lipoxygenase pathways

    PubMed Central

    2012-01-01

    Background Allergen induced early phase airway response and airway plasma exudation are predominantly mediated by inflammatory mast cell mediators including histamine, cysteinyl leukotrienes (cysLTs) and thromboxane A2 (TXA2). The aim of the present study was to evaluate whether repeated allergen exposure affects early phase airway response to allergen challenge. Methods A trimellitic anhydride (TMA) sensitized guinea pig model was used to investigate the effects of low dose repeated allergen exposure on cholinergic airway responsiveness, early phase airway response and plasma exudation, as well as local airway production of mast cell derived cysteinyl leukotrienes and thromboxane B2 (TXB2) after allergen challenge. Results Repeated low dose allergen exposure increased cholinergic airway responsiveness. In contrast, early phase airway response and plasma exudation in response to a high-dose allergen challenge were strongly attenuated after repeated low dose allergen exposure. Inhibition of the airway response was unspecific to exposed allergen and independent of histamine receptor blocking. Furthermore, a significant reduction of cysteinyl leukotrienes and TXB2 was found in the airways of animals repeatedly exposed to a low dose allergen. However, in vitro stimulation of airway tissue from animals repeatedly exposed to a low dose allergen with arachidonic acid and calcium ionophore (A23187) induced production of cysteinyl leukotrienes and TXB2, suggesting enhanced activity of 5-lipoxygenase and cyclooxygenase pathways. Conclusions The inhibition of the early phase airway response, cysteinyl leukotriene and TXB2 production after repeated allergen exposure may result from unresponsive effector cells. PMID:22439792

  4. THE 5-LIPOXYGENASE PATHWAY IS REQUIRED FOR ACUTE LUNG INJURY FOLLOWING HEMORRHAGIC SHOCK

    PubMed Central

    Eun, John C.; Moore, Ernest E.; Mauchley, David C.; Johnson, Chris A.; Meng, Xianzhong; Banerjee, Anirban; Wohlauer, Max V.; Zarini, Simona; Gijón, Miguel A.; Murphy, Robert C.

    2012-01-01

    The cellular and biochemical mechanisms leading to acute lung injury and subsequent multiple organ failure are only partially understood. In order to study the potential role of eicosanoids, particularly leukotrienes, as possible mediators of acute lung injury, we used a murine experimental model of acute lung injury induced by hemorrhagic shock after blood removal via cardiac puncture. Neutrophil sequestration as shown by immunofluorescence, and protein leakage into the alveolar space, were measured as markers of injury. We used liquid chromatography coupled to tandem mass spectrometry to unequivocally identify several eicosanoids in the bronchoalveolar lavage fluid of experimental animals. MK886, a specific inhibitor of the 5-lipoxygenase pathway, as well as transgenic mice deficient in 5-lipoxygenase, were used to determine the role of this enzymatic pathway in this model. Leukotriene B4 and leukotriene C4 were consistently elevated in shock-treated mice compared to sham-treated mice. MK886 attenuated neutrophil infiltration and protein extravasation induced by hemorrhagic shock. 5-lipoxygenase-deficient mice showed reduced neutrophil infiltration and protein extravasation after shock treatment, indicating greatly reduced lung injury. These results support the hypothesis that 5-lipoxygenase, most likely through the generation of leukotrienes, plays an important role in the pathogenesis of acute lung injury induced by hemorrhagic shock in mice. This pathway could represent a new target for pharmacological intervention to reduce lung damage following severe primary injury. PMID:22392149

  5. Inhibition of 5-lipoxygenase by vitamin E.

    PubMed

    Reddanna, P; Rao, M K; Reddy, C C

    1985-11-25

    Purified 5-lipoxygenase from potato tubers was inhibited strongly by vitamin E and its analogs. The inhibition by d-alpha-tocopherol was found to be irreversible and non-competitive with respect to arachidonic acid. An IC50 of 5 microM was calculated for d-alpha-tocopherol. The inhibition appears to be unrelated to its antioxidant function. Binding studies with 14C-labelled d-alpha-tocopherol revealed that there is a strong interaction between vitamin E and 5-lipoxygenase. Tryptic digestion and peptide mapping of 5-lipoxygenase-vitamin E complex indicate that vitamin E binds strongly to a single peptide. These studies suggest that cellular vitamin E levels may have profound influence on the formation of leukotrienes. PMID:3934003

  6. 5-Lipoxygenase-activating protein rescues activity of 5-lipoxygenase mutations that delay nuclear membrane association and disrupt product formation.

    PubMed

    Gerstmeier, Jana; Newcomer, Marcia E; Dennhardt, Sophie; Romp, Erik; Fischer, Jana; Werz, Oliver; Garscha, Ulrike

    2016-05-01

    Leukotrienes (LTs) are proinflammatory lipid mediators formed from arachidonic acid in a 2-step reaction catalyzed by 5-lipoxygenase (5-LOX) requiring the formation of 5-HPETE [5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid] and its subsequent transformation to LTA4 5-LOX is thought to receive arachidonic acid from the nuclear membrane-embedded 5-LOX-activating protein (FLAP). The crystal structure of 5-LOX revealed an active site concealed by F177 and Y181 (FY cork). We examined the influence of the FY cork on 5-LOX activity and membrane binding in HEK293 cells in the absence and presence of FLAP. Uncapping the 5-LOX active site by mutation of F177 and/or Y181 to alanine (5-LOX-F177A, 5-LOX-Y181A, 5-LOX-F177/Y181A) resulted in delayed and diminished 5-LOX membrane association in A23187-stimulated cells. For 5-LOX-F177A and 5-LOX-F177/Y181A, formation of 5-LOX products was dramatically reduced relative to 5-LOX-wild type (wt). Strikingly, coexpression of FLAP in A23187-activated HEK293 cells effectively restored formation of 5-H(p)ETE (5-hydroxy- and 5-peroxy-6-trans-8,11,14-cis-eicosatetraenoic acid) by these same 5-LOX mutants (≈60-70% 5-LOX-wt levels) but not of LTA4 hydrolysis products. Yet 5-LOX-Y181A generated 5-H(p)ETE at levels comparable to 5-LOX-wt but reduced LTA4 hydrolysis products. Coexpression of FLAP partially restored LTA4 hydrolysis product formation by 5-LOX-Y181A. Together, the data suggest that the concealed FY cork impacts membrane association and that FLAP may help shield an uncapped active site.-Gerstmeier, J., Newcomer, M. E., Dennhardt, S., Romp, E., Fischer, J., Werz, O., Garscha, U. 5-Lipoxygenase-activating protein rescues activity of 5-lipoxygenase mutations that delay nuclear membrane association and disrupt product formation. PMID:26842853

  7. 5-Lipoxygenase Activity Increases Susceptibility to Experimental Paracoccidioides brasiliensis Infection

    PubMed Central

    Tristão, Fabrine Sales Massafera; Rocha, Fernanda Agostini; Moreira, Ana Paula; Cunha, Fernando Queiroz; Rossi, Marcos Antonio

    2013-01-01

    Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the thermodimorphic fungus Paracoccidioides brasiliensis. Leukotrienes and lipoxins are lipid mediators produced after 5-lipoxygenase (5-LO) activation that exhibit pro- and anti-inflammatory roles, respectively. Here, we have investigated the contribution of 5-LO enzymatic activity in PCM using an experimental model of P. brasiliensis infection. B6.129 wild-type (B6.129) and 5-LO-deficient (5-LO−/−) mice were intravenously inoculated with a virulent strain of P. brasiliensis (Pb18), and the survival rate of the infected mice was investigated on different days after yeast infection. 5-LO−/− mice exhibited an increased survival rate associated with a decreased number of CFU. The resistance of 5-LO−/− during PCM was associated with augmented nitric oxide (NO) production and the formation of compact granulomas. In addition, the absence of 5-LO was associated with a diminished number of CD4+ CD25+ regulatory T cells, higher levels of gamma interferon and interleukin-12, and increased T-bet (a T-box transcription factor that directs Th1 lineage commitment) mRNA levels in the lungs. Taken together, our results show for the first time that 5-LO enzymatic activity increases susceptibility to P. brasiliensis, suggesting that this pathway may be a potential target for therapeutic intervention during PCM. PMID:23381993

  8. Blockade of TRPM7 Channel Activity and Cell Death by Inhibitors of 5-Lipoxygenase

    PubMed Central

    Chen, Hsiang-Chin; Xie, Jia; Zhang, Zheng; Su, Li-Ting; Yue, Lixia; Runnels, Loren W.

    2010-01-01

    TRPM7 is a ubiquitous divalent-selective ion channel with its own kinase domain. Recent studies have shown that suppression of TRPM7 protein expression by RNA interference increases resistance to ischemia-induced neuronal cell death in vivo and in vitro, making the channel a potentially attractive pharmacological target for molecular intervention. Here, we report the identification of the 5-lipoxygenase inhibitors, NDGA, AA861, and MK886, as potent blockers of the TRPM7 channel. Using a cell-based assay, application of these compounds prevented cell rounding caused by overexpression of TRPM7 in HEK-293 cells, whereas inhibitors of 12-lipoxygenase and 15-lipoxygenase did not prevent the change in cell morphology. Application of the 5-lipoxygenase inhibitors blocked heterologously expressed TRPM7 whole-cell currents without affecting the protein's expression level or its cell surface concentration. All three inhibitors were also effective in blocking the native TRPM7 current in HEK-293 cells. However, two other 5-lipoxygenase specific inhibitors, 5,6-dehydro-arachidonic acid and zileuton, were ineffective in suppressing TRPM7 channel activity. Targeted knockdown of 5-lipoxygenase did not reduce TRPM7 whole-cell currents. In addition, application of 5-hydroperoxyeicosatetraenoic acid (5-HPETE), the product of 5-lipoxygenase, or 5-HPETE's downstream metabolites, leukotriene B4 and leukotriene D4, did not stimulate TRPM7 channel activity. These data suggested that NDGA, AA861, and MK886 reduced the TRPM7 channel activity independent of their effect on 5-lipoxygenase activity. Application of AA861 and NDGA reduced cell death for cells overexpressing TRPM7 cultured in low extracellular divalent cations. Moreover, treatment of HEK-293 cells with AA861 increased cell resistance to apoptotic stimuli to a level similar to that obtained for cells in which TRPM7 was knocked down by RNA interference. In conclusion, NDGA, AA861, and MK886 are potent blockers of the TRPM7 channel

  9. Characterization of the human 5-lipoxygenase gene promoter

    SciTech Connect

    Hoshiko, S.; Radmark, O.; Samuelsson, B. )

    1990-12-01

    Nucleotide sequences that direct transcription of the human 5-lipoxygenase gene have been examined by ligation to the chloramphenicol acetyltransferase activity in transfected HeLa and HL-60 cells. Various lengths of 5{prime}-flanking sequences up to 5.9 kilobase pairs 5{prime} of the transcriptional initiation sites were tested. Two positive and two negative apparent regulatory regions were seen. Part of the promoter sequence ({minus}179 to {minus}56 from ATG), which includes five repeated GC boxes (the putative Spl binding sequence) was essential for transcription in both HeLa and HL-60 cells. Gel-shift assays (using the DNA fragment {minus}212 to {minus}88) revealed that the transcriptional factor Spl could bind to this region of the 5-lipoxygenase promoter. Furthermore, HL-60 nuclear extracts contained specific nuclear factor(s) binding to 5-lipoxygenase promoter DNA, which could not be detected in HeLa cell nuclear extracts.

  10. Molecular cloning and amino acid sequence of human 5-lipoxygenase

    SciTech Connect

    Matsumoto, T.; Funk, C.D.; Radmark, O.; Hoeoeg, J.O.; Joernvall, H.; Samuelsson, B.

    1988-01-01

    5-Lipoxygenase (EC 1.13.11.34), a Ca/sup 2 +/- and ATP-requiring enzyme, catalyzes the first two steps in the biosynthesis of the peptidoleukotrienes and the chemotactic factor leukotriene B/sub 4/. A cDNA clone corresponding to 5-lipoxygenase was isolated from a human lung lambda gt11 expression library by immunoscreening with a polyclonal antibody. Additional clones from a human placenta lambda gt11 cDNA library were obtained by plaque hybridization with the /sup 32/P-labeled lung cDNA clone. Sequence data obtained from several overlapping clones indicate that the composite DNAs contain the complete coding region for the enzyme. From the deduced primary structure, 5-lipoxygenase encodes a 673 amino acid protein with a calculated molecular weight of 77,839. Direct analysis of the native protein and its proteolytic fragments confirmed the deduced composition, the amino-terminal amino acid sequence, and the structure of many internal segments. 5-Lipoxygenase has no apparent sequence homology with leukotriene A/sub 4/ hydrolase or Ca/sup 2 +/-binding proteins. RNA blot analysis indicated substantial amounts of an mRNA species of approx. = 2700 nucleotides in leukocytes, lung, and placenta.

  11. Alveolar lining fluid regulates mononuclear phagocyte 5-lipoxygenase metabolism.

    PubMed

    Phare, S M; Peters-Golden, M; Coffey, M J

    1998-11-01

    The enzyme 5-lipoxygenase (5-LO) catalyses the synthesis of leukotrienes (LT), which are important in phagocytosis and killing of microorganisms. The alveolar macrophage (AM), the primary resident defender of the alveolar space, has a greater capacity for LT synthesis than its precursor, the peripheral blood monocyte (PBM). This study investigated whether the alveolar lining fluid (ALF) upregulates LT synthetic capacity in mononuclear phagocytes. Rat AM, peritoneal macrophages (PM) and ALF were obtained by lavage from pathogen-free animals. Human PBM were isolated from normal subjects. 5-LO metabolism and expression were measured with and without ALF. Rat ALF increased 5-LO metabolism (136.4+/-15.1% of control) in cultured PBM. This was associated with increased 5-LO activating protein (FLAP) (357+/-29.5 %), and 5-LO expression (188+/-31.3%). Culture of AM for 3 days resulted in a greater decrement in LTB4 synthesis (LTB4 15.4+/-6.9% of day 1) than in PM (54.7+/-8.3% of day 1), suggesting a greater dependence of AM 5-LO metabolism on ALF. 5-LO and FLAP expression decreased to a greater degree in AM than PM in culture. Furthermore, AM cultured with ALF maintained their LT synthetic capacity, FLAP and 5-LO expression compared with control cells cultured in medium alone. In conclusion, alveolar lining fluid increased 5-lipoxygenase metabolism in peripheral blood monocytes and maintained it in cultured alveolar macrophages, by a mechanism of increased 5-lipoxygenase and 5-lipoxygenase activating protein expression. This may boost host defence capabilities. PMID:9864011

  12. Identification of the substrate access portal of 5-Lipoxygenase

    PubMed Central

    Mitra, Sunayana; Bartlett, Sue G.

    2016-01-01

    The overproduction of inflammatory lipid mediators derived from arachidonic acid contributes to asthma and cardiovascular diseases, among other pathologies. Consequently, the enzyme that initiates the synthesis of pro-inflammatory leukotrienes, 5-lipoxygenase (5-LOX), is a target for drug design. The crystal structure of 5-LOX revealed a fully encapsulated active site, thus the point of substrate entry is not known. We asked whether a structural motif, a “cork” present in 5-LOX but absent in other mammalian lipoxygenases, might be ejected to allow substrate access. Our results indicate that reduction of cork volume facilitates access to the active site. However, if cork entry into the site is obstructed, enzyme activity is significantly compromised. The results support a model in which the “cork” that shields the active site in the absence of substrate serves as the active site portal, but the “corking” amino acid Phe-177 plays a critical role in providing a fully functional active site. Thus the more appropriate metaphor for this structural motif is a “twist-and-pour” cap. Additional mutagenesis data are consistent with a role for His-600, deep in the elongated cavity, in positioning the substrate for catalysis. PMID:26427761

  13. 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ω-3 polyunsaturated fatty acids.

    PubMed

    Sapieha, Przemyslaw; Stahl, Andreas; Chen, Jing; Seaward, Molly R; Willett, Keirnan L; Krah, Nathan M; Dennison, Roberta J; Connor, Kip M; Aderman, Christopher M; Liclican, Elvira; Carughi, Arianna; Perelman, Dalia; Kanaoka, Yoshihide; Sangiovanni, John Paul; Gronert, Karsten; Smith, Lois E H

    2011-02-01

    Lipid signaling is dysregulated in many diseases with vascular pathology, including cancer, diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration. We have previously demonstrated that diets enriched in ω-3 polyunsaturated fatty acids (PUFAs) effectively reduce pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy, in part through metabolic products that suppress microglial-derived tumor necrosis factor-α. To better understand the protective effects of ω-3 PUFAs, we examined the relative importance of major lipid metabolic pathways and their products in contributing to this effect. ω-3 PUFA diets were fed to four lines of mice deficient in each key lipid-processing enzyme (cyclooxygenase 1 or 2, or lipoxygenase 5 or 12/15), retinopathy was induced by oxygen exposure; only loss of 5-lipoxygenase (5-LOX) abrogated the protection against retinopathy of dietary ω-3 PUFAs. This protective effect was due to 5-LOX oxidation of the ω-3 PUFA lipid docosahexaenoic acid to 4-hydroxy-docosahexaenoic acid (4-HDHA). 4-HDHA directly inhibited endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor γ (PPARγ), independent of 4-HDHA's anti-inflammatory effects. Our study suggests that ω-3 PUFAs may be profitably used as an alternative or supplement to current anti-vascular endothelial growth factor (VEGF) treatment for proliferative retinopathy and points to the therapeutic potential of ω-3 PUFAs and metabolites in other diseases of vasoproliferation. It also suggests that cyclooxygenase inhibitors such as aspirin and ibuprofen (but not lipoxygenase inhibitors such as zileuton) might be used without losing the beneficial effect of dietary ω-3 PUFA. PMID:21307302

  14. Phospholipid Ozonation Products Activate the 5-Lipoxygenase Pathway in Macrophages.

    PubMed

    Zemski Berry, Karin A; Murphy, Robert C

    2016-08-15

    Ozone is a highly reactive environmental toxicant that can react with the double bonds of lipids in pulmonary surfactant. This study was undertaken to investigate the proinflammatory properties of the major lipid-ozone product in pulmonary surfactant, 1-palmitoyl-2-(9'-oxo-nonanoyl)-glycerophosphocholine (16:0/9al-PC), with respect to eicosanoid production. A dose-dependent increase in the formation of 5-lipoxygenase (5-LO) products was observed in murine resident peritoneal macrophages (RPM) and alveolar macrophages (AM) upon treatment with 16:0/9al-PC. In contrast, the production of cyclooxygenase (COX) derived eicosanoids did not change from basal levels in the presence of 16:0/9al-PC. When 16:0/9al-PC and the TLR2 ligand, zymosan, were added to RPM or AM, an enhancement of 5-LO product formation along with a concomitant decrease in COX product formation was observed. Neither intracellular calcium levels nor arachidonic acid release was influenced by the addition of 16:0/9al-PC to RPM. Results from mitogen-activated protein kinase (MAPK) inhibitor studies and direct measurement of phosphorylation of MAPKs revealed that 16:0/9al-PC activates the p38 MAPK pathway in RPM, which results in the activation of 5-LO. Our results indicate that 16:0/9al-PC has a profound effect on the eicosanoid pathway, which may have implications in inflammatory pulmonary disease states where eicosanoids have been shown to play a role. PMID:27448436

  15. Kinetic investigation of human 5-lipoxygenase with arachidonic acid.

    PubMed

    Mittal, Monica; Kumar, Ramakrishnan B; Balagunaseelan, Navisraj; Hamberg, Mats; Jegerschöld, Caroline; Rådmark, Olof; Haeggström, Jesper Z; Rinaldo-Matthis, Agnes

    2016-08-01

    Human 5-lipoxygenase (5-LOX) is responsible for the formation of leukotriene (LT)A4, a pivotal intermediate in the biosynthesis of the leukotrienes, a family of proinflammatory lipid mediators. 5-LOX has thus gained attention as a potential drug target. However, details of the kinetic mechanism of 5-LOX are still obscure. In this Letter, we investigated the kinetic isotope effect (KIE) of 5-LOX with its physiological substrate, arachidonic acid (AA). The observed KIE is 20±4 on kcat and 17±2 on kcat/KM at 25°C indicating a non-classical reaction mechanism. The observed rates show slight temperature dependence at ambient temperatures ranging from 4 to 35°C. Also, we observed low Arrhenius prefactor ratio (AH/AD=0.21) and a small change in activation energy (Ea(D)-Ea(H)=3.6J/mol) which suggests that 5-LOX catalysis involves tunneling as a mechanism of H-transfer. The measured KIE for 5-LOX involves a change in regioselectivity in response to deuteration at position C7, resulting in H-abstraction form C10 and formation of 8-HETE. The viscosity experiments influence the (H)kcat, but not (D)kcat. However the overall kcat/KM is not affected for labeled or unlabeled AA, suggesting that either the product release or conformational rearrangement might be involved in dictating kinetics of 5-LOX at saturating conditions. Investigation of available crystal structures suggests the role of active site residues (F421, Q363 and L368) in regulating the donor-acceptor distances, thus affecting H-transfer as well as regiospecificity. In summary, our study shows that that the H-abstraction is the rate limiting step for 5-LOX and that the observed KIE of 5-LOX is masked by a change in regioselectivity. PMID:27363940

  16. Ablation of 5-lipoxygenase mitigates pancreatic lesion development

    PubMed Central

    Knab, Lawrence M.; Schultz, Michelle; Principe, Daniel R.; Mascarinas, Windel E.; Gounaris, Elias; Munshi, Hidayatullah G.; Grippo, Paul J.; Bentrem, David J.

    2016-01-01

    Background Pancreatic ductal adenocarcinoma (PDAC), which continues to have a dismal prognosis, is associated with a pronounced fibro-inflammatory response. Inflammation in vivo can be mediated by 5-lipoxygenase (5LO), an enzyme that converts omega-6 fatty acids to eicosanoids, including leukotriene B4 (LTB4). We have previously shown that diets rich in omega-6 fatty acids (FA) increase pancreatic lesions and mast cell infiltration in EL-Kras mice. In this study, we evaluated the role of 5LO in generating higher levels of LTB4 from human cells and in mediating lesion development and mast cell infiltration in EL-Kras mice. Materials and Methods Human pancreatic ductal epithelial (HPDE) and cancer cells were treated with omega-6 FA in vitro. EL-Kras mice lacking 5LO (EL-Kras/5LO−/−) mice were generated and fed standard chow or omega-6 FA diets. Pancreatic lesion frequency and mast cell infiltration were compared to EL-Kras/5LO+/+ mice. Human PDAC tumors were evaluated for 5LO expression and mast cells. Results HPDE and cancer cells treated with omega-6 FA generated increased LTB4 levels in vitro. EL-Kras/5LO−/− developed fewer pancreatic lesions and had decreased mast cell infiltration when compared to EL-Kras/5LO+/+ mice. Human PDAC tumors with increased 5LO expression demonstrate increased mast cell infiltration. Additionally, diets rich in omega-6 FA failed to increase pancreatic lesion development and mast cell infiltration in EL-Kras/5LO−/− mice. Conclusions The expansion of mutant Kras-induced lesions via omega-6 FA is dependent on 5LO, and 5LO functions downstream of mutant Kras to mediate inflammation, suggesting that 5LO may be a potential chemo-preventive and therapeutic target in pancreatic cancer. PMID:25454978

  17. Exogenous action of 5-lipoxygenase by its metabolites on luteinizing hormone release in rat pituitary cells.

    PubMed

    Przylipiak, A; Kiesel, L; Habenicht, A J; Przylipiak, M; Runnebaum, B

    1990-02-12

    The stimulatory effect of exogenously administered potato 5-lipoxygenase (0.1-0.3 U/2 ml) on luteinizing hormone (LH) release was demonstrated in rat anterior pituitary cells in a superfusion system. Nordihydroguaiaretic acid (NDGA), an inhibitor of 5-lipoxygenase, abolished the effect of the enzyme on LH secretion. The secretory effect on LH after 5-lipoxygenase administration was biphasic and dependent on Ca2+ indicating that 5-lipoxygenase affects LH release through its oxygenation reaction. Another series of experiments demonstrated that activation of 5-lipoxygenase, expressed as production of leukotriene (LT) B4 and C4 (728 +/- 127 pg/10(6) cells and 178 +/- 23 pg/10(6) cells, respectively) occurs in rat pituitary cells after addition of Ca2+ ionophore A23187. However, LTB4 and LTC4 were not formed by pituitary cells that had previously been desensitized by gonadotropin-releasing hormone (GnRH), the physiological ligand of LH release. These results are consistent with a role of 5-lipoxygenase metabolites in the mechanism of GnRH-induced LH secretion. PMID:2157615

  18. 5-Lipoxygenase Negatively Regulates Th1 Response during Brucella abortus Infection in Mice

    PubMed Central

    Fahel, Júlia Silveira; de Souza, Mariana Bueno; Gomes, Marco Túlio Ribeiro; Corsetti, Patricia P.; Carvalho, Natalia B.; Marinho, Fabio A. V.; de Almeida, Leonardo A.; Caliari, Marcelo V.; Machado, Fabiana Simão

    2015-01-01

    Brucella abortus is a Gram-negative bacterium that infects humans and cattle, causing a chronic inflammatory disease known as brucellosis. A Th1-mediated immune response plays a critical role in host control of this pathogen. Recent findings indicate contrasting roles for lipid mediators in host responses against infections. 5-Lipoxygenase (5-LO) is an enzyme required for the production of the lipid mediators leukotrienes and lipoxins. To determine the involvement of 5-LO in host responses to B. abortus infection, we intraperitoneally infected wild-type and 5-LO-deficient mice and evaluated the progression of infection and concomitant expression of immune mediators. Here, we demonstrate that B. abortus induced the upregulation of 5-LO mRNA in wild-type mice. Moreover, this pathogen upregulated the production of the lipid mediators leukotriene B4 and lipoxin A4 in a 5-LO-dependent manner. 5-LO-deficient mice displayed lower bacterial burdens in the spleen and liver and less severe liver pathology, demonstrating an enhanced resistance to infection. Host resistance paralleled an increased expression of the proinflammatory mediators interleukin-12 (IL-12), gamma interferon (IFN-γ), and inducible nitric oxide synthase (iNOS) during the course of infection. Moreover, we demonstrated that 5-LO downregulated the expression of IL-12 in macrophages during B. abortus infection. Our results suggest that 5-LO has a major involvement in B. abortus infection, by functioning as a negative regulator of the protective Th1 immune responses against this pathogen. PMID:25583526

  19. Myeloid Cell 5-Lipoxygenase Activating Protein Modulates the Response to Vascular Injury

    PubMed Central

    Yu, Zhou; Ricciotti, Emanuela; Miwa, Takashi; Liu, Shulin; Ihida-Stansbury, Kaori; Landersberg, Gavin; Jones, Peter L.; Scalia, Rosario; Song, Wenchao; Assoian, Richard K.; FitzGerald, Garret A.

    2013-01-01

    Rationale Human genetics have implicated the 5- lipoxygenase (5-LO) enzyme in the pathogenesis of cardiovascular disease and an inhibitor of the 5-LO activating protein (FLAP) is in clinical development for asthma. Objective Here we determined whether FLAP deletion modifies the response to vascular injury. Methods and Results Vascular remodeling was characterized 4 weeks after femoral arterial injury in FLAP knockout (FLAP KO) mice and wild type (WT) controls. Both neointimal hyperplasia and the intima/media ratio of the injured artery were significantly reduced in the FLAP KOs while endothelial integrity was preserved. Lesional myeloid cells were depleted and vascular smooth muscle cell (VSMC) proliferation, as reflected by bromodeoxyuridine (BrdU) incorporation, was markedly attenuated by FLAP deletion. Inflammatory cytokine release from FLAP KO macrophages was depressed and their restricted ability to induce VSMC migration ex vivo was rescued with leukotriene B4 (LTB4). FLAP deletion restrained injury and attenuated upregulation of the extracellular matrix protein, tenascin C (TNC), which affords a scaffold for VSMC migration. Correspondingly, the phenotypic modulation of VSMC to a more synthetic phenotype, reflected by morphological change, loss of α-smooth muscle cell actin and upregulation of vascular cell adhesion molecule (VCAM) -1 was also suppressed in FLAP KO mice. Transplantation of FLAP replete myeloid cells rescued the proliferative response to vascular injury. Conclusion Expression of lesional FLAP in myeloid cells promotes LTB4 dependent VSMC phenotypic modulation, intimal migration and proliferation. PMID:23250985

  20. In vitro inhibition of 5-lipoxygenase by protolichesterinic acid from Cetraria islandica.

    PubMed

    Ingolfsdottir, K; Breu, W; Huneck, S; Gudjonsdottir, G A; Müller-Jakic, B; Wagner, H

    1994-12-01

    The aliphatic α-methylene-γ-lactone (+)-protolichesterinic acid (1), isolated from Cetraria islandica, has been shown to exhibit inhibitory effects on the enzyme 5-lipoxygenase in an in vitro assay in which porcine leucocytes are used as a source of the enzyme system. The isomeric compounds (+)-lichesterinic acid (2) and (-)-lichesterinic acid (4), prepared from (+)-protolichesterinic- and (-)-allo-protolichesterinic acids, respectively, exhibited anti-5-lipoxygenase activity of the same order of magnitude. (+)-Methyl lichesterinate (3) was, however, inactive. It was shown that despite its lipophilic nature, protolichesterinic acid is extractable into an aqueous medium, the concentration being dependent on the length of extraction. PMID:23195937

  1. 5-lipoxygenase pathway is essential for the control of granuloma extension induced by Schistosoma mansoni eggs in lung.

    PubMed

    Toffoli da Silva, Gabriel; Espíndola, Milena Sobral; Fontanari, Caroline; Rosada, Rogerio Silva; Faccioli, Lúcia Helena; Ramos, Simone Gusmão; Rodrigues, Vanderlei; Frantz, Fabiani Gai

    2016-08-01

    According to WHO, it is estimated that approximately 2 billion people are infected with intestinal helminths worldwide and the number of people who are cured of these diseases is relatively low, resulting in a large percentage of chronically infected individuals. Schistosomiasis is one of the most important parasitic diseases present in developing countries configuring it as a serious public health problem, directly related to poverty and social disadvantage. Once the parasite infection is established, Schistosoma mansoni eggs fall into the bloodstream and are trapped in the liver microcirculation where a strong granulomatous response and fibrosis formation occurs. In the experimental model, granulomas develop in the mouse lung after intravenous injection of purified eggs. Here we aim to understand how leukotrienes are involved in the granuloma formation. Leukotrienes are lipid mediators derived from arachidonic acid metabolites via 5-lipoxygenase (5LO) enzyme. They are potent proinflammatory agents and induce recruitment, cell activation, regulation of microbicidal activity of polymorphonuclear and mononuclear cells. In this study, 5LO deficient mice (5LO(-/-)) were inoculated with S. mansoni eggs for evaluation of immunopathological parameters involved in the induction of type 2 granulomas. We showed that in the absence of leukotrienes, the size of granulomas were decreased comparing to the wild type mice and the inflammatory compromised areas had a lower extension. In 5LO(-/-) mice granulomas presented extensive areas of fibrosis, detected by α-SMA expression along the lesions, indicating remodeling in attempt to reestablish the normal tissue. Also, comparing to WT mice we detected decrease of IL-4 and IL-13 and increase of TGF-β in the lung of 5LO(-/-), but these mice failed to produce protective IFN-γ and IL-12. These results evidenced 5-Lipoxygenase as an important pathway during lung injury due to Schistosoma-eggs injection. PMID:27262746

  2. Arachidonate 5-lipoxygenase gene variants affect response to fish oil supplementation by healthy African Americans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: To determine the effects of arachidonate 5-lipoxygenase gene (ALOX5) variants on plasma lipid and lipoprotein concentrations and changes in response to fish oil supplementation. We hypothesized that Sp1 variants in the ALOX5 promoter, which have previously been associated with cardiovascu...

  3. Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma.

    PubMed Central

    Nasser, S. M.; Bell, G. S.; Foster, S.; Spruce, K. E.; MacMillan, R.; Williams, A. J.; Lee, T. H.; Arm, J. P.

    1994-01-01

    BACKGROUND--The cysteinyl leukotrienes may play a central part in the mechanisms of aspirin-sensitive asthma. Previous work has shown that individuals with aspirin-sensitive asthma have high basal urinary LTE4 levels which increase further upon aspirin ingestion, and that sulphidopeptide leukotriene receptor antagonists attenuate aspirin-induced airflow obstruction. If the cysteinyl leukotrienes cause aspirin-induced asthmatic reactions, inhibition of the 5-lipoxygenase pathway should prevent aspirin-induced bronchospasm. This hypothesis has been tested with ZD2138, a specific non-redox 5-lipoxygenase inhibitor. METHODS--Seven subjects (four men) with aspirin-sensitive asthma with baseline FEV1 values > 67% were studied. ZD2138 (350 mg) or placebo was given on two separate occasions two weeks apart in a randomised double blind fashion. A single dose of aspirin was administered four hours after dosing and FEV1 was measured for six hours. Inhibition of the 5-lipoxygenase pathway by ZD2138 was assessed by measurements of urinary LTE4 levels and ex vivo calcium ionophore stimulated LTB4 generation in whole blood, before administration of drug or placebo and at regular time intervals after dosing and aspirin administration. RESULTS--ZD2138 protected against the aspirin-induced reduction in FEV1 with a 20.3 (4.9)% fall in FEV1 following placebo compared with 4.9 (2.9)% following ZD2138. This was associated with 72% inhibition of ex vivo LTB4 generation in whole blood at 12 hours and a 74% inhibition of the rise in urinary LTE4 excretion at six hours after aspirin ingestion. CONCLUSIONS--In aspirin-sensitive asthma the 5-lipoxygenase inhibitor ZD2138 inhibits the fall in FEV1 induced by aspirin and this is associated with substantial inhibition of 5-lipoxygenase. PMID:8091318

  4. A dual inhibitor of cyclooxygenase and 5-lipoxygenase protects against kainic acid-induced brain injury.

    PubMed

    Minutoli, Letteria; Marini, Herbert; Rinaldi, Mariagrazia; Bitto, Alessandra; Irrera, Natasha; Pizzino, Gabriele; Pallio, Giovanni; Calò, Margherita; Adamo, Elena Bianca; Trichilo, Vincenzo; Interdonato, Monica; Galfo, Federica; Squadrito, Francesco; Altavilla, Domenica

    2015-06-01

    Systemic administration of kainic acid causes inflammation and apoptosis in the brain, resulting in neuronal loss. Dual cyclooxygenase/5-lipoxygenase (COX/5-LOX) inhibitors could represent a possible neuroprotective approach in preventing glutamate excitotoxicity. Consequently, we investigated the effects of a dual inhibitor of COX/5-LOX following intraperitoneal administration of kainic acid (KA, 10 mg/kg) in rats. Animals were randomized to receive either the dual inhibitor of COX/5-LOX (flavocoxid, 20 mg/kg i.p.) or its vehicle (1 ml/kg i.p.) 30 min after KA administration. Sham brain injury rats were used as controls. We evaluated protein expression of phosphorylated extracellular signal-regulated kinase (p-ERK1/2) and tumor necrosis factor alpha (TNF-α) as well as levels of malondialdehyde (MDA), prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the hippocampus. Animals were also observed for monitoring behavioral changes according to Racine Scale. Finally, histological analysis and brain edema evaluation were carried out. Treatment with the dual inhibitor of COX/5-LOX decreased protein expression of p-ERK1/2 and TNF-α in hippocampus, markedly reduced MDA, LTB4 and PGE2 hippocampal levels, and also ameliorated brain edema. Histological analysis showed a reduction in cell damage in rats treated with the dual inhibitor of COX/5-LOX, particularly in hippocampal subregion CA3c. Moreover, flavocoxid significantly improved behavioral signs following kainic acid administration. Our results suggest that dual inhibition of COX/5-LOX by flavocoxid has neuroprotective effects during kainic acid-induced excitotoxicity. PMID:25893744

  5. Impact of simultaneous stimulation of 5-lipoxygenase and myeloperoxidase in human neutrophils.

    PubMed

    Zschaler, Josefin; Arnhold, Jürgen

    2016-04-01

    Human neutrophil 5-lipoxygenase (5-LOX) oxidizes arachidonic acid (AA) to 5S-hydro(pero)xy-6E,8Z,11Z, 14Z-eicosatetraenoic acid (5-H(p)ETE) and leukotriene (LT)A4, which is further converted to the chemoattractant LTB4. These cells contain also the heme enzyme myeloperoxidase (MPO) producing several potent oxidants such as hypochlorous acid (HOCl). Previously, it was shown that MPO-metabolites influence 5-LOX product formation. Here, we addressed the question, whether a simultaneous activation of MPO and 5-LOX in neutrophils results in comparable changes of 5-LOX activity. Human neutrophils were stimulated with H2O2 or phorbol 12-myristate 13-acetate (PMA) for MPO activation and subsequently treated with calcium ionophore A23187 inducing 5-LOX product formation on endogenous AA. Special attention was drawn to neutrophil vitality, formation of MPO-derived metabolites and redox status. The pre-stimulation with H2O2 resulted in a concentration-dependent increase in the ratio of 5-HETE to the sum of LTB4+6-trans-LTB4 in consequence of MPO activation. Thereby no impairment of cell vitality and only a slightly reduction of total glutathione level was observed. An influence of MPO on 5-LOX product formation could be suggested using an MPO inhibitor. In contrast, the pre-stimulation with PMA resulted in different changes of 5-LOX product formation leading to a reduced amount of 5-HETE unaffected by MPO inhibition. Furthermore, impaired cell vitality and diminished redox status was detected after PMA stimulation. Nevertheless, a MPO-induced diminution of LTB4 was obvious. Further work is necessary to define the type of 5-LOX modification and investigate the effect of physiological MPO activators. PMID:27033421

  6. Expression, purification and crystallization of human 5-lipoxygenase-activating protein with leukotriene-biosynthesis inhibitors

    SciTech Connect

    Xu, Shihua; McKeever, Brian M.; Wisniewski, Douglas; Miller, Douglas K.; Spencer, Robert H.; Chu, Lin; Ujjainwalla, Feroze; Yamin, Ting-Ting; Evans, Jilly F.; Becker, Joseph W.; Ferguson, Andrew D.

    2007-12-01

    The expression, purification and crystallization of human 5-lipoxygenase-activating protein in complex with two leukotriene-biosynthesis inhibitors is decribed. The processes that were used to generate diffraction quality crystals are presented in detail. The nuclear membrane protein 5-lipoxygenase-activating protein (FLAP) plays an essential role in leukotriene synthesis. Recombinant full-length human FLAP with a C-terminal hexahistidine tag has been expressed and purified from the cytoplasmic membrane of Escherichia coli. Diffraction-quality crystals of FLAP in complex with leukotriene-synthesis inhibitor MK-591 and with an iodinated analogue of MK-591 have been grown using the sitting-drop vapor-diffusion method. The crystals exhibit tetragonal symmetry (P42{sub 1}2) and diffracted to a resolution limit of 4 Å.

  7. Regulation of rotenone-induced microglial activation by 5-lipoxygenase and cysteinyl leukotriene receptor 1.

    PubMed

    Zhang, Xiao-Yan; Chen, Lu; Yang, Yi; Xu, Dong-Min; Zhang, Si-Ran; Li, Chen-Tan; Zheng, Wei; Yu, Shu-Ying; Wei, Er-Qing; Zhang, Li-Hui

    2014-07-14

    The 5-lipoxygenase (5-LOX) products cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators. CysLTs mediate their biological actions through activating CysLT receptors (CysLT(1)R and CysLT(2)R). We have recently reported that 5-LOX and CysLT(1)R mediated PC12 cell injury induced by high concentrations of rotenone (0.3-10 μM), which was reduced by the selective 5-LOX inhibitor zileuton and CysLT(1)R antagonist montelukast. The purpose of this study was to examine the regulatory roles of the 5-LOX/CysLT(1)R pathway in microglial activation induced by low concentration rotenone. After mouse microglial BV2 cells were stimulated with rotenone (0.3-3 nM), phagocytosis and release of pro-inflammatory cytokine were assayed as indicators of microglial activation. We found that rotenone (1 and 3 nM) increased BV2 microglial phagocytosis and the release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Zileuton and montelukast prevented rotenone (3 nM)-induced phagocytosis and cytokine release. Furthermore, rotenone significantly up-regulated 5-LOX expression, induced 5-LOX translocation to the nuclear envelope, and increased the production of CysLTs. These responses were inhibited by zileuton. Rotenone also increased CysLT(1)R expression and induced nuclear translocation of CysLT(1)R. In primary rat microglia, rotenone (10 nM) increased release of IL-1β and TNF-α, whereas zileuton (0.1 μΜ) and montelukast (0.01 μΜ) significantly inhibited this response. These results indicated that 5-LOX and CysLT(1)R might be key regulators of microglial activation induced by low concentration of rotenone. Interference of 5-LOX/CysLT(1)R pathway may be an effective therapeutic strategy for microglial inflammation. PMID:24858057

  8. Increased activity of 5-lipoxygenase in polymorphonuclear leukocytes from asthmatic patients

    SciTech Connect

    Mita, H.; Yui, Y.; Taniguchi, N.; Yasueda, H.; Shida, T.

    1985-09-09

    The formation of 5-lipoxygenase products of arachidonic acid, 5-HETE and 5,12-diHETE, was determined in 100,000 x g supernatant of polymorphonuclear leukocytes from 17 healthy subjects, 17 patients with extrinsic asthma and 15 patients with intrinsic asthma. After the supernatant was incubated with /sup 14/C-arachidonic acid in the presence of calcium and indomethacin, the lipoxygenase products of arachidonic acid were separated by thin layer chromatography. The results were expressed as the percentage conversion of /sup 14/C-arachidonic acid into the product per 10/sup 7/ cells. The formation of 5,12-diHETE, but not of the 5-HETE, was significantly increased in the cells from the group of patients with extrinsic asthma (4.38 +/- 0.78%, mean +/- S.E.; p < 0.01) and intrinsic asthma (6.09 +/- 1.11%; p < 0.01), when compared to normal subjects (1.74 +/- 0.30%). Both extrinsic and intrinsic asthmatics had significantly enhanced 5-lipoxygenase activity, which was expressed as the sum of percentage conversion of /sup 14/C-arachidonic acid into 5-HETE and 5,12-diHETE. The percentage conversion in normal subjects was 4.19 +/- 0.39%, 6.24 +/- 0.84% for 17 patients with extrinsic asthma (p < 0.05), and 8.59 +/- 1.29% for 15 patients with intrinsic asthma (p < 0.01). There was no significant difference between these asthmatic groups. These results indicate that 5-lipoxygenase activity is increased in patients with bronchial asthma. 22 references, 3 figures.

  9. Failure of the inhibition of rat gastric mucosal 5-lipoxygenase by novel acetohydroxamic acids to prevent ethanol-induced damage.

    PubMed

    Boughton-Smith, N K; Whittle, B J

    1988-09-01

    1. The role of leukotriene B4 (LTB4) and LTC4 as mediators of gastric mucosal damage following ethanol challenge in vivo has been investigated using two selective 5-lipoxygenase inhibitors, BW A4C and BW A137C. 2. Oral administration of ethanol to rats in vivo, induced macroscopic damage to the gastric mucosa and markedly increased the formation of the 5-lipoxygenase products, LTB4 and LTC4, from the mucosa ex vivo. 3. Pretreatment with the acetohydroxamic acids BW A4C and BW A137C (5-50 mg kg-1 p.o.) dose-dependently reduced ethanol-stimulated LTB4 and LTC4 formation by the gastric mucosa, with an ID50 of approximately 5 mg kg-1 p.o. 4. A single oral dose of BW A4C (20 mg kg-1) induced near-maximal inhibition of mucosal LTB4 formation within 30 min, which was well maintained for 5 h, whereas BW A137C (20 mg kg-1 p.o.) induced maximal inhibition between 30 and 60 min after administration, which then diminished over the subsequent 5 h. 5. The mucosal formation of the cyclo-oxygenase product, 6-keto-prostaglandin F1 alpha, which was unaltered following ethanol challenge, was not inhibited by the acetohydroxamic acids. Likewise, the small increase in mucosal thromboxane B2 formation following challenge was not inhibited by BW A4C. 6. Neither BW A4C nor BW A137C, at doses that almost completely inhibited the mucosal synthesis of LTB4 or LTC4, reduced the macroscopic gastric mucosal damage induced by ethanol. 7. Pretreatment with the lipoxygenase inhibitor BW 755C (5-50 mg kg-1 p.o.) did reduce mucosal damage, but there was a dissociation between the degree of protection and the inhibition of leukotriene biosynthesis. 8. Oral administration of high doses of either BW A4C or BW A137C (300mgkg-1) did not induce macroscopic gastric damage over a 3 h period. 9. These findings suggest that the leukotrienes, LTB4 and LTC4 are not the primary mediators of ethanol-induced acute mucosal damage, but do not exclude their role in more chronic gastric damage and inflammation. PMID

  10. Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment.

    PubMed

    Poczobutt, Joanna M; Nguyen, Teresa T; Hanson, Dwight; Li, Howard; Sippel, Trisha R; Weiser-Evans, Mary C M; Gijon, Miguel; Murphy, Robert C; Nemenoff, Raphael A

    2016-01-15

    Eicosanoids, including PGs, produced by cyclooxygenases (COX), and leukotrienes, produced by 5-lipoxygenase (5-LO) have been implicated in cancer progression. These molecules are produced by both cancer cells and the tumor microenvironment (TME). We previously reported that both COX and 5-LO metabolites increase during progression in an orthotopic immunocompetent model of lung cancer. Although PGs in the TME have been well studied, less is known regarding 5-LO products produced by the TME. We examined the role of 5-LO in the TME using a model in which Lewis lung carcinoma cells are directly implanted into the lungs of syngeneic WT mice or mice globally deficient in 5-LO (5-LO-KO). Unexpectedly, primary tumor volume and liver metastases were increased in 5-LO-KO mice. This was associated with an ablation of leukotriene (LT) production, consistent with production mainly mediated by the microenvironment. Increased tumor progression was partially reproduced in global LTC4 synthase KO or mice transplanted with LTA4 hydrolase-deficient bone marrow. Tumor-bearing lungs of 5-LO-KO had decreased numbers of CD4 and CD8 T cells compared with WT controls, as well as fewer dendritic cells. This was associated with lower levels of CCL20 and CXL9, which have been implicated in dendritic and T cell recruitment. Depletion of CD8 cells increased tumor growth and eliminated the differences between WT and 5-LO mice. These data reveal an antitumorigenic role for 5-LO products in the microenvironment during lung cancer progression through regulation of T cells and suggest that caution should be used in targeting this pathway in lung cancer. PMID:26663781

  11. Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment

    PubMed Central

    Poczobutt, Joanna M.; Nguyen, Teresa T.; Hanson, Dwight; Li, Howard; Sippel, Trisha R.; Weiser-Evans, Mary C. M.; Gijon, Miguel; Murphy, Robert C.

    2016-01-01

    Eicosanoids, including PGs, produced by cyclooxygenases (COX), and leukotrienes, produced by 5-lipoxygenase (5-LO) have been implicated in cancer progression. These molecules are produced by both cancer cells and the tumor microenvironment (TME). We previously reported that both COX and 5-LO metabolites increase during progression in an orthotopic immunocompetent model of lung cancer. Although PGs in the TME have been well studied, less is known regarding 5-LO products produced by the TME. We examined the role of 5-LO in the TME using a model in which Lewis lung carcinoma cells are directly implanted into the lungs of syngeneic WT mice or mice globally deficient in 5-LO (5-LO-KO). Unexpectedly, primary tumor volume and liver metastases were increased in 5-LO-KO mice. This was associated with an ablation of leukotriene (LT) production, consistent with production mainly mediated by the microenvironment. Increased tumor progression was partially reproduced in global LTC4 synthase KO or mice transplanted with LTA4 hydrolase-deficient bone marrow. Tumor-bearing lungs of 5-LO-KO had decreased numbers of CD4 and CD8 T cells compared with WT controls, as well as fewer dendritic cells. This was associated with lower levels of CCL20 and CXL9, which have been implicated in dendritic and T cell recruitment. Depletion of CD8 cells increased tumor growth and eliminated the differences between WT and 5-LO mice. These data reveal an antitumorigenic role for 5-LO products in the microenvironment during lung cancer progression through regulation of T cells and suggest that caution should be used in targeting this pathway in lung cancer. PMID:26663781

  12. 5-Lipoxygenase and cyclooxygenase-1 inhibitory active compounds from Atractylodes lancea.

    PubMed

    Resch, M; Steigel, A; Chen, Z L; Bauer, R

    1998-03-01

    Lipophilic extracts of Atractylodes lancea rhizomes exhibited potent inhibitory activities in 5-lipoxygenase [IC50 (5-LOX) = 2.9 micrograms/mL (n-hexane extract)] and cyclooxygenase-1 [IC50 (COX-1) = 30.5 micrograms/mL (n-hexane extract)] enzymatic assays. Bioactivity-guided fractionation of the n-hexane extract led to the isolation of a new compound atractylochromene (1), a potent inhibitor in both test systems [IC50 (5-LOX) = 0.6 microM, IC50 (COX-1) = 3.3 microM]. Also obtained was 2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2,5-cyclohexadiene-1 ,4-dione (2), which showed a selective inhibitory activity against 5-LOX [IC50 (5-LOX) 0.2 microM, IC50 (COX-1) 64.3 microM]. The sesquiterpene atractylon (3) and the coumarin osthol (4) turned out to be moderate but selective 5-lipoxygenase inhibitors. Atractylenolides I (5), II (6), and III (7) showed no significant inhibitory effects for either enzyme. Structures were established by spectral data interpretation. PMID:9544564

  13. Effect of a 5-lipoxygenase (5-LO)/cyclooxygenase (CO) inhibitor, WY-47, 288, on cutaneous models of inflammation.

    PubMed

    Carlson, R P; O'Neill-Davis, L; Calhoun, W; Datko, L; Musser, J H; Kreft, A F; Chang, J Y

    1989-03-01

    WY-47,288 (2-[(1-naphthalenyloxy)methyl]quinoline) demonstrated topical antiinflammatory activity in several animal models of skin inflammation. Application of WY-47,288 to mouse ear surfaces inhibited arachidonic acid (ED50 = 0.3 mg/ear) and tetradecanoylphorbol acetate (TPA)-induced inflammation (40% at 1 mg/ear). Administration of WY-47,288 (1 mg/ear) at 30 min and 5 h after TPA reduced ear edema and epidermal proliferation by 50%. WY-47,288 also inhibited oxazolone-induced contact hypersensitivity in mouse ears (ED50 = 0.4 mg/ear) and UVB-induced guinea pig skin erythema (ED50 approximately 0.25 mg/spot). These antiinflammatory effects may be due to inhibition of 5-lipoxygenase (5-LO) and cyclooxygenase (CO) since the synthesis of 5-LO and CO products by rat neutrophils and mouse macrophages was dose-dependently reduced by WY-47,288. By contrast, WY-47,288 demonstrated no appreciable inhibition of 12-LO (rabbit platelet), 15-LO (soybean) or phospholipase A2 (human platelet). Furthermore, no systemic adverse effects were observed after topical, parenteral or oral administration of WY-47,288, suggesting that WY-47,288 is a safe topical 5-LO/CO inhibitor for treating skin inflammation. PMID:2500009

  14. Zileuton, 5-Lipoxygenase Inhibitor, Acts as a Chemopreventive Agent in Intestinal Polyposis, by Modulating Polyp and Systemic Inflammation

    PubMed Central

    Heiferman, Jeffrey R.; Shrivastav, Manisha; Vitello, Dominic; Blatner, Nichole R.; Knab, Lawrence M.; Phillips, Joseph D.; Cheon, Eric C.; Grippo, Paul J.; Khazaie, Khashayarsha; Munshi, Hidayatullah G.; Bentrem, David J.

    2015-01-01

    Purpose Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD) have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO), the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice. Experimental Design In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation. Results Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4), product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice. Conclusions This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer. PMID:25747113

  15. The 5-lipoxygenase pathway: oxidative and inflammatory contributions to the Alzheimer’s disease phenotype

    PubMed Central

    Joshi, Yash B.; Praticò, Domenico

    2015-01-01

    Alzheimer’s disease (AD) is the most common, and, arguably, one of the most-well studied, neurodegenerative conditions. Several decades of investigation have revealed that amyloid-β and tau proteins are critical pathological players in this condition. Genetic analyses have revealed specific mutations in the cellular machinery that produces amyloid-β, but these mutations are found in only a small fraction of patients with the early-onset variant of AD. In addition to development of amyloid-β and tau pathology, oxidative damage and inflammation are consistently found in the brains of these patients. The 5-lipoxygenase protein enzyme (5LO) and its downstream leukotriene metabolites have long been known to be important modulators of oxidation and inflammation in other disease states. Recent in vivo evidence using murine knock-out models has implicated the 5LO pathway, which also requires the 5LO activating protein (FLAP), in the molecular pathology of AD, including the metabolism of amyloid-β and tau. In this manuscript, we will provide an overview of 5LO and FLAP, discussing their involvement in biochemical pathways relevant to AD pathogenesis. We will also discuss how the 5LO pathway contributes to the molecular and behavioral insults seen in AD and provide an assessment of how targeting these proteins could lead to therapeutics relevant not only for AD, but also other related neurodegenerative conditions. PMID:25642165

  16. Arachidonate 5-lipoxygenase (ALOX5) gene polymorphism is associated with Alzheimer's disease and body mass index.

    PubMed

    Šerý, Omar; Hlinecká, Lýdia; Povová, Jana; Bonczek, Ondřej; Zeman, Tomáš; Janout, Vladimír; Ambroz, Petr; Khan, Naim A; Balcar, Vladimir J

    2016-03-15

    Dementias of old age, in particular Alzheimer's disease (AD), pose a growing threat to the longevity and quality of life of individuals as well as whole societies world-wide. The risk factors are both genetic and environmental (life-style) and there is an overlap with similar factors predisposing to cardiovascular diseases (CVD). Using a case-control genetic approach, we have identified a SNP (rs10507391) in ALOX5 gene, previously associated with an increased risk of stroke, as a novel genetic risk factor for AD. ALOX5 gene encodes a 5'-lipoxygenase (5'-LO) activating protein (FLAP), a crucial component of the arachidonic acid/leukotriene inflammatory cascade. A-allele of rs4769874 polymorphism increases the risk of AD 1.41-fold (p<0.0001), while AA genotype does so 1.79-fold (p<0.0001). In addition, GG genotype of rs4769874 polymorphism is associated with a modest increase in body mass index (BMI). We discuss potential biochemical mechanisms linking the SNP to AD and suggest possible preventive pharmacotherapies some of which are based on commonly available natural products. Finally, we set the newly identified AD risk factors into a broader context of similar CVD risk factors to generate a more comprehensive picture of interacting genetics and life-style habits potentially leading to the deteriorating mental health in the old age. PMID:26944113

  17. Synthesis and Evaluation of 5-Lipoxygenase Translocation Inhibitors from Acylnitroso Hetero-Diels-Alder Cycloadducts†

    PubMed Central

    Bolger, Joshua K.; Tian, Wen; Wolter, William R.; Cho, Wonhwa; Suckow, Mark A.

    2012-01-01

    Acylnitroso cycloadducts have proven to be valuable intermediates in the syntheses of a plethora of biologically active molecules. Recently, organometallic reagents were shown to open bicyclic acylnitroso cycloadducts and, more interestingly, the prospect of highly regioselective openings was raised. This transformation was employed in the synthesis of a compound with excellent inhibitory activity against 5-lipoxygenase ((±)-4a, IC50 51 nM), an important mediator of inflammation intimately involved in a number of disease states including asthma and cancer. Optimization of the copper-mediated organometallic ring opening reaction was accomplished allowing the further exploration of the biological activity. Synthesis of a number of derivatives with varying affinity for metal binding as well as pendant groups in a range of sizes was accomplished. Analogues were tested in a whole cell assay which revealed a subset of the compounds to be inhibitors of enzyme translocation, a mode of action not previously known and, potentially, extremely important for better understanding of the enzyme and inhibitor development. Additionally, the lead compound was tested in vivo in an established colon cancer model and showed very encouraging anti-tumorogenic properties. PMID:21365098

  18. Penta- and hexadienoic acid derivatives: a novel series of 5-lipoxygenase inhibitors.

    PubMed

    Malleron, J L; Roussel, G; Gueremy, G; Ponsinet, G; Robin, J L; Terlain, B; Tissieres, J M

    1990-10-01

    The synthesis of a series of pentadienoic and hexadienoic acid derivatives is reported. These compounds were tested as inhibitors of 5-lipoxygenase (5 LO) and cyclooxygenase (CO) in vitro and as inhibitors of arachidonic acid (AA) induced ear edema in mice in vivo. Their potency is compared with that of the standard inhibitors nafazatrom, BW 755C, NDGA, KME4, quercetine, and L 652,243. The most potent compound in vivo, diethyl 2-hydroxy-5-(ethylthio)-2(Z),4(Z)-hexadienedioate (20) inhibited AA-induced ear edema when administered topically or orally, with an ED50 value of 0.01 mg/ear and 20 mg/kg, respectively. Among the standard compounds tested, L 652,243 was the most active compound in this test with an ED50 value of 0.01 mg/ear and 1 mg/kg po, but unlike this compound, 20 is a selective inhibitor of 5-LO (IC50 = 2 microM) without any significant activity against CO (IC50 greater than 50 microM). Most of the other compounds in this series are also selective 5-LO inhibitors. PMID:2213827

  19. Impact of Wines and Wine Constituents on Cyclooxygenase-1, Cyclooxygenase-2, and 5-Lipoxygenase Catalytic Activity

    PubMed Central

    Temml, Veronika; Maghradze, David; Vanek, Tomas

    2014-01-01

    Cyclooxygenases and lipoxygenases are proinflammatory enzymes; the former affects platelet aggregation, vasoconstriction, vasodilatation and later the development of atherosclerosis. Red wines from Georgia and central and western Europe inhibited cyclooxygenase-1 (COX-1) activity in the range of 63–94%, cyclooxygenase-2 (COX-2) activity in the range of 20–44% (tested at a concentration of 5 mL/L), and 5-lipoxygenase (5-LOX) activity in the range of 72–84% (at a concentration of 18.87 mL/L). White wines inhibited 5-LOX in the range of 41–68% at a concentration of 18.87 mL/L and did not inhibit COX-1 and COX-2. Piceatannol (IC50 = 0.76 μM) was identified as a strong inhibitor of 5-LOX followed by luteolin (IC50 = 2.25 μM), quercetin (IC50 = 3.29 μM), and myricetin (IC50 = 4.02 μM). trans-Resveratrol was identified as an inhibitor of COX-1 (IC50 = 2.27 μM) and COX-2 (IC50 = 3.40 μM). Red wine as a complex mixture is a powerful inhibitor of COX-1, COX-2, and 5-LOX, the enzymes involved in eicosanoid biosynthetic pathway. PMID:24976682

  20. Acrolein increases 5-lipoxygenase expression in murine macrophages through activation of ERK pathway

    SciTech Connect

    Kim, Chae E.; Lee, Seung J.; Seo, Kyo W.; Park, Hye M.; Yun, Jung W.; Bae, Jin U.; Bae, Sun S.; Kim, Chi D.

    2010-05-15

    Episodic exposure to acrolein-rich pollutants has been linked to acute myocardial infarction, and 5-lipoxygenase (5-LO) is involved in the production of matrix metalloproteinase-9 (MMP-9), which destabilizes atherosclerotic plaques. Thus, the present study determined the effect of acrolein on 5-LO/leukotriene B{sub 4} (LTB{sub 4}) production in murine macrophages. Stimulation of J774A.1 cells with acrolein led to increased LTB{sub 4} production in association with increased 5-LO expression. Acrolein-evoked 5-LO expression was blocked by pharmacological inhibition of the ERK pathway, but not by inhibitors for JNK and p38 MAPK pathways. In line with these results, acrolein exclusively increased the phosphorylation of ERK among these MAPK, suggesting a role for the ERK pathway in acrolein-induced 5-LO expression with subsequent production of LTB{sub 4}. Among the receptor tyrosine kinases including epidermal growth factor receptor (EGFR) and platelet derived growth factor receptor (PDGFR), acrolein-evoked ERK phosphorylation was attenuated by AG1478, an EGFR inhibitor, but not by AG1295, a PDGFR inhibitor. In addition, acrolein-evoked 5-LO expression was also inhibited by inhibition of EGFR pathway, but not by inhibition of PDGFR pathway. These observations suggest that acrolein has a profound effect on the 5-LO pathway via an EGFR-mediated activation of ERK pathway, leading to acute ischemic syndromes through the generation of LTB{sub 4}, subsequent MMP-9 production and plaque rupture.

  1. 5-Lipoxygenase/cyclooxygenase-2 cross-talk through cysteinyl leukotriene receptor 2 in endothelial cells.

    PubMed

    Lötzer, Katharina; Jahn, Steffen; Kramer, Cornelia; Hildner, Markus; Nüsing, Rolf; Funk, Colin D; Habenicht, Andreas J R

    2007-11-01

    The 5-lipoxygenase (5-LO) pathway generates lipid mediators, i.e. the cysteinyl leukotrienes (cysLTs) LTC(4)/LTD(4) and LTB(4). CysLT receptors are expressed in endothelial cells (EC) and EC cysLT(2)-R activation induces diverse pro-inflammatory genes in vitro. We now report that LTD(4) promotes formation of an atherosclerosis-protective and anti-thrombotic eicosanoid by markedly up-regulating EC cyclooxygenase-2 (COX-2). CysLT-induced COX-2 transcripts were transiently up-regulated as determined by microarray and QRT-PCR analyses though COX-2 protein remained elevated for several hours. Prostacyclin formation, measured as its stable metabolite 6-keto-PGF(1alpha), was increased several fold in LTD(4)-stimulated ECs, and was inhibited by the COX-2-specific inhibitor, NS-398. COX-2 up-regulation was Ca(2+)-dependent and was partially blocked by cyclosporin A indicating that the 5-LO/COX-2 cross-talk involved signaling through a nuclear factor of activated T cells (NFAT) dependent pathway. Since prostacyclin is a major blood vessel-protective and anti-thrombotic eicosanoid, the EC cysLT(2)-R may limit its otherwise pro-inflammatory actions through a protective Ca(2+)/calcineurin/NFAT-dependent COX-2 feedback loop. PMID:17991613

  2. Inhibitory effects of Angelica pubescens f. biserrata on 5-lipoxygenase and cyclooxygenase.

    PubMed

    Liu, J H; Zschocke, S; Reininger, E; Bauer, R

    1998-08-01

    Linoleic acid, osthol, osthenol and two polyacetylenes, falcarindiol and 11(S),16(R)-dihydroxyoctadeca-9Z,17-diene-12,14-diyn-1 -yl acetate were found to be the most active compounds responsible for the inhibitory activity of the dichloromethane extract of the roots of Angelica pubescens f. biserrata on 5-lipoxygenase (5-LO) and cyclooxygenase (COX-1) in vitro. They showed prominent inhibitory effect on 5-LO with IC50 values of 27.9 microM, 36.2 microM, 43.1 microM, 9.4 microM and 24.0 microM, respectively. Linoleic acid, osthenol, falcarindiol and 11(S), 16(R)-dihydroxyoctadeca-9Z,17-diene-12,14-diyn-1-yl acetate exhibited inhibitory activity on COX-1 with IC50 values of 13.3 microM, 64.3 microM, 66.0 microM and 73.3 microM. PMID:9741298

  3. Arachidonate 5 Lipoxygenase Expression in Papillary Thyroid Carcinoma Promotes Invasion via MMP-9 Induction

    PubMed Central

    Kummer, Nicolas T.; Nowicki, Theodore S; Azzi, Jean Paul; Reyes, Ismael; Iacob, Codrin; Xie, Suqing; Swati, Ismatun; Suslina, Nina; Schantz, Stimson; Tiwari, Raj K.; Geliebter, Jan

    2012-01-01

    Arachidonate 5-lipoxygenase (ALOX5) expression and activity has been implicated in tumor pathogenesis, yet its role in papillary thyroid carcinoma (PTC) has not been characterized. ALOX5 protein and mRNA were upregulated in PTC compared to matched, normal thyroid tissue, and ALOX5 expression correlated with invasive tumor histopathology. Evidence suggests that PTC invasion is mediated through the induction of matrix metalloproteinases (MMPs) that can degrade and remodel the extracellular matrix (ECM). A correlation between MMP-9 and ALOX5 protein expression was established by immunohistochemical analysis of PTC and normal thyroid tissues using a tissue array. Transfection of ALOX5 into a PTC cell line (BCPAP) increased MMP-9 secretion and cell invasion across an ECM barrier. The ALOX5 product, 5(S)-hydroxyeicosatetraenoic acid also increased MMP-9 protein expression by BCPAP in a dose-dependent manner. Inhibitors of MMP-9 and ALOX5 reversed ALOX5-enhanced invasion. Here we describe a new role for ALOX5 as a mediator of invasion via MMP-9 induction; this ALOX5/MMP9 pathway represents a new avenue in the search for functional biomarkers and/or potential therapeutic targets for aggressive PTC. PMID:22253131

  4. Structural and Functional Analysis of Calcium Ion Mediated Binding of 5-Lipoxygenase to Nanodiscs

    PubMed Central

    Kumar, Ramakrishnan B.; Zhu, Lin; Idborg, Helena; Rådmark, Olof; Jakobsson, Per-Johan; Rinaldo-Matthis, Agnes; Hebert, Hans; Jegerschöld, Caroline

    2016-01-01

    An important step in the production of inflammatory mediators of the leukotriene family is the Ca2+ mediated recruitment of 5 Lipoxygenase (5LO) to nuclear membranes. To study this reaction in vitro, the natural membrane mimicking environment of nanodiscs was used. Nanodiscs with 10.5 nm inner diameter were made with the lipid POPC and membrane scaffolding protein MSP1E3D1. Monomeric and dimeric 5LO were investigated. Monomeric 5LO mixed with Ca2+ and nanodiscs are shown to form stable complexes that 1) produce the expected leukotriene products from arachidonic acid and 2) can be, for the first time, visualised by native gel electrophoresis and negative stain transmission electron microscopy and 3) show a highest ratio of two 5LO per nanodisc. We interpret this as one 5LO on each side of the disc. The dimer of 5LO is visualised by negative stain transmission electron microscopy and is shown to not bind to nanodiscs. This study shows the advantages of nanodiscs to obtain basic structural information as well as functional information of a complex between a monotopic membrane protein and the membrane. PMID:27010627

  5. Synthesis and biological evaluation of novel pyrazolopyrimidines derivatives as anticancer and anti-5-lipoxygenase agents.

    PubMed

    Rahmouni, Ameur; Souiei, Sawssen; Belkacem, Mohamed Amine; Romdhane, Anis; Bouajila, Jalloul; Ben Jannet, Hichem

    2016-06-01

    A novel series of 6-aryl-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones 3a-h were synthesized in a single step via condensation of carboxamide 2 with some aromatic aldehydes (presence of iodine). Treatment of aminopyrazole 1a with acetic anhydride afforded pyrazolopyrimidines 4 which on treatment with ethyl chloroacetate in refluxing dry DMF furnished a single product identified as ethyl 2-(3,6-dimethyl-4-oxo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl) acetate 5. On the other hand, esterification of compound 6 with different alcohol, led to the formation of new esters linked pyrazolo[3,4-d]pyrimidinones hybrids 7a-f. The reaction of compound 2 with 3-propargyl bromide gave the compound 8 used as a dipolarophile to access to triazoles (4- and 5-regioisomers (9a-e) and (10a-e), respectively) via the 1,3-dipoar cycloaddition reaction. Finally, condensation reaction of aminopyrazole 1b with α-cyanocinnamonitiles gave the new pyrazolo[1,5-a]pyrimidine-3,6-dicarbonitriles 11a-e. Structures of compounds were established on the basis of (1)H/(13)C NMR and ESI-HRMS. Compounds were screened for their cytotoxic (HCT-116 and MCF-7) and 5-lipoxygenase inhibition activities. The structure-activity relationship (SAR) was discussed. PMID:27179178

  6. Pharmacophore modeling and virtual screening for designing potential 5-lipoxygenase inhibitors.

    PubMed

    Aparoy, P; Kumar Reddy, K; Kalangi, Suresh K; Chandramohan Reddy, T; Reddanna, P

    2010-02-01

    Inhibitors of the 5-Lipoxygenase (5-LOX) pathway have a therapeutic potential in a variety of inflammatory disorders such as asthma. In this study, chemical feature based pharmacophore models of inhibitors of 5-LOX have been developed with the aid of HipHop and HypoGen modules within Catalyst program package. The best quantitative pharmacophore model, Hypo1, which has the highest correlation coefficient (0.97), consists of two hydrogen-bond acceptors, one hydrophobic feature and one ring aromatic feature. Hypo1 was further validated by test set and cross validation method. The application of the model shows great success in predicting the activities of 65 known 5-LOX inhibitors in our test set with a correlation coefficient of 0.85 with a cross validation of 95% confidence level, proving that the model is reliable in identifying structurally diverse compounds for inhibitory activity against 5-LOX. Furthermore, Hypo1 was used as a 3D query for screening Maybridge and NCI databases within catalyst and also drug like compounds obtained from Enamine Ltd, which follow Lipinski's rule of five. The hit compounds were subsequently subjected to filtering by docking and visualization, to identify the potential lead molecules. Finally 5 potential lead compounds, identified in the above process, were evaluated for their inhibitory activities. These studies resulted in the identification of two compounds with potent inhibition of 5-LOX activity with IC(50) of 14 microM and 35 microM, respectively. These studies thus validate the pharmacophore model generated and suggest the usefulness of the model in screening of various small molecule libraries and identification of potential lead compounds for 5-LOX inhibition. PMID:20045317

  7. Minocycline protects PC12 cells against NMDA-induced injury via inhibiting 5-lipoxygenase activation.

    PubMed

    Song, Ying; Wei, Er-Qing; Zhang, Wei-Ping; Ge, Qiu-Fu; Liu, Jian-Ren; Wang, Meng-Ling; Huang, Xiao-Jia; Hu, Xin; Chen, Zhong

    2006-04-26

    Recently, we have reported that minocycline, a semi-synthetic tetracycline with neuroprotective effects, inhibits the in vitro ischemic-like injury and 5-lipoxygenase (5-LOX) activation in PC12 cells. In the present study, we further determined whether minocycline protects PC12 cells from excitotoxicity via inhibiting 5-LOX activation. We used N-methyl-d-aspartate (NMDA, 200 microM) to induce early (exposure for 6 h) and delayed (exposure for 6 h followed by 24 h recovery) injuries. We found that NMDA receptor antagonist ketamine, 5-LOX inhibitor caffeic acid and minocycline concentration dependently attenuated NMDA-induced early and delayed cell injuries (viability reduction and cell death). However, only ketamine (1 microM) inhibited NMDA-evoked elevation of intracellular calcium. In addition, immunohistochemical analysis showed that NMDA induced 5-LOX translocation to the nuclear membrane after 1- to 6-h exposure which was confirmed by Western blotting, indicating that 5-LOX was activated. Ketamine, caffeic acid and minocycline (each at 1 microM) inhibited 5-LOX translocation after early injury. After delayed injury, PC12 cells were shrunk, and 5-LOX was translocated to the nuclei and nuclear membrane; ketamine, caffeic acid and minocycline inhibited both cell shrinking and 5-LOX translocation. As a control, 12-LOX inhibitor baicalein showed a weak effect on cell viability and death, but no effect on 5-LOX translocation. Therefore, we conclude that the protective effect of minocycline on NMDA-induced injury is partly mediated by inhibiting 5-LOX activation. PMID:16574083

  8. Nutrigenetic association of the 5-lipoxygenase gene with myocardial infarction123

    PubMed Central

    Allayee, Hooman; Baylin, Ana; Hartiala, Jaana; Wijesuriya, Hemani; Mehrabian, Margarete; Lusis, Aldons J; Campos, Hannia

    2010-01-01

    Background 5-Lipoxygenase (5-LO) catalyzes the rate-limiting step of the biosynthesis of proinflammatory leukotrienes from arachidonic acid (AA) and has been associated with atherosclerosis in animal models and humans. We previously reported that variants of a 5-LO promoter repeat polymorphism were associated with carotid atherosclerosis in humans, an effect that was exacerbated by high dietary AA but mitigated by high dietary n–3 fatty acids. Objective We sought to confirm these initial observations with a more clinically relevant phenotype such as myocardial infarction (MI). Design The 5-LO polymorphism was genotyped in 1885 Costa Rican case-control pairs and tested for association with MI. Functional experiments were carried out to determine whether the associated alleles had differences in mRNA expression. Results The frequency of variant genotype groups did not differ significantly between cases and controls. However, a significant gene × diet interaction was observed, in which, relative to the common 5 repeat allele, the 3 and 4 alleles were associated with a higher MI risk in the high (≥0.25 g/d) dietary AA group (odds ratio: 1.31; 95% CI: 1.07, 1.61) and with a lower risk in the low (<0. 25 g/d)AA group (0.77; 0.63, 0.94) (P for interaction = 0.015). Using allele-specific quantitation, the short alleles had expression approximately twice that of the 5 allele (P < 0.0001). Conclusions The 3 and 4 variants lead to higher 5-LO expression and provide additional evidence that these alleles are associated with greater risks of atherosclerosis and MI in the context of a high-AA diet. PMID:18842779

  9. Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats.

    PubMed

    Jones, John E; Walker, Jennifer L; Song, Yanli; Weiss, Norbert; Cardoso, Wellington V; Tuder, Rubin M; Loscalzo, Joseph; Zhang, Ying-Yi

    2004-05-01

    5-Lipoxygenase (5-LO) and its downstream leukotriene products have been implicated in the development of pulmonary hypertension. In this study, we examined the effects of 5-LO overexpression in rat lungs on pulmonary hypertension using a recombinant adenovirus expressing 5-LO (Ad5-LO). Transthoracic echocardiography and right heart catheterization data showed that 5-LO overexpression in the lung did not cause pulmonary hypertension in normal rats; however, it markedly accelerated the progression of pulmonary hypertension in rats treated with monocrotaline (MCT). An increase in pulmonary artery pressure occurred earlier in the rats treated with MCT + Ad5-LO (7-10 days) compared with those treated with control vector, MCT + adenovirus expressing green fluorescent protein (AdGFP), or MCT alone (15-18 days). The weight ratio of the right ventricle to left ventricle plus septum was higher in the MCT + Ad5-LO group than that of the MCT + AdGFP or MCT group (0.45 +/- 0.08 vs. 0.35 +/- 0.03 or 0.33 +/- 0.06). Lung tissue histological sections from MCT + Ad5-LO rats exhibited more severe inflammatory cell infiltration and pulmonary vascular muscularization than those from MCT + AdGFP- or MCT-treated rats. Administration of 5-LO inhibitors, zileuton or MK-886, to either MCT- or MCT + Ad5-LO-treated rats prevented the development of pulmonary hypertension. These data suggest that 5-LO plays a critical role in the progression of pulmonary hypertension in rats and that the detrimental effect of 5-LO is manifest only in the setting of pulmonary vascular endothelial cell dysfunction. PMID:14726295

  10. Mesenteric lymph diversion abrogates 5-lipoxygenase activation in the kidney following trauma and hemorrhagic shock

    PubMed Central

    Stringham, John R.; Moore, Ernest E.; Gamboni, Fabia; Harr, Jeffrey N.; Fragoso, Miguel; Chin, Theresa L.; Carr, Caitlin E.; Silliman, Christopher C.; Banerjee, Anirban

    2014-01-01

    BACKGROUND Early acute kidney injury (AKI) following trauma is associated with multiorgan failure and mortality. Leukotrienes have been implicated both in AKI and in acute lung injury. Activated 5-lipoxygenase (5-LO) colocalizes with 5-LO–activating protein (FLAP) in the first step of leukotriene production following trauma and hemorrhagic shock (T/HS). Diversion of postshock mesenteric lymph, which is rich in the 5-LO substrate of arachidonate, attenuates lung injury and decreases 5-LO/FLAP associations in the lung after T/HS. We hypothesized that mesenteric lymph diversion (MLD) will also attenuate postshock 5-LO–mediated AKI. METHODS Rats underwent T/HS (laparotomy, hemorrhagic shock to a mean arterial pressure of 30 mm Hg for 45 minutes, and resuscitation), and MLD was accomplished via cannulation of the mesenteric duct. Extent of kidney injury was determined via histology score and verified by urinary neutrophil gelatinase-associated lipocalin assay. Kidney sections were immunostained for 5-LO and FLAP, and colocalization was determined by fluorescence resonance energy transfer signal intensity. The end leukotriene products of 5-LO were determined in urine. RESULTS AKI was evident in the T/HS group by derangement in kidney tubule architecture and confirmed by neutrophil gelatinase-associated lipocalin assay, whereas MLD during T/HS preserved renal tubule morphology at a sham level. MLD during T/HS decreased the associations between 5-LO and FLAP demonstrated by fluorescence resonance energy transfer microscopy and decreased leukotriene production in urine. CONCLUSION 5-LO and FLAP colocalize in the interstitium of the renal medulla following T/HS. MLD attenuates this phenomenon, which coincides with pathologic changes seen in tubules during kidney injury and biochemical evidence of AKI. These data suggest that gut-derived leukotriene substrate predisposes the kidney and the lung to subsequent injury. PMID:24747451

  11. Vanadium reduces mortality in phosphorus deficient chicks

    SciTech Connect

    Hill, C.H. )

    1991-03-15

    Since the vanadate anion is similar in structure to the phosphate ion, and since vanadate has been shown to interfere with phosphate metabolism both in vitro and in vivo, experiments were conducted to determine the effect of dietary vanadate (V) on chicks fed phosphorus (P) deficient diets. In these studies, broiler chicks of both sexes were fed the experimental diets from the day of hatching for 19 days. The diets were based on soybean meal and corn, supplemented with methionine, manganese, and vitamins to supply the chick's requirements. Calcium (Ca) and P levels were manipulated by use of feed grade dicalcium phosphate and limestone. V was added as ammonium metavanadate. Serum Ca and P were determined on representative chicks in each group. Increasing Ca levels increased serum Ca and decreased serum P. V increased serum P levels in the chicks receiving 0.2% P but not in those receiving 0.1% P.

  12. Modulation of LPS-induced memory insult, γ-secretase and neuroinflammation in 3xTg mice by 5-Lipoxygenase

    PubMed Central

    Joshi, Yash B.; Giannopoulos, Phillip F.; Chu, Jin; Praticò, Domenico

    2014-01-01

    Besides amyloid and tau pathology, a constant feature of Alzheimer’s disease (AD) is an intense inflammatory response, which is considered an active player in its pathogenesis. The 5-Lipoxygenase (5LO) is a proinflammatory enzyme and an endogenous modulator of AD-like phenotype in mouse models of the disease. To further understand the role of 5LO in AD pathogenesis, we exposed the 3xTg and 3xTg/5LO knockout mice to lipopolysaccharide (LPS), a known inducer of neuroinflammation, and evaluated its effect on their AD-like phenotype. 3xTg mice treated with LPS manifested a worsening of behavior, γ-secretase up-regulation, and increased neuroinflammatory responses. These effects were completely prevented in 3xTg mice genetically deficient for 5LO. By contrast, the absence of 5LO did not protect against increase in tau phosphorylation at specific epitopes that were mediated by the activation of the cyclin-dependent kinase 5. Our data demonstrate that the 5LO pathway affects key neuropathological features of the AD-like phenotype (behavior, Abeta, microgliosis, astrocytosis) but not others (tau pathology) in the LPS-dependent neuroinflammation model. The opposite ways whereby 5LO influences the LPS-dependent effects in vivo supports the complex nature of the neuroinflammatory response in AD and its differential role in modulating amyloid and tau neuropathology. PMID:24332986

  13. Impact of myeloperoxidase-derived oxidants on the product profile of human 5-lipoxygenase.

    PubMed

    Zschaler, Josefin; Dorow, Juliane; Schöpe, Louisa; Ceglarek, Uta; Arnhold, Jürgen

    2015-08-01

    Human 5-lipoxygenase (5-LOX) oxidizes arachidonic acid to 5S-hydroperoxy-6 E,8 Z,11 Z,14 Z-eicosatetraenoic acid (5-HpETE) and leukotriene (LT) A4. In neutrophils, LTA4 is further converted to the potent chemoattractant LTB4. These cells also contain the heme enzyme myeloperoxidase (MPO), which produces several potent oxidants such as hypochlorous acid (HOCl), which are involved in pathogen defense and immune regulation. Here, we addressed the question whether MPO-derived oxidants are able to affect the activity of 5-LOX and the product profile of this enzyme. Human 5-LOX was incubated with increasing amounts of HOCl or HOBr. Afterward, arachidonic acid metabolites of 5-LOX were analyzed by reverse-phase high-performance liquid chromatography as well as by liquid chromatography-electrospray ionization-tandem mass spectrometry. The incubation of 5-LOX with the MPO-derived oxidants significantly changed the product profile of 5-LOX. Thereby, HOCl and HOBr increased the ratio of 5-H(p)ETE to 6-trans-LTB4 in a concentration-dependent manner. At low oxidant concentrations, there was a strong decrease in the yield of 6-trans-LTB4, whereas 5-HpETE did not change or increased. Additionally, the formation of 8-HpETE and 12-HpETE by 5-LOX rose slightly with increasing HOCl and HOBr. Comparable results were obtained with the MPO-H2O2-Cl(-) system when glucose oxidase and glucose were applied as a source of H2O2. This was necessary because of a strong impairment of 5-LOX activity by H2O2. In summary, MPO-derived oxidants showed a considerable impact on 5-LOX, impairing the epoxidation of 5-HpETE, whereas the hydroperoxidation of arachidonic acid was unaffected. Apparently, this was caused by an oxidative modification of critical amino acid residues of 5-LOX. Further work is necessary to assess the specific type and position of oxidation in the substrate-binding cavity of 5-LOX and to specify whether this interaction between 5-LOX and MPO-derived oxidants also takes place in

  14. Association between arachidonate 5-lipoxygenase-activating protein (ALOX5AP) and lung function in a Korean population.

    PubMed

    Ro, M; Kim, S; Pyun, J-A; Shin, C; Cho, N H; Lee, J-Y; Koh, I; Kwack, K

    2012-08-01

    Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) plays a role in the 5-lipoxygenase (LO) pathway, which includes the LTC(4), LTD(4), LTE(4) and LTB(4). These leukotrienes are known causative factors of asthma, allergy, atopy and cardiovascular diseases. ALOX5AP lacks enzyme activity and acts by helping 5-LO function. In this study, healthy and general subjects who live in rural and urban areas of Korea were tested for the association of ALOX5AP polymorphisms with lung function. Lung function was also estimated by calculating the predicted values for forced expiratory volume in one second (FEV(1) _%PRED) and the proportion of the forced vital capacity exhaled in the first second (FEV(1) /FVC_PRED). The linear regression was adjusted for residence area, gender, age, height and smoking status. The analysis revealed associations between FEV(1) and the single-nucleotide polymorphism (SNP) rs9506352 and the haplotype TCAC (permuted P-value < 0.05). The linkage disequilibrium block that included the significant SNPs overlapped with SNPs that were revealed previously to associate with myocardial infarction and asthma and to affect lung function. This study is the first to demonstrate the association between lung function and ALOX5AP polymorphisms in a healthy and general population. PMID:22537113

  15. Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced Hamster Cheek Pouch Carcinogenesis by a 5-Lipoxygenase Inhibitor, Garcinol

    PubMed Central

    Shim, Joong-Youn; Sang, Shengmin; Sun, Zheng; Chen, Xiaoxin

    2013-01-01

    Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis, and can be targeted for cancer prevention. In order to develop potent topical agents for oral cancer chemoprevention, five known 5-Lox inhibitors from dietary and synthetic sources, Zileuton, ABT-761, Licofelone, Curcumin and Garcinol, were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis. PMID:23137051

  16. Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by a 5-lipoxygenase inhibitor, garcinol.

    PubMed

    Chen, Xin; Zhang, Xinyan; Lu, Ye; Shim, Joong-Youn; Sang, Shengmin; Sun, Zheng; Chen, Xiaoxin

    2012-01-01

    Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, licofelone, curcumin, and garcinol) were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis. PMID:23137051

  17. Synthesis, anti-inflammatory, analgesic, 5-lipoxygenase (5-LOX) inhibition activities, and molecular docking study of 7-substituted coumarin derivatives.

    PubMed

    Srivastava, Pavan; Vyas, Vivek K; Variya, Bhavesh; Patel, Palak; Qureshi, Gulamnizami; Ghate, Manjunath

    2016-08-01

    In the present study, 7-subsituted coumarin derivatives were synthesized using various aromatic and heterocyclic amines, and evaluated in vivo for anti-inflammatory and analgesic activity, and for ulcerogenic risk. The most active compounds were evaluated in vitro for 5-lipoxygenase (5-LOX) inhibition. Docking study was performed to predict the binding affinity, and orientation at the active site of the enzyme. In vivo anti-inflammatory and analgesic activity, and in vitro 5-LOX enzyme inhibition study revealed that compound 33 and 35 are the most potent compounds in all the screening methods. In vitro kinetic study of 35 showed mixed or non-competitive type of inhibition with 5-LOX enzyme. Presence of OCH3 group in 35 and Cl in 33 at C6-position of benzothiazole ring were found very important substitutions for potent activity. PMID:27376460

  18. Design, synthesis and evaluation of semi-synthetic triazole-containing caffeic acid analogues as 5-lipoxygenase inhibitors.

    PubMed

    De Lucia, Daniela; Lucio, Oscar Méndez; Musio, Biagia; Bender, Andreas; Listing, Monika; Dennhardt, Sophie; Koeberle, Andreas; Garscha, Ulrike; Rizzo, Roberta; Manfredini, Stefano; Werz, Oliver; Ley, Steven V

    2015-08-28

    In this work the synthesis, structure-activity relationship (SAR) and biological evaluation of a novel series of triazole-containing 5-lipoxygenase (5-LO) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent 5-LO inhibition with IC50 of 0.2 and 3.2 μm in cell-based and cell-free assays, respectively. Optimization of binding and functional potencies resulted in the identification of compound 13d, which showed an enhanced activity compared to the parent bioactive compound caffeic acid 5 and the clinically approved zileuton 3. Compounds 15 and 16 were identified as lead compounds in inhibiting 5-LO products formation in neutrophils. Their interference with other targets on the arachidonic acid pathway was also assessed. Cytotoxicity tests were performed to exclude a relationship between cytotoxicity and the increased activity observed after structure optimization. PMID:26197161

  19. Elucidation of the molecular mechanism and the efficacy in vivo of a novel 1,4-benzoquinone that inhibits 5-lipoxygenase

    PubMed Central

    Schaible, A M; Filosa, R; Temml, V; Krauth, V; Matteis, M; Peduto, A; Bruno, F; Luderer, S; Roviezzo, F; Di Mola, A; Rosa, M; D'Agostino, B; Weinigel, C; Barz, D; Koeberle, A; Pergola, C; Schuster, D; Werz, O

    2014-01-01

    Background and Purpose 1,4-Benzoquinones are well-known inhibitors of 5-lipoxygenase (5-LOX, the key enzyme in leukotriene biosynthesis), but the molecular mechanisms of 5-LOX inhibition are not completely understood. Here we investigated the molecular mode of action and the pharmacological profile of the novel 1,4-benzoquinone derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (RF-Id) in vitro and its effectiveness in vivo. Experimental Approach Mechanistic investigations in cell-free assays using 5-LOX and other enzymes associated with eicosanoid biosynthesis were conducted, along with cell-based studies in human leukocytes and whole blood. Molecular docking of RF-Id into the 5-LOX structure was performed to illustrate molecular interference with 5-LOX. The effectiveness of RF-Id in vivo was also evaluated in two murine models of inflammation. Key Results RF-Id consistently suppressed 5-LOX product synthesis in human leukocytes and human whole blood. RF-Id also blocked COX-2 activity but did not significantly inhibit COX-1, microsomal PGE2 synthase-1, cytosolic PLA2 or 12- and 15-LOX. Although RF-Id lacked radical scavenging activity, reducing conditions facilitated its inhibitory effect on 5-LOX whereas cell stress impaired its efficacy. The reduced hydroquinone form of RF-Id (RED-RF-Id) was a more potent inhibitor of 5-LOX as it had more bidirectional hydrogen bonds within the 5-LOX substrate binding site. Finally, RF-Id had marked anti-inflammatory effects in mice in vivo. Conclusions and Implications RF-Id represents a novel anti-inflammatory 1,4-benzoquinone that potently suppresses LT biosynthesis by direct inhibition of 5-LOX with effectiveness in vivo. Mechanistically, RF-Id inhibits 5-LOX in a non-redox manner by forming discrete molecular interactions within the active site of 5-LOX. PMID:24467325

  20. The novel benzimidazole derivative BRP-7 inhibits leukotriene biosynthesis in vitro and in vivo by targeting 5-lipoxygenase-activating protein (FLAP)

    PubMed Central

    Pergola, C; Gerstmeier, J; Mönch, B; Çalışkan, B; Luderer, S; Weinigel, C; Barz, D; Maczewsky, J; Pace, S; Rossi, A; Sautebin, L; Banoglu, E; Werz, O

    2014-01-01

    BACKGROUND AND PURPOSE Leukotrienes (LTs) are inflammatory mediators produced via the 5-lipoxygenase (5-LOX) pathway and are linked to diverse disorders, including asthma, allergic rhinitis and cardiovascular diseases. We recently identified the benzimidazole derivative BRP-7 as chemotype for anti-LT agents by virtual screening targeting 5-LOX-activating protein (FLAP). Here, we aimed to reveal the in vitro and in vivo pharmacology of BRP-7 as an inhibitor of LT biosynthesis. EXPERIMENTAL APPROACH We analysed LT formation and performed mechanistic studies in human neutrophils and monocytes, in human whole blood (HWB) and in cell-free assays. The effectiveness of BRP-7 in vivo was evaluated in rat carrageenan-induced pleurisy and mouse zymosan-induced peritonitis. KEY RESULTS BRP-7 potently suppressed LT formation in neutrophils and monocytes and this was accompanied by impaired 5-LOX co-localization with FLAP. Neither the cellular viability nor the activity of 5-LOX in cell-free assays was affected by BRP-7, indicating that a functional FLAP is needed for BRP-7 to inhibit LTs, and FLAP bound to BRP-7 linked to a solid matrix. Compared with the FLAP inhibitor MK-886, BRP-7 did not significantly inhibit COX-1 or microsomal prostaglandin E2 synthase-1, implying the selectivity of BRP-7 for FLAP. Finally, BRP-7 was effective in HWB and impaired inflammation in vivo, in rat pleurisy and mouse peritonitis, along with reducing LT levels. CONCLUSIONS AND IMPLICATIONS BRP-7 potently suppresses LT biosynthesis by interacting with FLAP and exhibits anti-inflammatory effectiveness in vivo, with promising potential for further development. PMID:24641614

  1. Conversion of human 5-lipoxygenase to a 15-lipoxygenase by a point mutation to mimic phosphorylation at Serine-663

    SciTech Connect

    Gilbert, Nathaniel C.; Rui, Zhe; Neau, David B.; Waight, Maria T.; Bartlett, Sue G.; Boeglin, William E.; Brash, Alan R.; Newcomer, Marcia E.

    2012-08-31

    The enzyme 5-lipoxygenase (5-LOX) initiates biosynthesis of the proinflammatory leukotriene lipid mediators and, together with 15-LOX, is also required for synthesis of the anti-inflammatory lipoxins. The catalytic activity of 5-LOX is regulated through multiple mechanisms, including Ca{sup 2+}-targeted membrane binding and phosphorylation at specific serine residues. To investigate the consequences of phosphorylation at S663, we mutated the residue to the phosphorylation mimic Asp, providing a homogenous preparation suitable for catalytic and structural studies. The S663D enzyme exhibits robust 15-LOX activity, as determined by spectrophotometric and HPLC analyses, with only traces of 5-LOX activity remaining; synthesis of the anti-inflammatory lipoxin A4 from arachidonic acid is also detected. The crystal structure of the S663D mutant in the absence and presence of arachidonic acid (in the context of the previously reported Stable-5-LOX) reveals substantial remodeling of helices that define the active site so that the once fully encapsulated catalytic machinery is solvent accessible. Our results suggest that phosphorylation of 5-LOX at S663 could not only down-regulate leukotriene synthesis but also stimulate lipoxin production in inflammatory cells that do not express 15-LOX, thus redirecting lipid mediator biosynthesis to the production of proresolving mediators of inflammation.

  2. Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy

    PubMed Central

    Hoobler, Eric K.; Rai, Ganesha; Warrilow, Andrew G. S.; Perry, Steven C.; Smyrniotis, Christopher J.; Jadhav, Ajit; Simeonov, Anton; Parker, Josie E.; Kelly, Diane E.; Maloney, David J.; Kelly, S. L.; Holman, Theodore R.

    2013-01-01

    We report the discovery of a novel dual inhibitor targeting fungal sterol 14α-demethylase (CYP51 or Erg11) and human 5-lipoxygenase (5-LOX) with improved potency against 5-LOX due to its reduction of the iron center by its phenylenediamine core. A series of potent 5-LOX inhibitors containing a phenylenediamine core, were synthesized that exhibit nanomolar potency and >30-fold selectivity against the LOX paralogs, platelet-type 12-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity against ovine cyclooxygenase-1 and human cyclooxygnease-2. The phenylenediamine core was then translated into the structure of ketoconazole, a highly effective anti-fungal medication for seborrheic dermatitis, to generate a novel compound, ketaminazole. Ketaminazole was found to be a potent dual inhibitor against human 5-LOX (IC50 = 700 nM) and CYP51 (IC50 = 43 nM) in vitro. It was tested in whole blood and found to down-regulate LTB4 synthesis, displaying 45% inhibition at 10 µM. In addition, ketaminazole selectively inhibited yeast CYP51 relative to human CYP51 by 17-fold, which is greater selectivity than that of ketoconazole and could confer a therapeutic advantage. This novel dual anti-fungal/anti-inflammatory inhibitor could potentially have therapeutic uses against fungal infections that have an anti-inflammatory component. PMID:23826084

  3. The 5-lipoxygenase inhibitor RF-22c potently suppresses leukotriene biosynthesis in cellulo and blocks bronchoconstriction and inflammation in vivo.

    PubMed

    Schaible, Anja M; Filosa, Rosanna; Krauth, Verena; Temml, Veronika; Pace, Simona; Garscha, Ulrike; Liening, Stefanie; Weinigel, Christina; Rummler, Silke; Schieferdecker, Sebastian; Nett, Markus; Peduto, Antonella; Collarile, Selene; Scuotto, Maria; Roviezzo, Fioretina; Spaziano, Giuseppe; de Rosa, Mario; Stuppner, Hermann; Schuster, Daniela; D'Agostino, Bruno; Werz, Oliver

    2016-07-15

    5-Lipoxygenase (5-LO) catalyzes the first two steps in leukotriene (LT) biosynthesis. Because LTs play pivotal roles in allergy and inflammation, 5-LO represents a valuable target for anti-inflammatory drugs. Here, we investigated the molecular mechanism, the pharmacological profile, and the in vivo effectiveness of the novel 1,2-benzoquinone-featured 5-LO inhibitor RF-22c. Compound RF-22c potently inhibited 5-LO product synthesis in neutrophils and monocytes (IC50⩾22nM) and in cell-free assays (IC50⩾140nM) without affecting 12/15-LOs, cyclooxygenase (COX)-1/2, or arachidonic acid release, in a specific and reversible manner, supported by molecular docking data. Antioxidant or iron-chelating properties were not evident for RF-22c and 5-LO-regulatory cofactors like Ca(2+) mobilization, ERK-1/2 activation, and 5-LO nuclear membrane translocation and interaction with 5-LO-activating protein (FLAP) were unaffected. RF-22c (0.1mg/kg; i.p.) impaired (I) bronchoconstriction in ovalbumin-sensitized mice challenged with acetylcholine, (II) exudate formation in carrageenan-induced paw edema, and (III) zymosan-induced leukocyte infiltration in air pouches. Taken together, RF-22c is a highly selective and potent 5-LO inhibitor in intact human leukocytes with pronounced effectiveness in different models of inflammation that warrants further preclinical analysis of this agent as anti-inflammatory drug. PMID:27157409

  4. Eugenol--the active principle from cloves inhibits 5-lipoxygenase activity and leukotriene-C4 in human PMNL cells.

    PubMed

    Raghavenra, H; Diwakr, B T; Lokesh, B R; Naidu, K A

    2006-01-01

    Polymorphonuclear leukocytes (PMNL) play an important role in the modulation of inflammatory conditions in humans. PMNL cells recruited at the site of inflammation, release inflammatory mediators such as leukotrienes, proteolytic enzymes and reactive oxygen species. Among these, leukotrienes are implicated in pathophysiology of allergic and inflammatory disorders like asthma, allergic rhinitis, arthritis, inflammatory bowel disease and psoriasis. 5-lipoxygenase (5-LO) is the key enzyme in biosynthetic pathway of leukotrienes. Our earlier studies showed that spice phenolic active principles significantly inhibit 5-LO enzyme in human PMNLs. In this study we have further characterized the inhibitory mechanism of eugenol, the active principle of spice-clove on 5-LO enzyme and also its effect on leukotriene C((4)) (LTC(4)). Substrate dependent enzyme kinetics showed that the inhibitory effect of eugenol on 5-LO was of a non-competitive nature. Further, eugenol was found to significantly inhibit the formation of LTC(4) in calcium ionophore A23187 and arachidonic acid (AA) stimulated PMNL cells. These data clearly suggest that eugenol inhibits 5-LO by non-competitive mechanism and also inhibits formation of LTC(4) in human PMNL cells and thus may have beneficial role in modulating 5-LO pathway in human PMNL cells. PMID:16216483

  5. Structural optimization and biological evaluation of 1,5-disubstituted pyrazole-3-carboxamines as potent inhibitors of human 5-lipoxygenase

    PubMed Central

    Zhou, Yu; Liu, Jun; Zheng, Mingyue; Zheng, Shuli; Jiang, Chunyi; Zhou, Xiaomei; Zhang, Dong; Zhao, Jihui; Ye, Deju; Zheng, Mingfang; Jiang, Hualiang; Liu, Dongxiang; Cheng, Jian; Liu, Hong

    2016-01-01

    Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1 µmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused-ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders. PMID:26904397

  6. A1 adenosine receptor deficiency or inhibition reduces atherosclerotic lesions in apolipoprotein E deficient mice

    PubMed Central

    Teng, Bunyen; Smith, Jonathan D.; Rosenfeld, Michael E.; Robinet, Peggy; Davis, Mary E.; Morrison, R. Ray; Mustafa, S. Jamal

    2014-01-01

    Aims The goal of this study was to determine whether the A1 adenosine receptor (AR) plays a role in atherosclerosis development and to explore its potential mechanisms. Methods and results Double knockout (DKO) mice, deficient in the genes encoding A1 AR and apolipoprotein E (apoE), demonstrated reduced atherosclerotic lesions in aortic arch (en face), aortic root, and innominate arteries when compared with apoE-deficient mice (APOE-KO) of the same age. Treating APOE-KO with an A1 AR antagonist (DPCPX) also led to a concentration-dependent reduction in lesions. The total plasma cholesterol and triglyceride levels were not different between DKO and APOE-KO; however, higher triglyceride was observed in DKO fed a high-fat diet. DKO also had higher body weights than APOE-KO. Plasma cytokine concentrations (IL-5, IL-6, and IL-13) were significantly lower in DKO. Proliferating cell nuclear antigen expression was also significantly reduced in the aorta from DKO. Despite smaller lesions in DKO, the composition of the innominate artery lesion and cholesterol loading and efflux from bone marrow-derived macrophages of DKO were not different from APOE-KO. Conclusion The A1 AR may play a role in the development of atherosclerosis, possibly due to its pro-inflammatory and mitogenic properties. PMID:24525840

  7. Regulation of tumorigenic Wnt signaling by cyclooxygenase-2, 5-lipoxygenase and their pharmacological inhibitors: A basis for novel drugs targeting cancer cells?

    PubMed

    Roos, Jessica; Grösch, Sabine; Werz, Oliver; Schröder, Peter; Ziegler, Slava; Fulda, Simone; Paulus, Patrick; Urbschat, Anja; Kühn, Benjamin; Maucher, Isabelle; Fettel, Jasmin; Vorup-Jensen, Thomas; Piesche, Matthias; Matrone, Carmela; Steinhilber, Dieter; Parnham, Michael J; Maier, Thorsten J

    2016-01-01

    Canonical Wnt signaling is a highly conserved pathway with a prominent role in embryogenic development, adult tissue homeostasis, cell polarization, stem cell biology, cell differentiation, and proliferation. Furthermore, canonical Wnt signaling is of pivotal importance in the pathogenesis of a number of cancer types and crucially affects tumor initiation, cancer cell proliferation, cancer cell apoptosis, and metastasis. Reports over the last decade have provided strong evidence for a pathophysiological role of Wnt signaling in non-malignant classical inflammatory and neurodegenerative diseases. Although, several agents suppressing the Wnt pathway at different levels have been identified, the development of clinically relevant Wnt-inhibiting agents remains challenging due to selectivity and toxicity issues. Several studies have shown that long-term administration of non-steroidal anti-inflammatory drugs protects against colon cancer and potentially other tumor types by interfering both with the COX and the Wnt pathway. Our own studies have shown that non-steroidal anti-inflammatory drugs suppress Wnt signaling by targeting the pro-inflammatory enzyme 5-lipoxygenase which is the key enzyme pathophysiologically involved in the synthesis of leukotrienes. Furthermore, we found a direct link between the 5-lipoxygenase and Wnt signaling pathways, which is essential for the maintenance of leukemic stem cells. Accordingly, genetic and pharmacological inhibition of 5-lipoxygenase led to an impairment of Wnt-dependent acute and chronic myeloid leukemic stem cells. We believe that 5-lipoxygenase inhibitors might represent a novel type of Wnt inhibitor activating a potentially naturally occurring novel mechanism of suppression of Wnt signaling that is non-toxic, at least in mice, and is potentially well tolerated in patients. PMID:26549540

  8. Suppression of Oxidative Stress and 5-Lipoxygenase Activation by Edaravone Improves Depressive-Like Behavior after Concussion

    PubMed Central

    Hoshijima, Michihiro; Yawata, Toshio; Nobumoto, Atsuya; Tsuda, Masayuki; Shimizu, Takahiro; Saito, Motoaki; Ueba, Tetuya

    2014-01-01

    Abstract Brain concussions are a serious public concern and are associated with neuropsychiatric disorders, such as depression. Patients with concussion who suffer from depression often experience distress. Nevertheless, few pre-clinical studies have examined concussion-induced depression, and there is little information regarding its pharmacological management. Edaravone, a free radical scavenger, can exert neuroprotective effects in several animal models of neurological disorders. However, the effectiveness of edaravone in animal models of concussion-induced depression remains unclear. In this study, we examined whether edaravone could prevent concussion-induced depression. Mice were subjected to a weight-drop injury and intravenously administered edaravone (3.0 mg/kg) or vehicle immediately after impact. Serial magnetic resonance imaging showed no abnormalities of the cerebrum on diffusion T1- and T2-weighted images. We found that edaravone suppressed concussion-induced depressive-like behavior in the forced swim test, which was accompanied by inhibition of increased hippocampal and cortical oxidative stress (OS) and suppression of 5-lipoxygenase (5-LOX) translocation to the nuclear envelope in hippocampal astrocytes. Hippocampal OS in concussed mice was also prevented by the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin, and administration of BWB70C, a 5-LOX inhibitor, immediately and 24 h after injury prevented depressive-like behaviors in concussed mice. Further, antidepressant effects of edaravone were observed in mice receiving 1.0 or 3.0 mg/kg of edaravone immediately after impact, but not at a lower dose of 0.1 mg/kg. This antidepressant effect persisted up to 1 h after impact, whereas edaravone treatment at 3 h after impact had no effect on concussion-induced depressive-like behavior. These results suggest that edaravone protects against concussion-induced depression, and this protection is mediated by suppression of

  9. Pharmacological characterization of SB 202235, a potent and selective 5-lipoxygenase inhibitor: effects in models of allergic asthma.

    PubMed

    Chabot-Fletcher, M C; Underwood, D C; Breton, J J; Adams, J L; Kagey-Sobotka, A; Griswold, D E; Marshall, L A; Sarau, H M; Winkler, J D; Hay, D W

    1995-06-01

    The peptidoleukotrienes and leukotriene B4, formed from arachidonic acid through the action of 5-lipoxygenase (5-LO), exert a spectrum of biological effects. It has been proposed that potent and selective 5-LO inhibitors will be effective therapy in diseases in which the peptidoleukotrienes and leukotriene B4 have been implicated, such as asthma and arthritis. The novel compound (S)-N-hydroxy-N-(2,3-dihydro-6-phenylmethoxy-3-benzyofuranyl )urea (SB 202235) was evaluated as a selective inhibitor of 5-LO in a cell-free system as well as in various cellular assays. In addition, the potential therapeutic value of SB 202235 was assessed in preclinical models of allergic asthma. The activity of the 5-LO enzyme isolated from rat basophilic leukemia-1 cells was inhibited by SB 202235 in a concentration-dependent manner with an IC50 value of 1.9 microM. Consistent with its ability to inhibit 5-LO, SB 202235 inhibited the production of leukotriene B4 by human monocytes and in human whole blood (IC50 values of 1.5 microM and 1.1 microM, respectively). The selectivity of SB 202235 was confirmed by its lack of effect against several other enzymes and receptors. SB 202235 potently and effectively inhibited the contraction produced by a single concentration of ovalbumin in guinea pig trachea (IC50 = 20 microM) and of anti-IgE in human bronchus (IC50 = 2 microM). SB 202235 (3-30 microM) also inhibited the contraction of guinea pig trachea in response to increasing concentration of ovalbumin. When administered orally (30 mg/kg) to conscious guinea pigs, SB 202235 attenuated antigen-induced broncho-constriction and the subsequent eosinophil influx.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7791085

  10. Active site characterization and structure based 3D-QSAR studies on non-redox type 5-lipoxygenase inhibitors.

    PubMed

    Ul-Haq, Zaheer; Khan, Naveed; Zafar, Syed Kashif; Moin, Syed Tarique

    2016-06-10

    Structure-based 3D-QSAR study was performed on a class of 5-benzylidene-2-phenylthiazolinones non-redox type 5-LOX inhibitors. In this study, binding pocket of 5-Lipoxygenase (pdb id 3o8y) was identified by manual docking using 15-LOX (pdb id 2p0m) as a reference structure. Additionally, most of the binding site residues were found conserved in both structures. These non-redox inhibitors were then docked into the binding site of 5-LOX. To generate reliable CoMFA and CoMSIA models, atom fit data base alignment method using docked conformation of the most active compound was employed. The q(2)cv and r(2)ncv values for CoMFA model were found to be 0.549 and 0.702, respectively. The q(2)cv and r(2)ncv values for the selected CoMSIA model comprised four descriptors steric, electrostatic, hydrophobic and hydrogen bond donor fields were found to be 0.535 and 0.951, respectively. Obtained results showed that our generated model was statistically reliable. Furthermore, an external test set validates the reliability of the predicted model by calculating r(2)pred i.e.0.787 and 0.571 for CoMFA and CoMSIA model, respectively. 3D contour maps generated from CoMFA and CoMSIA models were utilized to determine the key structural features of ligands responsible for biological activities. The applied protocol will be helpful to design more potent and selective inhibitors of 5-LOX. PMID:27044904

  11. Inhibition of 5-lipoxygenase triggers apoptosis in prostate cancer cells via down-regulation of protein kinase C-epsilon

    PubMed Central

    Sarveswaran, Sivalokanathan; Thamilselvan, Vijayalakshmi; Brodie, Chaya; Ghosh, Jagadananda

    2012-01-01

    Previous studies have shown that human prostate cancer cells constitutively generate 5-lipoxygenase (5-LOX) metabolites from arachidonic acid, and inhibition of 5-LOX blocks production of 5-LOX metabolites and triggers apoptosis in prostate cancer cells. This apoptosis is prevented by exogenous metabolites of 5-LOX, suggesting an essential role of 5-LOX metabolites in the survival of prostate cancer cells. However, downstream signaling mechanisms which mediate the survival-promoting effects of 5-LOX metabolites in prostate cancer cells are still unknown. Recently, we reported that MK591, a specific inhibitor of 5-LOX activity, induces apoptosis in prostate cancer cells without inhibition of Akt, or ERK, two well-characterized regulators of pro-survival mechanisms, suggesting the existence of an Akt and ERK-independent survival mechanism in prostate cancer cells regulated by 5-LOX. Here, we report that 5-LOX inhibition-induced apoptosis in prostate cancer cells occurs via rapid inactivation of protein kinase C-epsilon (PKCε), and that exogenous 5-LOX metabolites prevent both 5-LOX inhibition-induced down-regulation of PKCε and induction of apoptosis. Interestingly, pre-treatment of prostate cancer cells with diazoxide (a chemical activator of PKCε), or KAE1-1 (a cell-permeable, octa-peptide specific activator of PKCε) prevents 5-LOX inhibition-induced apoptosis, which indicates that inhibition of 5-LOX triggers apoptosis in prostate cancer cells via down-regulation of PKCε. Altogether, these findings suggest that metabolism of arachidonic acid by 5-LOX activity promotes survival of prostate cancer cells via signaling through PKCε, a pro-survival serine/threonine kinase. PMID:21824498

  12. Calcium Deficiency Reduces Circulating Levels of FGF23

    PubMed Central

    Rodriguez-Ortiz, María E.; Lopez, Ignacio; Muñoz-Castañeda, Juan R.; Martinez-Moreno, Julio M.; Ramírez, Alan Peralta; Pineda, Carmen; Canalejo, Antonio; Jaeger, Philippe; Aguilera-Tejero, Escolastico; Felsenfeld, Arnold; Almaden, Yolanda

    2012-01-01

    Fibroblast growth factor (FGF) 23 inhibits calcitriol production, which could exacerbate calcium deficiency or hypocalcemia unless calcium itself modulates FGF23 in this setting. In Wistar rats with normal renal function fed a diet low in both calcium and vitamin D, the resulting hypocalcemia was associated with low FGF23 despite high parathyroid hormone (PTH) and high calcitriol levels. FGF23 correlated positively with calcium and negatively with PTH. Addition of high dietary phosphorus to this diet increased FGF23 except in rats with hypocalcemia despite high PTH levels. In parathyroidectomized rats, an increase in dietary calcium for 10 days increased serum calcium, with an associated increase in FGF23, decrease in calcitriol, and no change in phosphorus. Also in parathyroidectomized rats, FGF23 increased significantly 6 hours after administration of calcium gluconate. Taken together, these results suggest that hypocalcemia reduces the circulating concentrations of FGF23. This decrease in FGF23 could be a response to avoid a subsequent reduction in calcitriol, which could exacerbate hypocalcemia. PMID:22581996

  13. Novel di-tertiary-butyl phenylhydrazones as dual cyclooxygenase-2/5-lipoxygenase inhibitors: synthesis, COX/LOX inhibition, molecular modeling, and insights into their cytotoxicities.

    PubMed

    Ghatak, Shibnath; Vyas, Alok; Misra, Suniti; O'Brien, Paul; Zambre, Ajit; Fresco, Victor M; Markwald, Roger R; Swamy, K Venkateshwara; Afrasiabi, Zahra; Choudhury, Amitava; Khetmalas, Madhukar; Padhye, Subhash

    2014-01-01

    Although dual inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) enzymes is highly effective than targeting COX or LOX alone, there are only a few reports of examining such compounds in case of colorectal cancers (CRC). In the present work we report that the novel di-tert-butyl phenol-based dual inhibitors DTPSAL, DTPBHZ, DTPINH, and DTPNHZ exhibit significant cytotoxicity against human CRC cell lines. Molecular docking studies revealed a good fit of these compounds in the COX-2 and 5-LOX protein cavities. The inhibitors show significant inhibition of COX-2 and 5-LOX activities and are effective against a panel of human colon cancer cell lines including HCA-7, HT-29, SW480 and intestinal Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressing colon cancer cells, through inhibition of the Hyaluronan/CD44v6 cell survival pathway. Western blot analysis and qRT-PCR analyses indicated that the di-tert-butyl phenol-based dual inhibitors reduce the expression of COX-2, 5-LOX, and CD44v6 in human colon cancer HCA-7 cells, while the combination of CD44v6shRNA and DTPSAL has an additional inhibitory effect on CD44v6 mRNA expression. The synergistic inhibitory effect of Celecoxib and Licofelone on CD44v6 mRNA expression suggests that the present dual inhibitors down-regulate cyclooxygenase and lipoxygenase enzymes through CD44v6. The compounds also exhibited enhanced antiproliferative potency compared to standard dual COX/LOX inhibitor, viz. Licofelone. Importantly, the HA/CD44v6 antagonist CD44v6shRNA in combination with synthetic compounds had a sensitizing effect on the cancer cells which enhanced their antiproliferative potency, a finding which is crucial for the anti-proliferative potency of the novel synthetic di-tert-butyl phenol based dual COX-LOX inhibitors in colon cancer cells. PMID:24295787

  14. Analysis of a nucleotide-binding site of 5-lipoxygenase by affinity labelling: binding characteristics and amino acid sequences.

    PubMed Central

    Zhang, Y Y; Hammarberg, T; Radmark, O; Samuelsson, B; Ng, C F; Funk, C D; Loscalzo, J

    2000-01-01

    5-Lipoxygenase (5LO) catalyses the first two steps in the biosynthesis of leukotrienes, which are inflammatory mediators derived from arachidonic acid. 5LO activity is stimulated by ATP; however, a consensus ATP-binding site or nucleotide-binding site has not been found in its protein sequence. In the present study, affinity and photoaffinity labelling of 5LO with 5'-p-fluorosulphonylbenzoyladenosine (FSBA) and 2-azido-ATP showed that 5LO bound to the ATP analogues quantitatively and specifically and that the incorporation of either analogue inhibited ATP stimulation of 5LO activity. The stoichiometry of the labelling was 1.4 mol of FSBA/mol of 5LO (of which ATP competed with 1 mol/mol) or 0.94 mol of 2-azido-ATP/mol of 5LO (of which ATP competed with 0.77 mol/mol). Labelling with FSBA prevented further labelling with 2-azido-ATP, indicating that the same binding site was occupied by both analogues. Other nucleotides (ADP, AMP, GTP, CTP and UTP) also competed with 2-azido-ATP labelling, suggesting that the site was a general nucleotide-binding site rather than a strict ATP-binding site. Ca(2+), which also stimulates 5LO activity, had no effect on the labelling of the nucleotide-binding site. Digestion with trypsin and peptide sequencing showed that two fragments of 5LO were labelled by 2-azido-ATP. These fragments correspond to residues 73-83 (KYWLNDDWYLK, in single-letter amino acid code) and 193-209 (FMHMFQSSWNDFADFEK) in the 5LO sequence. Trp-75 and Trp-201 in these peptides were modified by the labelling, suggesting that they were immediately adjacent to the C-2 position of the adenine ring of ATP. Given the stoichiometry of the labelling, the two peptide sequences of 5LO were probably near each other in the enzyme's tertiary structure, composing or surrounding the ATP-binding site of 5LO. PMID:11042125

  15. Flavocoxid, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, blunts pro-inflammatory phenotype activation in endotoxin-stimulated macrophages

    PubMed Central

    Altavilla, D; Squadrito, F; Bitto, A; Polito, F; Burnett, BP; Di Stefano, V; Minutoli, L

    2009-01-01

    Background and purpose: The flavonoids, baicalin and catechin, from Scutellaria baicalensis and Acacia catechu, respectively, have been used for various clinical applications. Flavocoxid is a mixed extract containing baicalin and catechin, and acts as a dual inhibitor of cyclooxygenase (COX) and 5-lipoxygenase (LOX) enzymes. The anti-inflammatory activity, measured by protein and gene expression of inflammatory markers, of flavocoxid in rat peritoneal macrophages stimulated with Salmonella enteritidis lipopolysaccharide (LPS) was investigated. Experimental approach: LPS-stimulated (1 µg·mL−1) peritoneal rat macrophages were co-incubated with different concentrations of flavocoxid (32–128 µg·mL−1) or RPMI medium for different incubation times. Inducible COX-2, 5-LOX, inducible nitric oxide synthase (iNOS) and inhibitory protein κB-α (IκB-α) levels were evaluated by Western blot analysis. Nuclear factor κB (NF-κB) binding activity was investigated by electrophoretic mobility shift assay. Tumour necrosis factor-α (TNF-α) gene and protein expression were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay respectively. Finally, malondialdehyde (MDA) and nitrite levels in macrophage supernatants were evaluated. Key results: LPS stimulation induced a pro-inflammatory phenotype in rat peritoneal macrophages. Flavocoxid (128 µg·mL−1) significantly inhibited COX-2 (LPS = 18 ± 2.1; flavocoxid = 3.8 ± 0.9 integrated intensity), 5-LOX (LPS = 20 ± 3.8; flavocoxid = 3.1 ± 0.8 integrated intensity) and iNOS expression (LPS = 15 ± 1.1; flavocoxid = 4.1 ± 0.4 integrated intensity), but did not modify COX-1 expression. PGE2 and LTB4 levels in culture supernatants were consequently decreased. Flavocoxid also prevented the loss of IκB-α protein (LPS = 1.9 ± 0.2; flavocoxid = 7.2 ± 1.6 integrated intensity), blunted increased NF-κB binding activity (LPS = 9.2 ± 2; flavocoxid = 2.4 ± 0.7 integrated intensity) and the

  16. Immobility reduces muscle fiber necrosis in dystrophin deficient muscular dystrophy.

    PubMed

    Kimura, S; Ikezawa, M; Nomura, K; Ito, K; Ozasa, S; Ueno, H; Yoshioka, K; Yano, S; Yamashita, T; Matuskura, M; Miike, T

    2006-08-01

    Duchenne/Becker muscular dystrophy is a progressive muscle disease, which is caused by the abnormality of dystrophin. Spina bifida is characterized by paralysis of the feet, with most of the upper extremities not being affected. We report here on the first case of Becker muscular dystrophy coinciding with spina bifida. The muscle biopsy specimens of the patient showed dystrophic changes in upper extremities, but clearly less in lower extremities. The results show that the restriction of excessive exercise is important for dystrophin deficiency disease. PMID:16516424

  17. Anti-proliferative effects of lichen-derived inhibitors of 5-lipoxygenase on malignant cell-lines and mitogen-stimulated lymphocytes.

    PubMed

    Ogmundsdóttir, H M; Zoëga, G M; Gissurarson, S R; Ingólfsdóttir, K

    1998-01-01

    Several lichen species have been used traditionally as medicinal plants. It has previously been shown that two low-molecular-weight lichen metabolites, lobaric acid isolated from Stereocaulon alpinum Laur. and protolichesterinic acid isolated from Cetraria islandica L. (Ach.), have in-vitro inhibitory effects on arachidonate 5-lipoxygenase. We have studied the effects of these compounds on cultured cells from man, including three malignant cell-lines (T-47D and ZR-75-1 from breast carcinomas and K-562 from erythro-leukaemia), as well as normal skin fibroblasts and peripheral blood lymphocytes. Both test substances caused a significant reduction in DNA synthesis, as measured by thymidine uptake, in all three malignant cell-lines; the dose inducing 50% of maximum inhibition (ED50) was between 1.1 and 24.6 microg mL(-1) for protolichesterinic acid and between 14.5 and 44.7 microg mL(-1) for lobaric acid. The breast-cancer cell-lines were more sensitive than K-562. The proliferative response of mitogen-stimulated lymphocytes was inhibited with a mean ED50 of 8.4 microg mL(-1) and 24.5 microg mL(-1) for protolichesterinic acid and lobaric acid, respectively. These concentrations are of the same order of magnitude as the IC50 values in the 5-lipoxygenase assay. Significant cell death (assessed by the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-( 4-sulfophenyl)-2H-tetrazolium) assay and trypan blue exclusion) occurred in the three malignant cell-lines at protolichesterinic acid and lobaric acid concentrations above 20 and 30 microg mL(-1), respectively. In K-562 morphological changes consistent with apoptosis were detected. Up to 38% cell death was observed at 20 microg mL(-1) for protolichesterinic acid and 15 microg mL(-1) for lobaric acid in mitogen-stimulated lymphocytes but unstimulated lymphocytes were clearly less sensitive. In contrast, the DNA synthesis, proliferation and survival of normal skin fibroblasts were not affected at doses up to 20

  18. 4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP).

    PubMed

    Banoglu, Erden; Çelikoğlu, Erşan; Völker, Susanna; Olgaç, Abdurrahman; Gerstmeier, Jana; Garscha, Ulrike; Çalışkan, Burcu; Schubert, Ulrich S; Carotti, Andrea; Macchiarulo, Antonio; Werz, Oliver

    2016-05-01

    In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives as LT biosynthesis inhibitors. Biological evaluation disclosed a new skeleton of potential anti-inflammatory agents, exemplified by 39 and 40, which potently inhibit cellular 5-LO product synthesis (IC50 = 0.24 μM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 ≥ 8 μM). Docking studies and molecular dynamic simulations with 5-LO and FLAP provide valuable insights into potential binding modes of the inhibitors. Together, these diaryl-isoxazol-3-carboxylic acids may possess potential as leads for development of effective anti-inflammatory drugs through inhibition of LT biosynthesis. PMID:26922224

  19. 5-Lipoxygenase is located in the euchromatin of the nucleus in resting human alveolar macrophages and translocates to the nuclear envelope upon cell activation.

    PubMed Central

    Woods, J W; Coffey, M J; Brock, T G; Singer, I I; Peters-Golden, M

    1995-01-01

    5-Lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) are two key proteins involved in the synthesis of leukotrienes (LT) from arachidonic acid. Although both alveolar macrophages (AM) and peripheral blood leukocytes (PBL) produce large amounts of LT after activation, 5-LO translocates from a soluble pool to a particulate fraction upon activation of PBL, but is contained in the particulate fraction in AM irrespective of activation. We have therefore examined the subcellular localization of 5-LO in autologous human AM and PBL collected from normal donors. While immunogold electron microscopy demonstrated little 5-LO in resting PBL, resting AM exhibited abundant 5-LO epitopes in the euchromatin region of the nucleus. The presence of substantial quantities of 5-LO in the nucleus of resting AM was verified by cell fractionation and immunoblot analysis and by indirect immunofluorescence microscopy. In both AM and PBL activated by A23187, all of the observable 5-LO immunogold labeling was found associated with the nuclear envelope. In resting cells of both types, FLAP was predominantly associated with the nuclear envelope, and its localization was not affected by activation with A23187. The effects of MK-886, which binds to FLAP, were examined in ionophore-stimulated AM and PBL. Although MK-886 inhibited LT synthesis in both cell types, it failed to prevent the translocation of 5-LO to the nuclear envelope. These results indicate that the nuclear envelope is the site at which 5-LO interacts with FLAP and arachidonic acid to catalyze LT synthesis in activated AM as well as PBL, and that in resting AM the euchromatin region of the nucleus is the predominant source of the translocated enzyme. In addition, LT synthesis is a two-step process consisting of FLAP-independent translocation of 5-LO to the nuclear envelope followed by the FLAP-dependent activation of the enzyme. Images PMID:7738170

  20. 5-lipoxygenase activation is involved in the mechanisms of chronic hepatic injury in a rat model of chronic aluminum overload exposure.

    PubMed

    Mai, Shaoshan; He, Qin; Wang, Hong; Hu, Xinyue; Luo, Ying; Yang, Yang; Kuang, Shengnan; Tian, Xiaoyan; Ma, Jie; Yang, Junqing

    2016-08-15

    We previously confirmed that rats overloaded with aluminum exhibited hepatic function damage and increased susceptibility to hepatic inflammation. However, the mechanism of liver toxicity by chronic aluminum overload is poorly understood. In this study, we investigated changes in the 5-lipoxygenase (5-LO) signaling pathway and its effect on liver injury in aluminum-overloaded rats. A rat hepatic injury model of chronic aluminum injury was established via the intragastric administration of aluminum gluconate (Al(3+) 200mg/kg per day, 5days a week for 20weeks). The 5-LO inhibitor, caffeic acid (10 and 30mg/kg), was intragastrically administered 1h after aluminum administration. Hematoxylin and eosin staining was used to visualize pathological changes in rat liver tissue. A series of biochemical indicators were measured with biochemistry assay or ELISAs. Immunochemistry and RT-PCR methods were used to detect 5-LO protein and mRNA expression in the liver, respectively. Caffeic acid administration protected livers against histopathological injury, decreased plasma ALT, AST, and ALP levels, decreased TNF-α, IL-6, IL-1β and LTs levels, increased the reactive oxygen species content, and down-regulated the mRNA and protein expressions of 5-LO in aluminum overloaded rats. Our results indicate that 5-lipoxygenase activation is mechanistically involved in chronic hepatic injury in a rat model of chronic aluminum overload exposure and that the 5-LO signaling pathway, which associated with inflammation and oxidative stress, is a potential therapeutic target for chronic non-infection liver diseases. PMID:27368151

  1. CCL5 deficiency reduces neointima formation following arterial injury and thrombosis in apolipoprotein E-deficient mice.

    PubMed

    Czepluch, Frauke S; Meier, Julia; Binder, Claudia; Hasenfuss, Gerd; Schäfer, Katrin

    2016-08-01

    Activated platelets secrete different chemokines, among others CCL5, thereby triggering inflammatory cell recruitment into the vessel wall. Here, we investigated how CCL5 deficiency influences vascular remodeling processes. Experiments were performed in apolipoprotein E and CCL5 double deficient (ApoE(-/-)×CCL5(-/-)) mice, using ApoE(-/-)×CCL5(+/+) mice as controls. The ferric chloride model was applied to induce thrombosis at the site of carotid artery injury within minutes and the formation of a smooth muscle cell-rich neointima within 3weeks. In both groups, vascular injury resulted in thrombus formation. CCL5 deficiency did not alter thrombus resolution examined at day 7. Analysis at 21days revealed that CCL5 absence was associated with a significant reduction in the neointima area (p<0.05), neointima-to-media ratio (p<0.05) and lumen stenosis (p<0.05) compared to ApoE(-/-)×CCL5(+/+) mice. Immunohistochemical analysis of CCL5 receptors showed decreased CCR5 positive staining in ApoE(-/-)×CCL5(-/-) mice (p<0.01), whereas the amount of CCR1 (p=0.053) and Mac2-positive macrophages (p<0.05) was increased. The amount of SMA-positive smooth muscle cells was lower in ApoE(-/-) mice lacking CCL5 (p<0.05). Positive staining for Krüppel-like factor 4 (KLF4), an atheroprotective transcription factor, was increased in the neointima of ApoE(-/-)×CCL5(-/-) mice (p<0.05) and found to co-localize with smooth muscle cells. In summary, CCL5 deficiency resulted in reduced neointima formation after carotid artery injury and thrombosis. Hemodynamic and histochemical analyses suggested that this was not due to differences in thrombus formation or resolution. Possibly, the atheroprotective effect of CCL5 deficiency is mediated by KLF4 upregulation in smooth muscle cells. PMID:27337700

  2. Intestinal Cgi-58 deficiency reduces postprandial lipid absorption.

    PubMed

    Xie, Ping; Guo, Feng; Ma, Yinyan; Zhu, Hongling; Wang, Freddy; Xue, Bingzhong; Shi, Hang; Yang, Jian; Yu, Liqing

    2014-01-01

    Comparative Gene Identification-58 (CGI-58), a lipid droplet (LD)-associated protein, promotes intracellular triglyceride (TG) hydrolysis in vitro. Mutations in human CGI-58 cause TG accumulation in numerous tissues including intestine. Enterocytes are thought not to store TG-rich LDs, but a fatty meal does induce temporary cytosolic accumulation of LDs. Accumulated LDs are eventually cleared out, implying existence of TG hydrolytic machinery in enterocytes. However, identities of proteins responsible for LD-TG hydrolysis remain unknown. Here we report that intestine-specific inactivation of CGI-58 in mice significantly reduces postprandial plasma TG concentrations and intestinal TG hydrolase activity, which is associated with a 4-fold increase in intestinal TG content and large cytosolic LD accumulation in absorptive enterocytes during the fasting state. Intestine-specific CGI-58 knockout mice also display mild yet significant decreases in intestinal fatty acid absorption and oxidation. Surprisingly, inactivation of CGI-58 in intestine significantly raises plasma and intestinal cholesterol, and reduces hepatic cholesterol, without altering intestinal cholesterol absorption and fecal neutral sterol excretion. In conclusion, intestinal CGI-58 is required for efficient postprandial lipoprotein-TG secretion and for maintaining hepatic and plasma lipid homeostasis. Our animal model will serve as a valuable tool to further define how intestinal fat metabolism influences the pathogenesis of metabolic disorders, such as obesity and type 2 diabetes. PMID:24618586

  3. PD-L1 Deficiency within Islets Reduces Allograft Survival in Mice

    PubMed Central

    Ma, Dongxia; Duan, Wu; Li, Yakun; Wang, Zhimin; Li, Shanglin; Gong, Nianqiao; Chen, Gang; Chen, Zhishui; Wan, Chidan; Yang, Jun

    2016-01-01

    Background Islet transplantation may potentially cure type 1 diabetes mellitus (T1DM). However, immune rejection, especially that induced by the alloreactive T-cell response, remains a restraining factor for the long-term survival of grafted islets. Programmed death ligand-1 (PD-L1) is a negative costimulatory molecule. PD-L1 deficiency within the donor heart accelerates allograft rejection. Here, we investigate whether PD-L1 deficiency in donor islets reduces allograft survival time. Methods Glucose Stimulation Assays were performed to evaluate whether PD-L1 deficiency has detrimental effects on islet function. Islets isolated from PDL1-deficient mice or wild- type (WT) mice (C57BL/6j) were implanted beneath the renal capsule of streptozotocin (STZ)-induced diabetic BALB/c mice. Blood glucose levels and graft survival time after transplantation were monitored. Moreover, we analyzed the residual islets, infiltrating immune cells and alloreactive cells from the recipients. Results PD-L1 deficiency within islets does not affect islet function. However, islet PD-L1 deficiency increased allograft rejection and was associated with enhanced inflammatory cell infiltration and recipient T-cell alloreactivity. Conclusions This is the first report to demonstrate that PD-L1 deficiency accelerated islet allograft rejection and regulated recipient alloimmune responses. PMID:26990974

  4. Impaired brain development and reduced cognitive function in phospholipase D-deficient mice.

    PubMed

    Burkhardt, Ute; Stegner, David; Hattingen, Elke; Beyer, Sandra; Nieswandt, Bernhard; Klein, Jochen

    2014-06-20

    The phospholipases D (PLD1 and 2) are signaling enzymes that catalyze the hydrolysis of phosphatidylcholine to phosphatidic acid, a lipid second messenger involved in cell proliferation, and choline, a precursor of acetylcholine (ACh). In the present study, we investigated development and cognitive function in mice that were deficient for PLD1, or PLD2, or both. We found that PLD-deficient mice had reduced brain growth at 14-27 days post partum when compared to wild-type mice. In adult PLD-deficient mice, cognitive function was impaired in social and object recognition tasks. Using brain microdialysis, we found that wild-type mice responded with a 4-fold increase of hippocampal ACh release upon behavioral stimulation in the open field, while PLD-deficient mice released significantly less ACh. These results may be relevant for cognitive dysfunctions observed in fetal alcohol syndrome and in Alzheimer' disease. PMID:24813107

  5. Computational insight into the catalytic implication of head/tail-first orientation of arachidonic acid in human 5-lipoxygenase: consequences for the positional specificity of oxygenation.

    PubMed

    Saura, Patricia; Maréchal, Jean-Didier; Masgrau, Laura; Lluch, José M; González-Lafont, Àngels

    2016-08-17

    In the present work we have combined homology modeling, protein-ligand dockings, quantum mechanics/molecular mechanics calculations and molecular dynamics simulations to generate human 5-lipoxygenase (5-LOX):arachidonic acid (AA) complexes consistent with the 5-lipoxygenating activity (which implies hydrogen abstraction at the C7 position). Our results suggest that both the holo and the apo forms of human Stable 5-LOX could accommodate AA in a productive form for 5-lipoxygenation. The former, in a tail-first orientation, with the AA carboxylate end interacting with Lys409, gives the desired structures with C7 close to the Fe-OH(-) cofactor and suitable barrier heights for H7 abstraction. Only when using the apo form structure, a head-first orientation with the AA carboxylate close to His600 (a residue recently proposed as essential for AA positioning) is obtained in the docking calculations. However, the calculated barrier heights for this head-first orientation are in principle consistent with 5-LOX specificity, but also with 12/8 regioselectivity. Finally, long MD simulations give support to the recent hypothesis that the Phe177 + Tyr181 pair needs to close the active site access during the chemical reaction, and suggest that in the case of a head-first orientation Phe177 may be the residue interacting with the AA carboxylate. PMID:27489112

  6. A Single Amino Acid Difference between Mouse and Human 5-Lipoxygenase Activating Protein (FLAP) Explains the Speciation and Differential Pharmacology of Novel FLAP Inhibitors.

    PubMed

    Blevitt, Jonathan M; Hack, Michael D; Herman, Krystal; Chang, Leon; Keith, John M; Mirzadegan, Tara; Rao, Navin L; Lebsack, Alec D; Milla, Marcos E

    2016-06-10

    5-Lipoxygenase activating protein (FLAP) plays a critical role in the metabolism of arachidonic acid to leukotriene A4, the precursor to the potent pro-inflammatory mediators leukotriene B4 and leukotriene C4 Studies with small molecule inhibitors of FLAP have led to the discovery of a drug binding pocket on the protein surface, and several pharmaceutical companies have developed compounds and performed clinical trials. Crystallographic studies and mutational analyses have contributed to a general understanding of compound binding modes. During our own efforts, we identified two unique chemical series. One series demonstrated strong inhibition of human FLAP but differential pharmacology across species and was completely inactive in assays with mouse or rat FLAP. The other series was active across rodent FLAP, as well as human and dog FLAP. Comparison of rodent and human FLAP amino acid sequences together with an analysis of a published crystal structure led to the identification of amino acid residue 24 in the floor of the putative binding pocket as a likely candidate for the observed speciation. On that basis, we tested compounds for binding to human G24A and mouse A24G FLAP mutant variants and compared the data to that generated for wild type human and mouse FLAP. These studies confirmed that a single amino acid mutation was sufficient to reverse the speciation observed in wild type FLAP. In addition, a PK/PD method was established in canines to enable preclinical profiling of mouse-inactive compounds. PMID:27129215

  7. ATP Allosterically Activates the Human 5-Lipoxygenase Molecular Mechanism of Arachidonic Acid and 5(S)-Hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic Acid

    PubMed Central

    2015-01-01

    5-Lipoxygenase (5-LOX) reacts with arachidonic acid (AA) to first generate 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid [5(S)-HpETE] and then an epoxide from 5(S)-HpETE to form leukotriene A4, from a single polyunsaturated fatty acid. This work investigates the kinetic mechanism of these two processes and the role of ATP in their activation. Specifically, it was determined that epoxidation of 5(S)-HpETE (dehydration of the hydroperoxide) has a rate of substrate capture (Vmax/Km) significantly lower than that of AA hydroperoxidation (oxidation of AA to form the hydroperoxide); however, hyperbolic kinetic parameters for ATP activation indicate a similar activation for AA and 5(S)-HpETE. Solvent isotope effect results for both hydroperoxidation and epoxidation indicate that a specific step in its molecular mechanism is changed, possibly because of a lowering of the dependence of the rate-limiting step on hydrogen atom abstraction and an increase in the dependency on hydrogen bond rearrangement. Therefore, changes in ATP concentration in the cell could affect the production of 5-LOX products, such as leukotrienes and lipoxins, and thus have wide implications for the regulation of cellular inflammation. PMID:24893149

  8. Further studies on ethyl 5-hydroxy-indole-3-carboxylate scaffold: design, synthesis and evaluation of 2-phenylthiomethyl-indole derivatives as efficient inhibitors of human 5-lipoxygenase.

    PubMed

    Peduto, Antonella; Bruno, Ferdinando; Dehm, Friedrike; Krauth, Verena; de Caprariis, Paolo; Weinigel, Christina; Barz, Dagmar; Massa, Antonio; De Rosa, Mario; Werz, Oliver; Filosa, Rosanna

    2014-06-23

    5-Lipoxygenase (5-LO), an enzyme that catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes, is an attractive drug target for the pharmacotherapy of inflammatory and allergic diseases. Here, we present the design, synthesis and biological evaluation of novel series of ethyl 5-hydroxyindole-3-carboxylate derivatives that efficiently inhibit human 5-LO. SAR analysis revealed that the potency of compounds is closely related to the positioning of the substituents at the phenylthiomethyl ring. The introduction of methyl or chlorine groups in ortho- and ortho/para-position of thiophenol represent the most favorable modifications. Among all tested compounds, ethyl 5-hydroxy-2-(mesitylthiomethyl)-1-methyl-1H-indole-3-carboxylate (19) is the most potent derivative which blocks 5-LO activity in cell-free assays with IC50 = 0.7 μM, and suppressed 5-LO product synthesis in polymorphonuclear leukocytes with IC50 = 0.23 μM. PMID:24871899

  9. An interleukin-33/ST2 signaling deficiency reduces overt pain-like behaviors in mice

    PubMed Central

    Magro, D.A.C.; Hohmann, M.S.N.; Mizokami, S.S.; Cunha, T.M.; Alves-Filho, J.C.; Casagrande, R.; Ferreira, S.H.; Liew, F.Y.; Cunha, F.Q.; Verri, W.A.

    2013-01-01

    Interleukin (IL)-33, the most recent member of the IL family of cytokines, signals through the ST2 receptor. IL-33/ST2 signaling mediates antigen challenge-induced mechanical hyperalgesia in the joints and cutaneous tissues of immunized mice. The present study asked whether IL-33/ST2 signaling is relevant to overt pain-like behaviors in mice. Acetic acid and phenyl-p-benzoquinone induced significant writhing responses in wild-type (WT) mice; this overt nociceptive behavior was reduced in ST2-deficient mice. In an antigen-challenge model, ST2-deficient immunized mice had reduced induced flinch and licking overt pain-like behaviors. In the formalin test, ST2-deficient mice also presented reduced flinch and licking responses, compared with WT mice. Naive WT and ST2-deficient mice presented similar responses in the rota-rod, hot plate, and electronic von Frey tests, indicating no impairment of motor function or alteration in basal nociceptive responses. The results demonstrate that IL-33/ST2 signaling is important in the development of overt pain-like behaviors. PMID:23903682

  10. The Dual Cyclooxygenase/5-Lipoxygenase Inhibitor Licofelone Attenuates P-Glycoprotein-Mediated Drug Resistance in the Injured Spinal Cord

    PubMed Central

    Dulin, Jennifer N.; Moore, Meredith L.

    2013-01-01

    Abstract There are currently no proven effective treatments that can improve recovery of function in spinal cord injury (SCI) patients. Many therapeutic compounds have shown promise in pre-clinical studies, but clinical trials have been largely unsuccessful. P-glycoprotein (Pgp, Abcb1b) is a drug efflux transporter of the blood–spinal cord barrier that limits spinal cord penetration of blood-borne xenobiotics. Pathological Pgp upregulation in diseases such as cancer causes heightened resistance to a broad variety of therapeutic drugs. Importantly, several drugs that have been evaluated for the treatment of SCI, such as riluzole, are known substrates of Pgp. We therefore examined whether Pgp-mediated pharmacoresistance diminishes delivery of riluzole to the injured spinal cord. Following moderate contusion injury at T10 in male Sprague–Dawley rats, we observed a progressive, spatial spread of increased Pgp expression from 3 days to 10 months post-SCI. Spinal cord uptake of i.p.-delivered riluzole was significantly reduced following SCI in wild type but not Abcb1a-knockout rats, highlighting a critical role for Pgp in mediating drug resistance following SCI. Because inflammation can drive Pgp upregulation, we evaluated the ability of the new generation dual anti-inflammatory drug licofelone to promote spinal cord delivery of riluzole following SCI. We found that licofelone both reduced Pgp expression and enhanced riluzole bioavailability within the lesion site at 72 h post-SCI. This work highlights Pgp-mediated drug resistance as an important obstacle to therapeutic drug delivery for SCI, and suggests licofelone as a novel combinatorial treatment strategy to enhance therapeutic drug delivery to the injured spinal cord. PMID:22947335

  11. The Medicinal Timber Canarium patentinervium Miq. (Burseraceae Kunth.) Is an Anti-Inflammatory Bioresource of Dual Inhibitors of Cyclooxygenase (COX) and 5-Lipoxygenase (5-LOX)

    PubMed Central

    Mogana, R.; Teng-Jin, K.; Wiart, C.

    2013-01-01

    The barks and leaves extracts of Canarium patentinervium Miq. (Burseraceae Kunth.) were investigated for cyclooxygenase (COX) and 5-lipoxygenase (LOX) inhibition via in vitro models. The corresponding antioxidative power of the plant extract was also tested via nonenzyme and enzyme in vitro assays. The ethanolic extract of leaves inhibited the enzymatic activity of 5-LOX, COX-1, and COX-2 with IC50 equal to 49.66 ± 0.02 μg/mL, 0.60 ± 0.01 μg/mL, and 1.07 ± 0.01 μg/mL, respectively, with selective COX-2 activity noted in ethanolic extract of barks with COX-1/COX-2 ratio of 1.22. The ethanol extract of barks confronted oxidation in the ABTS, DPPH, and FRAP assay with EC50 values equal to 0.93 ± 0.01 μg/mL, 2.33 ± 0.02 μg/mL, and 67.00 ± 0.32 μg/mL, respectively, while the ethanol extract of leaves confronted oxidation in β-carotene bleaching assay and superoxide dismutase (SOD) assay with EC50 value of 6.04 ± 0.02 μg/mL and IC50 value of 3.05 ± 0.01 μg/mL. The ethanol extract acts as a dual inhibitor of LOX and COX enzymes with potent antioxidant capacity. The clinical significance of these data is quite clear that they support a role for Canarium patentinervium Miq. (Burseraceae Kunth.) as a source of lead compounds in the management of inflammatory diseases. PMID:25937987

  12. Inhibition of soluble epoxide hydrolase enhances the anti-inflammatory effects of aspirin and 5-lipoxygenase activation protein inhibitor in a murine model.

    PubMed

    Liu, Jun-Yan; Yang, Jun; Inceoglu, Bora; Qiu, Hong; Ulu, Arzu; Hwang, Sung-Hee; Chiamvimonvat, Nipavan; Hammock, Bruce D

    2010-03-15

    Inflammation is a multi-staged process whose expansive phase is thought to be driven by acutely released arachidonic acid (AA) and its metabolites. Inhibition of cyclooxygenase (COX), lipoxygenase (LOX), or soluble epoxide hydrolase (sEH) is known to be anti-inflammatory. Inhibition of sEH stabilizes the cytochrome P450 (CYP450) products epoxyeicosatrienoic acids (EETs). Here we used a non-selective COX inhibitor aspirin, a 5-lipoxygenase activation protein (FLAP) inhibitor MK886, and a sEH inhibitor t-AUCB to selectively modulate the branches of AA metabolism in a lipopolysaccharide (LPS)-challenged murine model. We used metabolomic profiling to simultaneously monitor representative AA metabolites of each branch. In addition to the significant crosstalk among branches of the AA cascade during selective modulation of COX, LOX, or sEH, we demonstrated that co-administration of t-AUCB enhanced the anti-inflammatory effects of aspirin or MK886, which was evidenced by the observations that co-administration resulted in favorable eicosanoid profiles and better control of LPS-mediated hypotension as well as hepatic protein expression of COX-2 and 5-LOX. Targeted disruption of the sEH gene displayed a parallel profile to that produced by t-AUCB. These observations demonstrate a significant level of crosstalk among the three major branches of the AA cascade and that they are not simply parallel pathways. These data illustrate that inhibition of sEH by both pharmacological intervention and gene knockout enhances the anti-inflammatory effects of aspirin and MK886, suggesting the possibility of modulating multiple branches to achieve better therapeutic effects. PMID:19896470

  13. 4-Hydroxynonenal enhances MMP-9 production in murine macrophages via 5-lipoxygenase-mediated activation of ERK and p38 MAPK

    SciTech Connect

    Lee, Seung J.; Kim, Chae E.; Yun, Mi R.; Seo, Kyo W.; Park, Hye M.; Yun, Jung W.; Shin, Hwa K.; Bae, Sun S.; Kim, Chi D.

    2010-01-15

    Exaggerated levels of 4-hydroxynonenal (HNE) and 5-lipoxygenase (5-LO) co-exist in macrophages in atherosclerotic lesions, and activated macrophages produce MMP-9 that degrades atherosclerotic plaque constituents. This study investigated the effects of HNE on MMP-9 production, and the potential role for 5-LO derivatives in MMP-9 production in murine macrophages. Stimulation of J774A.1 cells with HNE led to activation of 5-LO, as measured by leukotriene B{sub 4} (LTB{sub 4}) production. This was associated with an increased production of MMP-9, which was blunted by inhibition of 5-LO with MK886, a 5-LO inhibitor or with 5-LO siRNA. A cysteinyl-LT{sub 1} (cysLT{sub 1}) receptor antagonist, REV-5901 as well as a BLT{sub 1} receptor antagonist, U-75302, also attenuated MMP-9 production induced by HNE. Furthermore, LTB{sub 4} and cysLT (LTC{sub 4} and LTD{sub 4}) enhanced MMP-9 production in macrophages, suggesting a pivotal role for 5-LO in HNE-mediated production of MMP-9. Among the MAPK pathways, LTB{sub 4} and cysLT enhanced phosphorylation of ERK and p38 MAPK, but not JNK. Linked to these results, a p38 MAPK inhibitor as well as an ERK inhibitor blunted MMP-9 production induced by LT. Collectively, these data suggest that 5-LO-derived LT mediates HNE-induced MMP-9 production via activation of ERK and p38 MAPK pathways, consequently leading to plaque instability in atherosclerosis.

  14. Ku86 deficiency leads to reduced intrachromosomal homologous recombination in vivo in mice.

    PubMed

    Reliene, Ramune; Bishop, Alexander J R; Li, Gloria; Schiestl, Robert H

    2004-02-01

    Ku70 and Ku86 together with DNA-PKcs form the DNA-dependent protein kinase (DNA-PK) complex that is involved in DNA double-strand break repair by nonhomologous end joining. We investigated the effect of Ku86 mutation on intrachromosomal homologous recombination (HR) resulting in deletions in vivo in mice. We quantified such deletion events using a phenotypic pigmentation assay. Deletion of one copy of a 70 kb DNA duplication in the pink-eyed unstable (pun) allele results in reversion to the wildtype pink-eyed dilution (p) gene, allowing black pigment accumulation in cells of the retinal pigment epithelium (RPE). We found that the frequency of homologous recombination was significantly reduced in Ku86 deficient mice. Furthermore, the proliferation of cells in which recombination events occurred was reduced and developmentally delayed in the Ku86 deficient mice. These data indicate a role for Ku86 directly or indirectly in homologous recombination in vivo. PMID:14706343

  15. Aquaporin-1 Deficiency Protects Against Myocardial Infarction by Reducing Both Edema and Apoptosis in Mice

    PubMed Central

    Li, Lihua; Weng, Zhiyong; Yao, Chenjuan; Song, Yuanlin; Ma, Tonghui

    2015-01-01

    Many studies have determined that AQP1 plays an important role in edema formation and resolution in various tissues via water transport across the cell membrane. The aim of this research was to determine both if and how AQP1 is associated with cardiac ischemic injury, particularly the development of edema following myocardial infarction (MI). AQP1+/+ and AQP1−/− mice were used to create the MI model. Under physiological conditions, AQP1−/− mice develop normally; however, in the setting of MI, they exhibit cardioprotective properties, as shown by reduced cardiac infarct size determined via NBT staining, improved cardiac function determined via left ventricular catheter measurements, decreased AQP1-dependent myocardial edema determined via water content assays, and decreased apoptosis determined via TUNEL analysis. Cardiac ischemia caused by hypoxia secondary to AQP1 deficiency stabilized the expression of HIF-1α in endothelial cells and subsequently decreased microvascular permeability, resulting in the development of edema. The AQP1-dependent myocardial edema and apoptosis contributed to the development of MI. AQP1 deficiency protected cardiac function from ischemic injury following MI. Furthermore, AQP1 deficiency reduced microvascular permeability via the stabilization of HIF-1α levels in endothelial cells and decreased cellular apoptosis following MI. PMID:26348407

  16. Aquaporin-1 Deficiency Protects Against Myocardial Infarction by Reducing Both Edema and Apoptosis in Mice.

    PubMed

    Li, Lihua; Weng, Zhiyong; Yao, Chenjuan; Song, Yuanlin; Ma, Tonghui

    2015-01-01

    Many studies have determined that AQP1 plays an important role in edema formation and resolution in various tissues via water transport across the cell membrane. The aim of this research was to determine both if and how AQP1 is associated with cardiac ischemic injury, particularly the development of edema following myocardial infarction (MI). AQP1+/+ and AQP1-/- mice were used to create the MI model. Under physiological conditions, AQP1-/- mice develop normally; however, in the setting of MI, they exhibit cardioprotective properties, as shown by reduced cardiac infarct size determined via NBT staining, improved cardiac function determined via left ventricular catheter measurements, decreased AQP1-dependent myocardial edema determined via water content assays, and decreased apoptosis determined via TUNEL analysis. Cardiac ischemia caused by hypoxia secondary to AQP1 deficiency stabilized the expression of HIF-1α in endothelial cells and subsequently decreased microvascular permeability, resulting in the development of edema. The AQP1-dependent myocardial edema and apoptosis contributed to the development of MI. AQP1 deficiency protected cardiac function from ischemic injury following MI. Furthermore, AQP1 deficiency reduced microvascular permeability via the stabilization of HIF-1α levels in endothelial cells and decreased cellular apoptosis following MI. PMID:26348407

  17. Cernunnos deficiency reduces thymocyte life span and alters the T cell repertoire in mice and humans.

    PubMed

    Vera, Gabriella; Rivera-Munoz, Paola; Abramowski, Vincent; Malivert, Laurent; Lim, Annick; Bole-Feysot, Christine; Martin, Christelle; Florkin, Benoit; Latour, Sylvain; Revy, Patrick; de Villartay, Jean-Pierre

    2013-02-01

    Cernunnos is a DNA repair factor of the nonhomologous end-joining machinery. Its deficiency in humans causes radiosensitive severe combined immune deficiency (SCID) with microcephaly, characterized in part by a profound lymphopenia. In contrast to the human condition, the immune system of Cernunnos knockout (KO) mice is not overwhelmingly affected. In particular, Cernunnos is dispensable during V(D)J recombination in lymphoid cells. Nevertheless, the viability of thymocytes is reduced in Cernunnos KO mice, owing to the chronic activation of a P53-dependent DNA damage response. This translates into a qualitative alteration of the T cell repertoire to one in which the most distal Vα and Jα segments are missing. This results in the contraction of discrete T cell populations, such as invariant natural killer T (iNKT) and mucosa-associated invariant T (MAIT) cells, in both humans and mice. PMID:23207905

  18. Reduced brain injury in CD18 deficient mice after experimental intracerebral hemorrhage

    PubMed Central

    Titova, Elena; Ostrowski, Robert P.; Kevil, Christopher G.; Tong, Weni; Rojas, Hugo; Sowers, Lawrence C.; Zhang, John H.; Tang, Jiping

    2008-01-01

    Many studies have indicated leukocytes as one of the major contributors to brain injuries caused by intracerebral hemorrhage (ICH). Leukocyte-expressed CD18 is important for neutrophil-endothelial interactions in the vasculature and CD18 deficiency protects against ischemia-reperfusion injury. We investigated whether CD18 deficiency provides protection against ICH-induced brain injury. Male wild type (WT) CD18+/+ mice and CD18−/− knockout mice were used in this study. ICH was induced by a collagenase injection. Mortality, neurological function, brain edema and myeloperoxidase (MPO) activity as well as tissue expression of nitrotyrosine and MPO were evaluated at 24 hours after ICH. We discovered a significantly reduced brain edema and diminished mortality with a concomitant decrease in MPO and nitrotyrosine immunoreactivities in brains of CD18 knockout mice. PMID:18615643

  19. Interleukin-6 reduces cartilage destruction during experimental arthritis. A study in interleukin-6-deficient mice.

    PubMed Central

    van de Loo, F. A.; Kuiper, S.; van Enckevort, F. H.; Arntz, O. J.; van den Berg, W. B.

    1997-01-01

    Using interleukin (IL)-6-deficient (IL-6(0/0) mice or wild-type mice, we investigated the controversial role of IL-6 in joint inflammation and cartilage pathology during zymosan-induced arthritis (ZIA). Monoarticular arthritis was elicited by injection of zymosan into the right knee joint cavity. Production of IL-1, tumor necrosis factor (TNF), IL-6, and nitric oxide by the inflamed knee was assessed in washouts of joint capsule specimens. Plasma corticosterone was measured using a radioimmunoassay. Proteoglycan synthesis was assessed using [35S]sulfate incorporation into patellas ex vivo. Joint swelling was quantified by joint uptake of circulating 99mTechnetium pertechnetate. Histology was taken to evaluate cellular infiltration and cartilage damage. Zymosan caused a rapid increase in articular IL-1, IL-6, TNF, and NO levels. Except for IL-6, the released amounts and time course of these mediators were comparable in the IL-6-deficient mice and the wild-type mice. Elevated plasma corticosterone levels were measured during the first day of arthritis in both strains. At day 2 of ZIA, joint inflammation (joint swelling and cell exudate) in IL-6-deficient mice was comparable with that in the wild-type mice. The marked suppression of chondrocyte proteoglycan synthesis and proteoglycan degradation were on the average higher in the IL-6-deficient mice. Together this resulted in a more pronounced proteoglycan depletion in the IL-6-deficient mice as compared with the wild-type mice during the first week of arthritis. Injection of recombinant IL-6 into the joint cavity corrected the IL-6 deficiency and significantly reduced cartilage destruction. Inflammation was more chronic in the wild-type mice, and these mice also showed a higher prevalence for osteophyte formation. In ZIA, IL-6 plays a dual role in connective tissue pathology, reducing proteoglycan loss in the acute phase and enhancing osteophyte formation in the chronic phase. The latter could be related to the more

  20. The shunt from the cyclooxygenase to lipoxygenase pathway in human osteoarthritic subchondral osteoblasts is linked with a variable expression of the 5-lipoxygenase-activating protein.

    PubMed

    Maxis, Kelitha; Delalandre, Aline; Martel-Pelletier, Johanne; Pelletier, Jean-Pierre; Duval, Nicolas; Lajeunesse, Daniel

    2006-01-01

    Osteoarthritis (OA) is characterized by articular cartilage degradation and hypertrophic bone changes with osteophyte formation and abnormal bone remodeling. Two groups of OA patients were identified via the production of variable and opposite levels of prostaglandin E2 (PGE2) or leukotriene B4 (LTB4) by subchondral osteoblasts, PGE2 levels discriminating between low and high subgroups. We studied whether the expression of 5-lipoxygenase (5-LO) or 5-LO-activating protein (FLAP) is responsible for the shunt from prostaglandins to leukotrienes. FLAP mRNA levels varied in low and high OA groups compared with normal, whereas mRNA levels of 5-LO were similar in all osteoblasts. Selective inhibition of cyclooxygenase-2 (COX-2) with NS-398-stimulated FLAP expression in the high OA osteoblasts subgroup, whereas it was without effect in the low OA osteoblasts subgroup. The addition of PGE2 to the low OA osteoblasts subgroup decreased FLAP expression but failed to affect it in the high OA osteoblasts subgroup. LTB4 levels in OA osteoblasts were stimulated about twofold by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plus transforming growth factor-beta (TGF-beta), a situation corresponding to their effect on FLAP mRNA levels. Treatments with 1,25(OH)2D3 and TGF-beta also modulated PGE2 production. TGF-beta stimulated PGE2 production in both OA osteoblast groups, whereas 1,25(OH)2D3 alone had a limited effect but decreased the effect of TGF-beta in the low OA osteoblasts subgroup. This modulation of PGE2 production was mirrored by the synthesis of COX-2. IL-18 levels were only slightly increased in a subgroup of OA osteoblasts compared with normal; however, no relationship was observed overall between IL-18 and PGE2 levels in normal and OA osteoblasts. These results suggest that the shunt from the production of PGE2 to LTB4 is through regulation of the expression of FLAP, not 5-LO, in OA osteoblasts. The expression of FLAP in OA osteoblasts is also modulated differently by 1,25(OH

  1. Photoreception in Neurospora crassa: correlation of reduced light sensitivity with flavin deficiency.

    PubMed Central

    Paietta, J; Sargent, M L

    1981-01-01

    The effect of flavin deficiency on blue light responses in Neurospora crassa was studied through the use of two riboflavin mutants (rib-1 and rib-2). The photoresponses assayed were the suppression of circadian conidiation, the phase shifting of the circadian conidiation rhythm, and the induction of carotenoid synthesis. Flavin deficiency was induced in the rib-1 mutant by restrictive growth temperatures and in the rib-2 mutant by low levels of supplemental riboflavin. At 26 degrees C, a semirestrictive growth temperature, the rib-1 mutant is about 1/80th as sensitive to light for the photosuppression of circadian conidiation. Flavin deficiency in the rib-1 and rib-2 strains was effective in reducing the photosensitivity for phase shifting and carotenogenesis to about 1/16th and 1/4th of normal, respectively. Experiments with permissive temperatures, riboflavin supplementation, and revertants at the rib locus all indicated that the effects on light sensitivity were due solely to the presence of the rib mutations. These results provide evidence that one or more flavin photoreceptors are involved in the blue light responses of Neurospora. Images PMID:6458042

  2. Arginase 2 deficiency reduces hyperoxia-mediated retinal neurodegeneration through the regulation of polyamine metabolism.

    PubMed

    Narayanan, S P; Xu, Z; Putluri, N; Sreekumar, A; Lemtalsi, T; Caldwell, R W; Caldwell, R B

    2014-01-01

    Hyperoxia treatment has been known to induce neuronal and glial death in the developing central nervous system. Retinopathy of prematurity (ROP) is a devastating disease in premature infants and a major cause of childhood vision impairment. Studies indicate that, in addition to vascular injury, retinal neurons are also affected in ROP. Using an oxygen-induced retinopathy (OIR) mouse model for ROP, we have previously shown that deletion of the arginase 2 (A2) significantly reduced neuro-glial injury and improved retinal function. In the current study, we investigated the mechanism of A2 deficiency-mediated neuroprotection in the OIR retina. Hyperoxia treatment has been known to induce neuronal death in neonates. During the hyperoxia phase of OIR, a significant increase in the number of apoptotic cells was observed in the wild-type (WT) OIR retina compared with A2-deficient OIR. Mass spectrometric analysis showed alterations in polyamine metabolism in WT OIR retina. Further, increased expression level of spermine oxidase was observed in WT OIR retina, suggesting increased oxidation of polyamines in OIR retina. These changes were minimal in A2-deficient OIR retina. Treatment using the polyamine oxidase inhibitor, N, N'-bis (2, 3-butadienyl)-1, 4-butanediamine dihydrochloride, significantly improved neuronal survival during OIR treatment. Our data suggest that retinal arginase is involved in the hyperoxia-induced neuronal degeneration in the OIR model, through the regulation of polyamine metabolism. PMID:24556690

  3. Soil Potassium Deficiency Reduces Cotton Fiber Strength by Accelerating and Shortening Fiber Development

    PubMed Central

    Yang, Jia-Shuo; Hu, Wei; Zhao, Wenqing; Meng, Yali; Chen, Binglin; Wang, Youhua; Zhou, Zhiguo

    2016-01-01

    Low potassium (K)-induced premature senescence in cotton has been observed worldwide, but how it affects cotton fiber properties remain unclear. We hypothesized that K deficiency affects cotton fiber properties by causing disordered fiber development, which may in turn be caused by the induction of a carbohydrate acquisition difficulty. To investigate this issue, we employed a low-K-sensitive cotton cultivar Siza 3 and a low-K-tolerant cultivar Simian 3 and planted them in three regions of different K supply. Data concerning lint yield, Pn and main fiber properties were collected from three years of testing. Soil K deficiency significantly accelerated fiber cellulose accumulation and dehydration processes, which, together with previous findings, suggests that the low-K induced carbohydrate acquisition difficulty could cause disordered fiber development by stimulating the expression of functional proteins such as CDKA (cyclin-dependent kinase). As a result, fiber strength and lint weight were reduced by up to 7.8% and 2.1%, respectively. Additional quantitative analysis revealed that the degree of accelerated fiber development negatively correlated with fiber strength. According to the results of this study, it is feasible to address the effects of soil K deficiency on fiber properties using existing cultivation strategies to prevent premature senescence of cotton plants. PMID:27350236

  4. FILAGGRIN DEFICIENCY CONFERS A PARACELLULAR BARRIER ABNORMALITY THAT REDUCES INFLAMMATORY THRESHOLDS TO IRRITANTS AND HAPTENS

    PubMed Central

    Scharschmidt, Tiffany C.; Man, Mao-Qiang; Hatano, Yutaka; Crumrine, Debra; Gunathilake, Roshan; Sundberg, John P.; Silva, Kathleen A.; Mauro, Theodora M.; Hupe, Melanie; Cho, Soyun; Wu, Yan; Celli, Anna; Schmuth, Matthias; Feingold, Kenneth R.; Elias, Peter M.

    2010-01-01

    Background Mutations in filaggrin (FLG) are associated with atopic dermatitis (AD), and are presumed to provoke a barrier abnormality. Yet, additional acquired stressors may be necessary, since the same mutations can result in a non-inflammatory disorder, ichthyosis vulgaris. Objective We examined here whether FLG deficiency alone suffices to produce a barrier abnormality; the basis for the putative abnormality; and its pro-inflammatory consequences. Methods Using the flaky-tail (ft/ft) mouse, which lacks processed flg due to a frame-shift mutation in profilaggrin that mimics some mutations in human AD, we assessed whether FLG deficiency provokes a barrier abnormality; further localized the defect; identified its subcellular basis; and assessed thresholds to irritant and hapten-induced dermatitis. Results Flaky-tail mice exhibit low-grade inflammation, with increased bidirectional, paracellular permeability of water-soluble xenobiotes due to impaired lamellar body secretion and altered stratum corneum extracellular membranes. This barrier abnormality correlates with reduced inflammatory thresholds to both topical irritants and haptens. Moreover, when exposed repeatedly to topical haptens, at doses that produce no inflammation in +/+ mice, ft/ft mice develop a severe AD-like dermatosis, with a further deterioration in barrier function and features of a th2 immunophenotype (increased CRTH + inflammation, elevated serum IgE levels, and reduced antimicrobial peptide [mBD3] expression). Conclusions FLG deficiency alone provokes a paracellular barrier abnormality in mice that reduces inflammatory thresholds to topical irritants/haptens, likely accounting for enhanced antigen penetration in FLG-associated AD. PMID:19733297

  5. Deficiency of Antigen Presenting Cell Invariant Chain Reduces Atherosclerosis in Mice

    PubMed Central

    Sun, Jiusong; Hartvigsen, Karsten; Chou, Meng-Yun; Zhang, Yadong; Sukhova, Galina K.; Zhang, Jie; Lopez-Ilasaca, Marco; Diehl, Cody J.; Yakov, Niva; Harats, Dror; George, Jacob; Witztum, Joseph L.; Libby, Peter; Ploegh, Hidde; Shi, Guo-Ping

    2010-01-01

    Background Adaptive and innate immunity play important roles in atherogenesis. Invariant chain (CD74) mediates antigen presenting cell (APC) antigen presentation and T cell activation. This study tested the hypothesis that CD74-deficient mice have reduced numbers of active T cells and resist atherogenesis. Methods and Results In low-density lipoprotein receptor-deficient mice (Ldlr−/−), CD74 deficiency (Ldlr−/−Cd74−/−) significantly reduced atherosclerosis and CD25+ activated T cells in the atheromata. While Ldlr−/−Cd74−/− mice had decreased levels of plasma IgG1, IgG2b, and IgG2c against malondialdehyde-modified LDL (MDA-LDL), presumably due to impaired APC function, Ldlr−/−Cd74−/− mice showed higher levels of anti-MDA-LDL IgM and IgG3. After immunization with MDA-LDL, Ldlr−/−Cd74−/− mice had lower levels of all anti-MDA-LDL immunoglobulin (Ig) isotypes compared with Ldlr−/− mice. As anticipated, only Ldlr−/− splenocytes responded to in vitro stimulation with MDA-LDL, producing Th1/Th2 cytokines. Heat shock protein-65 (HSP65) immunization enhanced atherogenesis in Ldlr−/− mice, but Ldlr−/−Cd74−/− mice remained protected. Compared with Ldlr−/− mice, Ldlr−/−Cd74−/− mice had higher anti-MDA-LDL autoantibody titers, fewer lesion CD25+ activated T cells, impaired release of Th1/Th2 cytokines from APC after HSP65-stimulation, and reduced levels of all plasma anti-HSP65 Ig isotypes. Cytofluorimetry of splenocytes and peritoneal cavity cells of MDA-LDL- or HSP65-immunized mice showed increased percentages of autoantibody-producing marginal zone-B and B-1 cells in Ldlr−/−Cd74−/− mice compared to Ldlr−/− mice. Conclusion Invariant chain deficiency in Ldlr−/− mice reduced atherosclerosis. This finding was associated with an impaired adaptive immune response to disease-specific antigens. Concomitantly, there occurred an unexpected increase in the number of innate-like peripheral B-1 cell

  6. Dietary copper deficiency reduces iron absorption and duodenal enterocyte hephaestin protein in male and female rats.

    PubMed

    Reeves, Philip G; Demars, Lana C S; Johnson, W Thomas; Lukaski, Henry C

    2005-01-01

    The mechanism for reduced Fe absorption in Cu deficiency is unknown, but may involve the intestinal Cu-dependent ferroxidase, Hephaestin (Hp). A 2 x 2 factorial experiment was designed to include Cu-deficient (CuD) and Cu-adequate (CuA) male and female rats. Weanling rats of both sexes were randomly divided into 2 groups each and fed an AIN-93G diet with low (<0.3 mg/kg; CuD) or adequate Cu (5.0 mg/kg; CuA). After 19 d, rats were fed 1.0 g each of their respective diets labeled with (59)Fe. Retained (59)Fe was monitored by whole-body counting for 12 d. Then, rats were killed for (59)Fe and Fe measurements in blood and various organs. Duodenal enterocytes were isolated for Western blot analysis of Hp. Signs of Cu and Fe deficiency were evident in both sexes. CuD male rats absorbed 60% as much Fe as CuA male rats (P < 0.001), whereas CuD female rats absorbed 70% (P < 0.001) as much as CuA females, with no difference between the sexes. Hp protein in enterocytes of CuD rats of both sexes was only 35% of that in CuA rats. The biological half-life of (59)Fe in CuD rats was only 50% (P < 0.001) of that in CuA rats, suggesting that Fe turnover was faster in CuD rats than CuA rats. Serum, spleen, and kidney Fe were lower (P < 0.001) in CuD rats than in CuA rats. Duodenal mucosa and liver Fe were higher (P < 0.01) in CuD male rats than CuA rats. Duodenal Fe but not liver Fe was higher in CuD female rats than CuA rats. Liver Fe was much higher (<0.001) overall in females than males. The data suggest that Cu deficiency reduces Fe absorption in rats through reduced expression of duodenal Hp protein. PMID:15623839

  7. Neonatal Leptin Deficiency Reduces Frontal Cortex Volumes and Programs Adult Hyperactivity in Mice

    PubMed Central

    Dexter, Benjamin C; Rahmouni, Kamal; Cushman, Taylor; Hermann, Gregory M; Ni, Charles; Nopoulos, Peg C; Thedens, Daniel L; Roghair, Robert D

    2014-01-01

    Intrauterine growth restriction and premature delivery decrease circulating levels of the neurotrophic hormone leptin and increase the risk of adult psychiatric disease. In mouse models, neonatal leptin replacement normalizes brain growth and improves the neurodevelopmental outcomes of growth restricted mice, but leptin supplementation of well-grown mice decreases adult locomotor activity. We hypothesized isolated neonatal leptin deficiency is sufficient to reduce adult brain volumes and program behavioral outcomes, including hyperactivity. C57Bl/6 pups were randomized to daily injections of saline or PEG-leptin antagonist (LX, 12.5 mg/kg) from postnatal day 4 to 14. After 4 months, fear conditioning and open field testing were performed followed by carotid radiotelemetry for the measurement of baseline activity and blood pressure. Neonatal LX did not significantly increase cue-based fear or blood pressure, but increased adult locomotor activity during assessment in both the open field (beam breaks: control 930±40, LX 1099±42, P<0.01) and the home cage (radiotelemetry counts: control 4.5±0.3, LX 5.6±0.3, P=0.02). Follow-up MRI revealed significant reductions in adult frontal cortex volumes following neonatal LX administration (control 45.1±0.4 mm3, LX 43.8±0.4 mm3, P=0.04). This was associated with a significant increase in cerebral cortex leptin receptor mRNA expression. In conclusion, isolated neonatal leptin deficiency increases cerebral cortex leptin receptor expression and reduces frontal cortex volumes in association with increased adult locomotor activity. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with perinatal growth restriction, and postnatal leptin therapy may be protective. PMID:24472638

  8. Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction.

    PubMed

    Kubli, Dieter A; Zhang, Xiaoxue; Lee, Youngil; Hanna, Rita A; Quinsay, Melissa N; Nguyen, Christine K; Jimenez, Rebecca; Petrosyan, Susanna; Murphy, Anne N; Gustafsson, Asa B

    2013-01-11

    It is known that loss-of-function mutations in the gene encoding Parkin lead to development of Parkinson disease. Recently, Parkin was found to play an important role in the removal of dysfunctional mitochondria via autophagy in neurons. Although Parkin is expressed in the heart, its functional role in this tissue is largely unexplored. In this study, we have investigated the role of Parkin in the myocardium under normal physiological conditions and in response to myocardial infarction. We found that Parkin-deficient (Parkin(-/-)) mice had normal cardiac function for up to 12 months of age as determined by echocardiographic analysis. Although ultrastructural analysis revealed that Parkin-deficient hearts had disorganized mitochondrial networks and significantly smaller mitochondria, mitochondrial function was unaffected. However, Parkin(-/-) mice were much more sensitive to myocardial infarction when compared with wild type mice. Parkin(-/-) mice had reduced survival and developed larger infarcts when compared with wild type mice after the infarction. Interestingly, Parkin protein levels and mitochondrial autophagy (mitophagy) were rapidly increased in the border zone of the infarct in wild type mice. In contrast, Parkin(-/-) myocytes had reduced mitophagy and accumulated swollen, dysfunctional mitochondria after the infarction. Overexpression of Parkin in isolated cardiac myocytes also protected against hypoxia-mediated cell death, whereas nonfunctional Parkinson disease-associated mutants ParkinR42P and ParkinG430D had no effect. Our results suggest that Parkin plays a critical role in adapting to stress in the myocardium by promoting removal of damaged mitochondria. PMID:23152496

  9. Deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice

    PubMed Central

    Liu, Jian; Divoux, Adeline; Sun, Jiusong; Zhang, Jie; Clément, Karine; Glickman, Jonathan N.; Sukhova, Galina K.; Wolters, Paul J.; Du, Juan; Gorgun, Cem Z.; Doria, Alessandro; Libby, Peter; Blumberg, Richard S.; Kahn, Barbara B.; Hotamisligil, Gokhan S.; Shi, Guo-Ping

    2009-01-01

    Although mast cell functions classically relate to allergic responses1–3, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm, and cancer4–8. This study presents evidence that mast cells contribute importantly to diet-induced obesity and diabetes. White adipose tissues (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Genetically determined mast cell deficiency and pharmacological stabilization of mast cells in mice reduce body weight gain and levels of inflammatory cytokines, chemokines, and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer of cytokine-deficient mast cells established that these cells contribute to mice adipose tissue cysteine protease cathepsin expression, apoptosis, and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance by production of IL6 and IFN-γ. Mast cell stabilizing agents in clinical use reduced obesity and diabetes in mice, suggesting the potential of developing novel therapies for these common human metabolic disorders. PMID:19633655

  10. Efficacy, safety and tolerability of GSK2190915, a 5-lipoxygenase activating protein inhibitor, in adults and adolescents with persistent asthma: a randomised dose-ranging study

    PubMed Central

    2013-01-01

    Background GSK2190915 is a high affinity 5-lipoxygenase-activating protein inhibitor being developed for the treatment of asthma. The objective of this study was to evaluate GSK2190915 efficacy, dose–response and safety in subjects with persistent asthma treated with short-acting beta2-agonists (SABAs) only. Methods Eight-week multicentre, randomised, double-blind, double-dummy, stratified (by age and smoking status), parallel-group, placebo-controlled study in subjects aged ≥12 years with a forced expiratory volume in 1 second (FEV1) of 50–85% predicted. Subjects (n = 700) were randomised to receive once-daily (QD) oral GSK2190915 (10–300 mg), twice-daily inhaled fluticasone propionate 100 μg, oral montelukast 10 mg QD or placebo. The primary endpoint was mean change from baseline (randomisation) in trough (morning pre-dose and pre-rescue bronchodilator) FEV1 at the end of the 8-week treatment period. Secondary endpoints included morning and evening peak expiratory flow, symptom-free days and nights, rescue-free days and nights, day and night-time symptom scores, day and night-time rescue medication use, withdrawals due to lack of efficacy, Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. Results For the primary endpoint, there was no statistically significant difference between any dose of GSK2190915 QD and placebo. However, repeated measures sensitivity analysis demonstrated nominal statistical significance for GSK2190915 30 mg QD compared with placebo (mean difference: 0.115 L [95% confidence interval: 0.00, 0.23], p = 0.044); no nominally statistically significant differences were observed with any of the other doses. For the secondary endpoints, decreases were observed in day-time symptom scores and day-time SABA use for GSK2190915 30 mg QD versus placebo (p ≤ 0.05). No dose–response relationship was observed for the primary and secondary endpoints across the GSK2190915 dose range studied; the 10

  11. Reduced Discrimination in the Tritanopic Confusion Line for Congenital Color Deficiency Adults.

    PubMed

    Costa, Marcelo F; Goulart, Paulo R K; Barboni, Mirella T S; Ventura, Dora F

    2016-01-01

    In congenital color blindness the red-green discrimination is impaired resulting in an increased confusion between those colors with yellow. Our post-receptoral physiological mechanisms are organized in two pathways for color perception, a red-green (protanopic and deuteranopic) and a blue-yellow (tritanopic). We argue that the discrimination losses in the yellow area in congenital color vision deficiency subjects could generate a subtle loss of discriminability in the tritanopic channel considering discrepancies with yellow perception. We measured color discrimination thresholds for blue and yellow of tritanopic channel in congenital color deficiency subjects. Chromaticity thresholds were measured around a white background (0.1977 u', 0.4689 v' in the CIE 1976) consisting of a blue-white and white-yellow thresholds in a tritanopic color confusion line of 21 congenital colorblindness subjects (mean age = 27.7; SD = 5.6 years; 14 deuteranomalous and 7 protanomalous) and of 82 (mean age = 25.1; SD = 3.7 years) normal color vision subjects. Significant increase in the whole tritanopic axis was found for both deuteranomalous and protanomalous subjects compared to controls for the blue-white (F 2,100 = 18.80; p < 0.0001) and white-yellow (F 2,100 = 22.10; p < 0.0001) thresholds. A Principal Component Analysis (PCA) found a weighting toward to the yellow thresholds induced by deuteranomalous subjects. In conclusion, the discrimination in the tritanopic color confusion axis is significantly reduced in congenital color vision deficiency compared to normal subjects. Since yellow discrimination was impaired the balance of the blue-yellow channels is impaired justifying the increased thresholds found for blue-white discrimination. The weighting toward the yellow region of the color space with the deuteranomalous contributing to that perceptual distortion is discussed in terms of physiological mechanisms. PMID:27065909

  12. Reduced Discrimination in the Tritanopic Confusion Line for Congenital Color Deficiency Adults

    PubMed Central

    Costa, Marcelo F.; Goulart, Paulo R. K.; Barboni, Mirella T. S.; Ventura, Dora F.

    2016-01-01

    In congenital color blindness the red–green discrimination is impaired resulting in an increased confusion between those colors with yellow. Our post-receptoral physiological mechanisms are organized in two pathways for color perception, a red–green (protanopic and deuteranopic) and a blue–yellow (tritanopic). We argue that the discrimination losses in the yellow area in congenital color vision deficiency subjects could generate a subtle loss of discriminability in the tritanopic channel considering discrepancies with yellow perception. We measured color discrimination thresholds for blue and yellow of tritanopic channel in congenital color deficiency subjects. Chromaticity thresholds were measured around a white background (0.1977 u′, 0.4689 v′ in the CIE 1976) consisting of a blue–white and white–yellow thresholds in a tritanopic color confusion line of 21 congenital colorblindness subjects (mean age = 27.7; SD = 5.6 years; 14 deuteranomalous and 7 protanomalous) and of 82 (mean age = 25.1; SD = 3.7 years) normal color vision subjects. Significant increase in the whole tritanopic axis was found for both deuteranomalous and protanomalous subjects compared to controls for the blue–white (F2,100 = 18.80; p < 0.0001) and white–yellow (F2,100 = 22.10; p < 0.0001) thresholds. A Principal Component Analysis (PCA) found a weighting toward to the yellow thresholds induced by deuteranomalous subjects. In conclusion, the discrimination in the tritanopic color confusion axis is significantly reduced in congenital color vision deficiency compared to normal subjects. Since yellow discrimination was impaired the balance of the blue–yellow channels is impaired justifying the increased thresholds found for blue–white discrimination. The weighting toward the yellow region of the color space with the deuteranomalous contributing to that perceptual distortion is discussed in terms of physiological mechanisms. PMID:27065909

  13. Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling.

    PubMed

    Ko, A; Kanehisa, A; Martins, I; Senovilla, L; Chargari, C; Dugue, D; Mariño, G; Kepp, O; Michaud, M; Perfettini, J-L; Kroemer, G; Deutsch, E

    2014-01-01

    Clinical oncology heavily relies on the use of radiotherapy, which often leads to merely transient responses that are followed by local or distant relapse. The molecular mechanisms explaining radioresistance are largely elusive. Here, we identified a dual role of autophagy in the response of cancer cells to ionizing radiation. On one hand, we observed that the depletion of essential autophagy-relevant gene products, such as ATG5 and Beclin 1, increased the sensitivity of human or mouse cancer cell lines to irradiation, both in vitro (where autophagy inhibition increased radiation-induced cell death and decreased clonogenic survival) and in vivo, after transplantation of the cell lines into immunodeficient mice (where autophagy inhibition potentiated the tumour growth-inhibitory effect of radiotherapy). On the other hand, when tumour proficient or deficient for autophagy were implanted in immunocompetent mice, it turned out that defective autophagy reduced the efficacy of radiotherapy. Indeed, radiotherapy elicited an anti-cancer immune response that was dependent on autophagy-induced ATP release from stressed or dying tumour cells and was characterized by dense lymphocyte infiltration of the tumour bed. Intratumoural injection of an ecto-ATPase inhibitor restored the immune infiltration of autophagy-deficient tumours post radiotherapy and improved the growth-inhibitory effect of ionizing irradiation. Altogether, our results reveal that beyond its cytoprotective function, autophagy confers immunogenic properties to tumours, hence amplifying the efficacy of radiotherapy in an immunocompetent context. This has far-reaching implications for the development of pharmacological radiosensitizers. PMID:24037090

  14. Neuropeptide Y and Agouti-Related Peptide Mediate Complementary Functions of Hyperphagia and Reduced Energy Expenditure in Leptin Receptor Deficiency

    PubMed Central

    Luo, Na; Marcelin, Genevieve; Liu, Shun Mei; Schwartz, Gary

    2011-01-01

    Neuropeptide Y (NPY) and agouti-related peptide (AGRP) can produce hyperphagia, reduce energy expenditure, and promote triglyceride deposition in adipose depots. As these two neuropeptides are coexpressed within the hypothalamic arcuate nucleus and mediate a major portion of the obesity caused by leptin signaling deficiency, we sought to determine whether the two neuropeptides mediated identical or complementary actions. Because of separate neuropeptide receptors and signal transduction mechanisms, there is a possibility of distinct encoding systems for the feeding and energy expenditure aspects of leptin-regulated metabolism. We have genetically added NPY deficiency and/or AGRP deficiency to LEPR deficiency isolated to AGRP cells. Our results indicate that the obesity of LEPR deficiency in AGRP/NPY neurons can produce obesity with either AGRP or NPY alone with AGRP producing hyperphagia while NPY promotes reduced energy expenditure. The absence of both NPY and AGRP prevents the development of obesity attributable to isolated LEPR deficiency in AGRP/NPY neurons. Operant behavioral testing indicated that there were no alterations in the reward for a food pellet from the AGRP-specific LEPR deficiency. PMID:21285324

  15. Reduced Synchronization Persistence in Neural Networks Derived from Atm-Deficient Mice

    PubMed Central

    Levine-Small, Noah; Yekutieli, Ziv; Aljadeff, Jonathan; Boccaletti, Stefano; Ben-Jacob, Eshel; Barzilai, Ari

    2011-01-01

    Many neurodegenerative diseases are characterized by malfunction of the DNA damage response. Therefore, it is important to understand the connection between system level neural network behavior and DNA. Neural networks drawn from genetically engineered animals, interfaced with micro-electrode arrays allowed us to unveil connections between networks’ system level activity properties and such genome instability. We discovered that Atm protein deficiency, which in humans leads to progressive motor impairment, leads to a reduced synchronization persistence compared to wild type synchronization, after chemically imposed DNA damage. Not only do these results suggest a role for DNA stability in neural network activity, they also establish an experimental paradigm for empirically determining the role a gene plays on the behavior of a neural network. PMID:21519382

  16. Reduced salivary gland size and increased presence of epithelial progenitor cells in DLK1-deficient mice.

    PubMed

    García-Gallastegui, P; Luzuriaga, J; Aurrekoetxea, M; Baladrón, V; Ruiz-Hidalgo, M J; García-Ramírez, J J; Laborda, J; Unda, F; Ibarretxe, G

    2016-06-01

    DLK1 (PREF1, pG2, or FA1) is a transmembrane and secreted protein containing epidermal growth factor-like repeats. Dlk1 expression is abundant in many tissues during embryonic and fetal development and is believed to play an important role in the regulation of tissue differentiation and fetal growth. After birth, Dlk1 expression is abolished in most tissues but is possibly reactivated to regulate stem cell activation and responses to injury. We have recently reported that DLK1 regulates many aspects of salivary gland organogenesis. Here, we have extended our studies of the salivary gland phenotype of Dlk1 knock-out mice. We have observed that salivary glands are smaller and weigh significantly less in both Dlk1 knock-out males and females compared with gender and age-matched wild-type mice and regardless of the natural sexual dimorphism in rodent salivary glands. This reduced size correlates with a reduced capacity of Dlk1-deficient mice to secrete saliva after stimulation with pilocarpine. However, histological and ultrastructural analyses of both adult and developing salivary gland tissues have revealed no defects in Dlk1 ((-/-)) mice, indicating that genetic compensation accounts for the relatively mild salivary phenotype in these animals. Finally, despite their lack of severe anomalies, we have found that salivary glands from Dlk1-deficient mice present a higher amount of CK14-positive epithelial progenitors at various developmental stages, suggesting a role for DLK1 in the regulation of salivary epithelial stem cell balance. PMID:26711912

  17. TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis.

    PubMed

    Hsieh, Joanne; Koseki, Masahiro; Molusky, Matthew M; Yakushiji, Emi; Ichi, Ikuyo; Westerterp, Marit; Iqbal, Jahangir; Chan, Robin B; Abramowicz, Sandra; Tascau, Liana; Takiguchi, Shunichi; Yamashita, Shizuya; Welch, Carrie L; Di Paolo, Gilbert; Hussain, M Mahmood; Lefkowitch, Jay H; Rader, Daniel J; Tall, Alan R

    2016-07-14

    Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, are poorly understood. Despite the fact that its synthetic agonists induce fatty liver, the liver X receptor (LXR) transcription factor remains a target of interest because of its anti-atherogenic, cholesterol removal, and anti-inflammatory activities. Here we show that tetratricopeptide repeat domain protein 39B (Ttc39b, C9orf52) (T39), a high-density lipoprotein gene discovered in human genome-wide association studies, promotes the ubiquitination and degradation of LXR. Chow-fed mice lacking T39 (T39(-/-)) display increased high-density lipoprotein cholesterol levels associated with increased enterocyte ATP-binding cassette transporter A1 (Abca1) expression and increased LXR protein without change in LXR messenger RNA. When challenged with a high fat/high cholesterol/bile salt diet, T39(-/-) mice or mice with hepatocyte-specific T39 deficiency show increased hepatic LXR protein and target gene expression, and unexpectedly protection from steatohepatitis and death. Mice fed a Western-type diet and lacking low-density lipoprotein receptor (Ldlr(-/-)T39(-/-)) show decreased fatty liver, increased high-density lipoprotein, decreased low-density lipoprotein, and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibits hepatic sterol regulatory element-binding protein 1 (SREBP-1, ADD1) processing. This is explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids, linked to an LXRα-dependent increase in expression of enzymes mediating phosphatidylcholine biosynthesis and incorporation of polyunsaturated fatty acids into phospholipids. The preservation of endogenous LXR protein activates a beneficial profile of gene expression that promotes cholesterol removal and inhibits lipogenesis. T39 inhibition could

  18. Hepatic overexpression of methionine sulfoxide reductase A reduces atherosclerosis in apolipoprotein E-deficient mice.

    PubMed

    Xu, Yan-Yong; Du, Fen; Meng, Bing; Xie, Guang-Hui; Cao, Jia; Fan, Daping; Yu, Hong

    2015-10-01

    Methionine sulfoxide reductase A (MsrA), a specific enzyme that converts methionine-S-sulfoxide to methionine, plays an important role in the regulation of protein function and the maintenance of redox homeostasis. In this study, we examined the impact of hepatic MsrA overexpression on lipid metabolism and atherosclerosis in apoE-deficient (apoE(-/-)) mice. In vitro study showed that in HepG2 cells, lentivirus-mediated human MsrA (hMsrA) overexpression upregulated the expression levels of several key lipoprotein-metabolism-related genes such as liver X receptor α, scavenger receptor class B type I, and ABCA1. ApoE(-/-) mice were intravenously injected with lentivirus to achieve high-level hMsrA expression predominantly in the liver. We found that hepatic hMsrA expression significantly reduced plasma VLDL/LDL levels, improved plasma superoxide dismutase, and paraoxonase-1 activities, and decreased plasma serum amyloid A level in apoE(-/-) mice fed a Western diet, by significantly altering the expression of several genes in the liver involving cholesterol selective uptake, conversion and excretion into bile, TG biosynthesis, and inflammation. Moreover, overexpression of hMsrA resulted in reduced hepatic steatosis and aortic atherosclerosis. These results suggest that hepatic MsrA may be an effective therapeutic target for ameliorating dyslipidemia and reducing atherosclerosis-related cardiovascular diseases. PMID:26318157

  19. Impaired Erectile Function in CD73-deficient Mice with Reduced Endogenous Penile Adenosine Production

    PubMed Central

    Wen, Jiaming; Dai, Yingbo; Zhang, Yujin; Zhang, Weiru; Kellems, Rodney E.; Xia, Yang

    2012-01-01

    Introduction Adenosine has been implicated in normal and abnormal penile erection. However, a direct role of endogenous adenosine in erectile physiology and pathology has not been established. Aim To determine the functional role of endogenous adenosine production in erectile function. Methods CD73-deficient mice (CD73−/−) and age-matched wild-type (WT) mice were used. Some WT mice were treated with alpha, beta-methylene adenosine diphosphate (ADP) (APCP), a CD73-specific inhibitor. High-performance liquid chromatography was used to measure adenosine levels in mouse penile tissues. In vivo assessment of intracorporal pressure (ICP) normalized to mean arterial pressure (MAP) in response to electrical stimulation (ES) of the cavernous nerve was used. Main Outcome Measurement The main outcome measures of this study were the in vivo assessment of initiation and maintenance of penile erection in WT mice and mice with deficiency in CD73 (ecto-5′-nucleotidase), a key cell-surface enzyme to produce extracellular adenosine. Results Endogenous adenosine levels were elevated in the erected state induced by ES of cavernous nerve compared to the flaccid state in WT mice but not in CD73−/− mice. At cellular levels, we identified that CD73 was highly expressed in the neuronal, endothelial cells, and vascular smooth muscle cells in mouse penis. Functionally, we found that the ratio of ES-induced ICP to MAP in CD73−/− mice was reduced from 0.48 ± 0.03 to 0.33 ± 0.05 and ES-induced slope was reduced from 0.30 ± 0.13 mm Hg/s to 0.15 ± 0.05 mm Hg/s (both P < 0.05). The ratio of ES-induced ICP to MAP in APCP-treated WT mice was reduced from 0.49 ± 0.03 to 0.38 ± 0.06 and ES-induced slope was reduced from 0.29 ± 0.11 mm Hg/s to 0.19 ± 0.04 mm Hg/s (both P < 0.05). Conclusion Overall, our findings demonstrate that CD73-dependent production of endogenous adenosine plays a direct role in initiation and maintenance of penile erection. PMID:21595838

  20. Muscle-specific VEGF deficiency greatly reduces exercise endurance in mice.

    PubMed

    Olfert, I Mark; Howlett, Richard A; Tang, Kechun; Dalton, Nancy D; Gu, Yusu; Peterson, Kirk L; Wagner, Peter D; Breen, Ellen C

    2009-04-15

    Vascular endothelial growth factor (VEGF) is required for vasculogenesis and angiogenesis during embryonic and early postnatal life. However the organ-specific functional role of VEGF in adult life, particularly in skeletal muscle, is less clear. To explore this issue, we engineered skeletal muscle-targeted VEGF deficient mice (mVEGF-/-) by crossbreeding mice that selectively express Cre recombinase in skeletal muscle under the control of the muscle creatine kinase promoter (MCKcre mice) with mice having a floxed VEGF gene (VEGFLoxP mice). We hypothesized that VEGF is necessary for regulating both cardiac and skeletal muscle capillarity, and that a reduced number of VEGF-dependent muscle capillaries would limit aerobic exercise capacity. In adult mVEGF-/- mice, VEGF protein levels were reduced by 90 and 80% in skeletal muscle (gastrocnemius) and cardiac muscle, respectively, compared to control mice (P < 0.01). This was accompanied by a 48% (P < 0.05) and 39% (P < 0.05) decreases in the capillary-to-fibre ratio and capillary density, respectively, in the gastrocnemius and a 61% decrease in cardiac muscle capillary density (P < 0.05). Hindlimb muscle oxidative (citrate synthase, 21%; beta-HAD, 32%) and glycolytic (PFK, 18%) regulatory enzymes were also increased in mVEGF-/- mice. However, this limited adaptation to reduced muscle VEGF was insufficient to maintain aerobic exercise capacity, and maximal running speed and endurance running capacity were reduced by 34% and 81%, respectively, in mVEGF-/- mice compared to control mice (P < 0.05). Moreover, basal and dobutamine-stimulated cardiac function, measured by transthoracic echocardiography and left ventricular micromanomtery, showed only a minimal reduction of contractility (peak +dP/dt) and relaxation (peak -dP/dt, tau(E)). Collectively these data suggests adequate locomotor muscle capillary number is important for achieving full exercise capacity. Furthermore, VEGF is essential in regulating postnatal muscle

  1. ABCA2 transporter deficiency reduces incidence of TRAMP prostate tumor metastasis and cellular chemotactic migration

    PubMed Central

    Mack, Jody T.; Helke, Kristi L.; Normand, Gabrielle; Green, CoDanielle; Townsend, Danyelle M.; Tew, Kenneth D.

    2010-01-01

    In order to study the effects of ATP-binding cassette transporter 2 (ABCA2) deficiency on the progression of prostate cancer, congenic Abca2 knockout (KO) mice were crossed to the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. ABCA2 expression was elevated in wild-type/TRAMP (WT/Tg) dorsal prostate, a region comprising the most aggressive tumors in this model, compared to non-transgenic WT mice. Primary prostate tumor progression was similar in KO/Tg and WT/Tg mice with respect to pathological score, prostate tumor growth, as calculated using MRI volumetry, and proliferative index, as determined by PCNA immunostaining. Vimentin, a marker of the epithelial-mesenchymal transition, was expressed at similar levels in prostate, but elevated in histologically normal seminal vesicles (SV) in KO/Tg mice (P < 0.02), concomitant with an increased SV volume (P < 0.01). These changes in the SV did not exacerbate the metastatic phenotype of this disease model; rather, KO/Tg mice aged 20-25 weeks had no detectable metastases while 38% of WT/Tg developed metastases to lung and/or lymph nodes. The absence of a metastatic phenotype in KO/Tg mice was reprised in stable ABCA2 knockdown (KD) cells where chemotactic, but not random, migration was impaired (P = 0.0004). Expression levels of sphingolipid biosynthetic enzymes were examined due to the established link of the transporter with sphingolipid homeostasis. Galactosylceramide synthase (GalCerS) mRNA levels were over 8-fold higher in KD cells (P = 0.001), while lactosylceramide synthase (LacCerS) and CTP:choline cytidylyltransferase (CCT) were significantly reduced (P < 0.0001 and 0.03, respectively). Overall, we demonstrate that ABCA2 deficiency inhibits prostate tumor metastasis in vivo and decreases chemotactic potential of cells, conceivably due to altered sphingolipid metabolism. PMID:21041019

  2. Food fortification to reduce vitamin A deficiency: International Vitamin A Consultative Group recommendations.

    PubMed

    Dary, Omar; Mora, Jose O

    2002-09-01

    In developed countries, food fortification has proven an effective and low-cost way to increase the micronutrient supply and reduce the consequences of micronutrient deficiencies. It has been rarely used in the developing world, but general conclusions can be drawn. The biological efficacy, but not the effectiveness, of fortifying oil and hydrogenated oil products as well as cereal flours and meals with vitamin A has been shown. Sugar has been fortified with vitamin A in Central American countries for years, and biological efficacy and program effectiveness are well established. Efficacy of fortifying monosodium glutamate with vitamin A was demonstrated but a program has not been established. Fortification with vitamin A in the developing world should satisfy certain elements for success. a) A potential food matrix (a food regularly consumed, produced by a few centralized factories, without sensorial changes compared with the nonfortified equivalent, and nutrient remains bioavailable and in a sufficient amount) is required. b) Fortified foods should provide at least 15% of the recommended daily intakes for the target group (e.g., individuals consuming the lowest amount of the fortified food). c) Voluntary fortification of processed foods should be regulated to prevent excessive consumption of vitamin A. d) Neighboring countries should harmonize technical standards, facilitate compliance and minimize conflicts over global trade laws. e) A practical monitoring system should be instituted. f) Social marketing activities should be permanent and aimed at industry, government and consumers. g) Food fortification should be combined with other strategies (e.g., supplementation) to reach those not adequately covered by fortification alone. Infants and small children, whose dietary habits differ from those of adults, require special attention. Fortification of food commodities is a very attractive and economic way to prevent and control vitamin A deficiency. Effective food

  3. Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency

    PubMed Central

    Pacheco-Colón, Ileana; Washington, Stuart D.; Sprouse, Courtney; Helman, Guy; Gropman, Andrea L.; VanMeter, John W.

    2015-01-01

    Background and Purpose Ornithine transcarbamylase deficiency (OTCD) is an X-chromosome linked urea cycle disorder (UCD) that causes hyperammonemic episodes leading to white matter injury and impairments in executive functioning, working memory, and motor planning. This study aims to investigate differences in functional connectivity of two resting-state networks—default mode and set-maintenance—between OTCD patients and healthy controls. Methods Sixteen patients with partial OTCD and twenty-two control participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, we identified the nodes that comprised each network in each group, and assessed internodal connectivity. Results Group comparisons revealed reduced functional connectivity in the default mode network (DMN) of OTCD patients, particularly between the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) node and bilateral inferior parietal lobule (IPL), as well as between the ACC/mPFC node and the posterior cingulate cortex (PCC) node. Patients also showed reduced connectivity in the set-maintenance network, especially between right anterior insula/frontal operculum (aI/fO) node and bilateral superior frontal gyrus (SFG), as well as between the right aI/fO and ACC and between the ACC and right SFG. Conclusion Internodal functional connectivity in the DMN and set-maintenance network is reduced in patients with partial OTCD compared to controls, most likely due to hyperammonemia-related white matter damage. Because several of the affected areas are involved in executive functioning, it is postulated that this reduced connectivity is an underlying cause of the deficits OTCD patients display in this cognitive domain. PMID:26067829

  4. Monocyte chemotactic protein-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet.

    PubMed

    Yan, Lin; Sundaram, Sneha

    2016-04-26

    Adipose-produced pro-inflammatory cytokines contribute to obesity and cancer. This 2x2 experiment was designed to investigate effects of monocyte chemotactic protein-1 (MCP-1) deficiency on pulmonary metastasis of Lewis lung carcinoma (LLC) in MCP-1 deficient and wild-type mice fed a modified AIN93G diet containing 16% and 45% of energy from corn oil, respectively. The high-fat diet significantly increased the number and size (cross-sectional area and volume) of lung metastases compared to the AIN93G control diet. Deficiency in MCP-1 reduced lung metastases by 37% in high-fat diet-fed mice; it reduced metastatic cross-sectional area by 46% and volume by 69% compared to wild-type mice. Adipose and plasma concentrations of MCP-1 were significantly higher in high-fat diet-fed wild-type mice than in their AIN93G-fed counterparts; they were not detectable in MCP-1 deficient mice regardless of diet. Plasma concentrations of plasminogen activator inhibitor-1, tumor necrosis factor-α, vascular endothelial growth factor and tissue inhibitor of metalloproteinase-1 were significantly higher in MCP-1 deficient mice compared to wild-type mice. We conclude that adipose-produced MCP-1 contributes to high-fat diet-enhanced metastasis. While MCP-1 deficiency reduces metastasis, the elevation of pro-inflammatory cytokines and angiogenic factors in the absence of MCP-1 may support the metastatic development and growth of LLC in MCP-1 deficient mice. PMID:27028862

  5. Reduced secreted mu mRNA synthesis in selective IgM deficiency of Bloom's syndrome.

    PubMed Central

    Kondo, N; Ozawa, T; Kato, Y; Motoyoshi, F; Kasahara, K; Kameyama, T; Orii, T

    1992-01-01

    Serum IgM concentrations were low although serum IgG and IgA concentrations were normal in both our patients with Bloom's syndrome. Although the percentages of surface IgM-bearing cells were not reduced, the numbers of IgM-secreting cells were markedly reduced. The membrane-bound mu (microns) and secreted mu (microseconds) mRNAs are produced from transcripts of a single immunoglobulin mu gene by alternative RNA processing pathways. The control of microseconds mRNA synthesis depends on the addition of poly(A) to microseconds C-terminal segment. In both patients, mu mRNA was well detected but microseconds C-terminal mRNA was scarcely detected, suggesting that microns mRNA was well transcribed but microseconds mRNA was not. There was, at least, no mutation or deletion in the microseconds C-terminal coding sequence, the RNA splice site (GG/TAAAC) at the 5' end of microseconds C-terminal segment and the AATAAA poly(A) signal sequence in both patients. Our results suggest that selective IgM deficiency in Bloom's syndrome is due to an abnormality in the maturation of surface IgM-bearing B cells into IgM-secreting cells and a failure of microseconds mRNA synthesis. Moreover, reduced microseconds mRNA synthesis may be due to the defect on developmental regulation of the site at which poly(A) is added to transcripts of the mu gene. Images Fig. 2 PMID:1563106

  6. Melatonin reduces endoplasmic reticulum stress and autophagy in liver of leptin-deficient mice.

    PubMed

    de Luxán-Delgado, Beatriz; Potes, Yaiza; Rubio-González, Adrian; Caballero, Beatriz; Solano, Juan José; Fernández-Fernández, María; Bermúdez, Manuel; Rodrigues Moreira Guimarães, Marcela; Vega-Naredo, Ignacio; Boga, José Antonio; Coto-Montes, Ana

    2016-08-01

    The sedentary lifestyle of modern society along with the high intake of energetic food has made obesity a current worldwide health problem. Despite great efforts to study the obesity and its related diseases, the mechanisms underlying the development of these diseases are not well understood. Therefore, identifying novel strategies to slow the progression of these diseases is urgently needed. Experimental observations indicate that melatonin has an important role in energy metabolism and cell signalling; thus, the use of this molecule may counteract the pathologies of obesity. In this study, wild-type and obese (ob/ob) mice received daily intraperitoneal injections of melatonin at a dose of 500 μg/kg body weight for 4 weeks, and the livers of these mice were used to evaluate the oxidative stress status, proteolytic (autophagy and proteasome) activity, unfolded protein response, inflammation and insulin signalling. Our results show, for the first time, that melatonin could significantly reduce endoplasmic reticulum stress in leptin-deficient obese animals and ameliorate several symptoms that characterize this disease. Our study supports the potential of melatonin as a therapeutic treatment for the most common type of obesity and its liver-associated disorders. PMID:27090356

  7. Reduced knee joint moment in ACL deficient patients at a cost of dynamic stability during landing.

    PubMed

    Oberländer, Kai Daniel; Brüggemann, Gert-Peter; Höher, Jürgen; Karamanidis, Kiros

    2012-05-11

    The current study aimed to examine the effect of anterior cruciate ligament deficiency (ACLd) on joint kinetics and dynamic stability control after a single leg hop test (SLHT). Twelve unilateral ACLd patients and a control subject group (n=13) performed a SLHT over a given distance with both legs. The calculation of joint kinetics was done by means of a soft-tissue artifact optimized rigid full-body model. Margin of stability (MoS) was quantified by the difference between the base of support and the extrapolated center of mass. During landing, the ACLd leg showed lower external knee flexion moments but demonstrated higher moments at the ankle and hip compared to controls (p<0.05). The main reason for the joint moment redistribution in the ACLd leg was a more anterior position of the ground reaction force (GRF) vector, which affected the moment arms of the GRF acting about the joints (p<0.05). For the ACLd leg, trunk angle was more flexed over the entire landing phase compared to controls (p<0.05) and we found a significant correlation between moment arms at the knee joint and trunk angle (r² = 0.48;p<0.01). The consequence of this altered landing strategy in ACLd legs was a more anterior position of the center of mass reducing the MoS (p<0.05). The results illustrate the interaction between trunk angle, joint kinetics and dynamic stability during landing maneuvers and provide evidence of a feedforward adaptive adjustment in ACLd patients (i.e. more flexed trunk angle) aimed at reducing knee joint moments at the cost of dynamic stability control. PMID:22440611

  8. Plasminogen deficiency causes reduced corticospinal axonal plasticity and functional recovery after stroke in mice.

    PubMed

    Liu, Zhongwu; Li, Yi; Qian, Jianyong; Cui, Yisheng; Chopp, Michael

    2014-01-01

    Tissue plasminogen activator (tPA) has been implicated in neurite outgrowth and neurological recovery post stroke. tPA converts the zymogen plasminogen (Plg) into plasmin. In this study, using plasminogen knockout (Plg-/-) mice and their Plg-native littermates (Plg+/+), we investigated the role of Plg in axonal remodeling and neurological recovery after stroke. Plg+/+ and Plg-/- mice (n = 10/group) were subjected to permanent intraluminal monofilament middle cerebral artery occlusion (MCAo). A foot-fault test and a single pellet reaching test were performed prior to and on day 3 after stroke, and weekly thereafter to monitor functional deficit and recovery. Biotinylated dextran amine (BDA) was injected into the left motor cortex to anterogradely label the corticospinal tract (CST). Animals were euthanized 4 weeks after stroke. Neurite outgrowth was also measured in primary cultured cortical neurons harvested from Plg+/+ and Plg-/- embryos. In Plg+/+ mice, the motor functional deficiency after stroke progressively recovered with time. In contrast, recovery in Plg-/- mice was significantly impaired compared to Plg+/+ mice (p<0.01). BDA-positive axonal density of the CST originating from the contralesional cortex in the denervated side of the cervical gray matter was significantly reduced in Plg-/- mice compared with Plg+/+ mice (p<0.05). The behavioral outcome was highly correlated with the midline-crossing CST axonal density (R2>0.82, p<0.01). Plg-/- neurons exhibited significantly reduced neurite outgrowth. Our data suggest that plasminogen-dependent proteolysis has a beneficial effect during neurological recovery after stroke, at least in part, by promoting axonal remodeling in the denervated spinal cord. PMID:24732409

  9. Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons

    PubMed Central

    Hong, J; Sha, S; Zhou, L; Wang, C; Yin, J; Chen, L

    2015-01-01

    Sigma-1 receptor (σ1R) has been reported to be decreased in nigrostriatal motor system of Parkinson's disease patients. Using heterozygous and homozygous σ1R knockout (σ1R+/− and σ1R−/−) mice, we investigated the influence of σ1R deficiency on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-impaired nigrostriatal motor system. The injection of MPTP for 5 weeks in wild-type mice (MPTP-WT mice), but not in σ1R+/− or σ1R−/− mice (MPTP-σ1R+/− or MPTP-σ1R−/− mice), caused motor deficits and ~40% death of dopaminergic neurons in substantia nigra pars compacta with an elevation of N-methyl-d-aspartate receptor (NMDAr) NR2B phosphorylation. The σ1R antagonist NE100 or the NR2B inhibitor Ro25-6981 could alleviate the motor deficits and the death of dopaminergic neurons in MPTP-WT mice. By contrast, MPTP-σ1R+/− mice treated with the σ1R agonist PRE084 or MPTP-σ1R−/− mice treated with the NMDAr agonist NMDA appeared to have similar motor deficits and loss of dopaminergic neurons as MPTP-WT mice. The pharmacological or genetic inactivation of σ1R suppressed the expression of dopamine transporter (DAT) in substantia nigra, which was corrected by NMDA. The activation of σ1R by PRE084 enhanced the DAT expression in WT mice or σ1R+/− mice. By contrast, the level of vesicular monoamine transporter 2 (VMAT2) in σ1R+/− mice or σ1R−/− mice had no difference from WT mice. Interestingly, MPTP-WT mice showed the reduction in the levels of DAT and VMAT2, but MPTP-σ1R−/− mice did not. The inactivation of σ1R by NE100 could prevent the reduction of VMAT2 in MPTP-WT mice. In addition, the activation of microglia cells in substantia nigra was equally enhanced in MPTP-WT mice and MPTP-σ1R−/− mice. The number of activated astrocytes in MPTP-σ1R−/− mice was less than that in MPTP-WT mice. The findings indicate that the σ1R deficiency through suppressing NMDAr function and DAT expression can reduce MPTP-induced death of

  10. S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice.

    PubMed

    Fuso, Andrea; Nicolia, Vincenzina; Ricceri, Laura; Cavallaro, Rosaria A; Isopi, Elisa; Mangia, Franco; Fiorenza, Maria Teresa; Scarpa, Sigfrido

    2012-07-01

    Methylation reactions linked to homocysteine in the one-carbon metabolism are increasingly elicited in Alzheimer's disease, although the association of hyperhomocysteinemia and of low B vitamin levels with the disease is still debated. We previously demonstrated that hyperhomocysteinemia and DNA hypomethylation induced by B vitamin deficiency are associated with PSEN1 and BACE1 overexpression and amyloid production. The present study is aimed at assessing S-adenosylmethionine effects in mice kept under a condition of B vitamin deficiency. To this end, TgCRND8 mice and wild-type littermates were assigned to control or B vitamin deficient diet, with or without S-adenosylmethionine supplementation. We found that S-adenosylmethionine reduced amyloid production, increased spatial memory in TgCRND8 mice and inhibited the upregulation of B vitamin deficiency-induced PSEN1 and BACE1 expression and Tau phosphorylation in TgCRND8 and wild-type mice. Furthermore, S-adenosylmethionine treatment reduced plaque spreading independently on B vitamin deficiency. These results strengthen our previous observations on the possible role of one-carbon metabolism in Alzheimer's disease, highlighting hyperhomocysteinemia-related mechanisms in dementia onset/progression and encourage further studies aimed at evaluating the use of S-adenosylmethionine as a potential candidate drug for the treatment of the disease. PMID:22221883

  11. Reduced endoplasmic reticulum stress-induced apoptosis and impaired unfolded protein response in TRPC3-deficient M1 macrophages

    PubMed Central

    Solanki, Sumeet; Dube, Prabhatchandra R.; Tano, Jean-Yves; Birnbaumer, Lutz

    2014-01-01

    Endoplasmic reticulum (ER) stress is a prominent mechanism of macrophage apoptosis in advanced atherosclerotic lesions. Recent studies from our laboratory showed that advanced atherosclerotic plaques in Apoe−/− mice with bone marrow deficiency of the calcium-permeable channel Transient Receptor Potential Canonical 3 (TRPC3) are characterized by reduced areas of necrosis and fewer apoptotic macrophages than animals transplanted with Trpc3+/+ bone marrow. In vitro, proinflammatory M1 but not anti-inflammatory M2 macrophages derived from Trpc3−/−Apoe−/− animals exhibited reduced ER stress-induced apoptosis. However, whether this was due to a specific effect of TRPC3 deficiency on macrophage ER stress signaling remained to be determined. In the present work we used polarized macrophages derived from mice with macrophage-specific deficiency of TRPC3 to examine the expression level of ER stress markers and the activation status of some typical mediators of macrophage apoptosis. We found that the reduced susceptibility of TRPC3-deficient M1 macrophages to ER stress-induced apoptosis correlates with an impaired unfolded protein response (UPR), reduced mitochondrion-dependent apoptosis, and reduced activation of the proapoptotic molecules calmodulin-dependent protein kinase II and signal transducer and activator of transcription 1. Notably, none of these pathways was altered in TRPC3-deficient M2 macrophages. These findings show for the first time an obligatory requirement for a member of the TRPC family of cation channels in ER stress-induced apoptosis in macrophages, underscoring a rather selective role of the TRPC3 channel on mechanisms related to the UPR signaling in M1 macrophages. PMID:25031020

  12. Vitamin E deficiency reduced lumbar bone calcium content in female rats.

    PubMed

    Norazlina, M; Chua, C W; Ima-Nirwana, S

    2004-12-01

    Vitamin E deficiency has been found to impair bone calcification. This study was done to determine the effects of vitamin E deficiency and supplementation on parathyroid hormone, i.e. the hormone involved in bone regulation. Female Sprague-Dawley rats were divided into 4 groups: 1) normal rat chow (RC), 2) vitamin E deficiency (VED), vitamin E deficient rats supplemented with 3) 60 mg/kg alpha-tocotrienol (ATT) and 4) 60 mg/kg (alpha-tocopherol (ATF). Treatment was carried out for 3 months. Vitamin E deficiency caused hypocalcaemia during the first month of the treatment period, increased the parathyroid hormone level in the second month and decreased the bone calcium content in the 4th lumbar bone at the end of the treatment. Vitamin E supplementation (ATT and ATF) failed to improve these conditions. The bone formation marker, osteocalcin, and the bone resorption marker, deoxypyridinoline did not change throughout the study period. In conclusion vitamin E deficiency impaired bone calcium homeostasis with subsequent secondary hyperparathyroidism and vertebral bone loss. Replacing the vitamin E with pure ATF or pure ATT alone failed to correct the changes seen. PMID:15889565

  13. Citrullus lanatus 'sentinel' (watermelon) extract reduces atherosclerosis in LDL receptor-deficient mice.

    PubMed

    Poduri, Aruna; Rateri, Debra L; Saha, Shubin K; Saha, Sibu; Daugherty, Alan

    2013-05-01

    Watermelon (Citrullus lanatus or C. lanatus) has many potentially bioactive compounds including citrulline, which may influence atherosclerosis. In this study, we determined the effects of C. lanatus, provided as an extract of the cultivar 'sentinel,' on hypercholesterolemia-induced atherosclerosis in mice. Male low-density lipoprotein receptor-deficient mice at 8 weeks old were given either C. lanatus 'sentinel' extract (2% vol/vol; n=10) or a mixture of matching carbohydrates (2% vol/vol; n=8) as the control in drinking water while being fed a saturated fat-enriched diet for 12 weeks ad libitum. Mice consuming C. lanatus 'sentinel' extract had significantly increased plasma citrulline concentrations. Systolic blood pressure was comparable between the two groups. Consumption of C. lanatus 'sentinel' extract led to lower body weight and fat mass without influencing lean mass. There were no differences in food and water intake and in urine output between the two groups. C. lanatus 'sentinel' extract administration decreased plasma cholesterol concentrations that were attributed to reductions of intermediate-/low-density lipoprotein cholesterol. Plasma concentrations of monocyte chemoattractant protein-1 and interferon-gamma were decreased and those of interleukin-10 were increased in mice consuming C. lanatus 'sentinel' extract. Intake of C. lanatus 'sentinel' extract resulted in reductions of atherosclerosis in both aortic arch and thoracic regions. In conclusion, consumption of C. lanatus 'sentinel' extract led to reduced body weight gain, decreased plasma cholesterol concentrations, improved homeostasis of pro- and anti-inflammatory cytokines, and attenuated development of atherosclerosis without affecting systolic blood pressure in hypercholesterolemic mice. PMID:22902326

  14. Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity.

    PubMed

    Ham, Mira; Choe, Sung Sik; Shin, Kyung Cheul; Choi, Goun; Kim, Ji-Won; Noh, Jung-Ran; Kim, Yong-Hoon; Ryu, Je-Won; Yoon, Kun-Ho; Lee, Chul-Ho; Kim, Jae Bum

    2016-09-01

    Glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, plays important roles in redox regulation and de novo lipogenesis. It was recently demonstrated that aberrant upregulation of G6PD in obese adipose tissue mediates insulin resistance as a result of imbalanced energy metabolism and oxidative stress. It remains elusive, however, whether inhibition of G6PD in vivo may relieve obesity-induced insulin resistance. In this study we showed that a hematopoietic G6PD defect alleviates insulin resistance in obesity, accompanied by reduced adipose tissue inflammation. Compared with wild-type littermates, G6PD-deficient mutant (G6PD(mut)) mice were glucose tolerant upon high-fat-diet (HFD) feeding. Intriguingly, the expression of NADPH oxidase genes to produce reactive oxygen species was alleviated, whereas that of antioxidant genes was enhanced in the adipose tissue of HFD-fed G6PD(mut) mice. In diet-induced obesity (DIO), the adipose tissue of G6PD(mut) mice decreased the expression of inflammatory cytokines, accompanied by downregulated proinflammatory macrophages. Accordingly, macrophages from G6PD(mut) mice greatly suppressed lipopolysaccharide-induced proinflammatory signaling cascades, leading to enhanced insulin sensitivity in adipocytes and hepatocytes. Furthermore, adoptive transfer of G6PD(mut) bone marrow to wild-type mice attenuated adipose tissue inflammation and improved glucose tolerance in DIO. Collectively, these data suggest that inhibition of macrophage G6PD would ameliorate insulin resistance in obesity through suppression of proinflammatory responses. PMID:27284106

  15. Reduced Food Intake and Body Weight in Mice Deficient for the G Protein-Coupled Receptor GPR82

    PubMed Central

    Teupser, Daniel; Holdt, Lesca Miriam; Tönjes, Anke; Kern, Matthias; Dietrich, Kerstin; Kovacs, Peter; Krügel, Ute; Scheidt, Holger A.; Schiller, Jürgen; Huster, Daniel; Brockmann, Gudrun A.; Augustin, Martin; Thiery, Joachim; Blüher, Matthias; Stumvoll, Michael; Schöneberg, Torsten; Schulz, Angela

    2011-01-01

    G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods of human evolution. Indeed, several genomic loci with signatures of recent selection in humans contain GPCR genes among them the X-chromosomally located gene for GPR82. This gene encodes a so-called orphan GPCR with unknown function. To address the functional relevance of GPR82 gene-deficient mice were characterized. GPR82-deficient mice were viable, reproduced normally, and showed no gross anatomical abnormalities. However, GPR82-deficient mice have a reduced body weight and body fat content associated with a lower food intake. Moreover, GPR82-deficient mice showed decreased serum triacylglyceride levels, increased insulin sensitivity and glucose tolerance, most pronounced under Western diet. Because there were no differences in respiratory and metabolic rates between wild-type and GPR82-deficient mice our data suggest that GPR82 function influences food intake and, therefore, energy and body weight balance. GPR82 may represent a thrifty gene most probably representing an advantage during human expansion into new environments. PMID:22216272

  16. N-glycosylation deficiency reduces ICAM-1 induction and impairs inflammatory response

    PubMed Central

    He, Ping; Srikrishna, Geetha; Freeze, Hudson H

    2014-01-01

    Congenital disorders of glycosylation (CDGs) result from mutations in various N-glycosylation genes. The most common type, phosphomannomutase-2 (PMM2)-CDG (CDG-Ia), is due to deficient PMM2 (Man-6-P → Man-1-P). Many patients die from recurrent infections, but the mechanism is unknown. We found that glycosylation-deficient patient fibroblasts have less intercellular adhesion molecule-1 (ICAM-1), and because of its role in innate immune response, we hypothesized that its reduction might help explain recurrent infections in CDG patients. We, therefore, studied mice with mutations in Mpi encoding phosphomannose isomerase (Fru-6-P → Man-6-P), the cause of human MPI-CDG. We challenged MPI-deficient mice with an intraperitoneal injection of zymosan to induce an inflammatory response and found decreased neutrophil extravasation compared with control mice. Immunohistochemistry of mesenteries showed attenuated neutrophil egress, presumably due to poor ICAM-1 response to acute peritonitis. Since phosphomannose isomerase (MPI)-CDG patients and their cells improve glycosylation when given mannose, we provided MPI-deficient mice with mannose-supplemented water for 7 days. This restored ICAM-1 expression on mesenteric endothelial cells and enhanced transendothelial migration of neutrophils during acute inflammation. Attenuated inflammatory response in glycosylation-deficient mice may result from a failure to increase ICAM-1 on the vascular endothelial surface and may help explain recurrent infections in patients. PMID:24474243

  17. Deficiency of IκB Kinase β in Myeloid Cells Reduces Severity of Experimental Autoimmune Encephalomyelitis.

    PubMed

    Hao, Wenlin; Decker, Yann; Schnöder, Laura; Schottek, Andrea; Li, Dong; Menger, Michael D; Fassbender, Klaus; Liu, Yang

    2016-05-01

    In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), peripherally developed myelin-reactive T lymphocytes stimulate myeloid cells (ie, microglia and infiltrated macrophages) to trigger an inflammatory reaction in the central nervous system, resulting in demyelination and neurodegeneration. IκB kinase β (IKKβ) is a kinase that modulates transcription of inflammatory genes. To investigate the pathogenic role of IKKβ in MS, we developed strains in which IKKβ was conditionally ablated in myeloid cells and established active or passive EAE in these animals. Deficiency of IKKβ in myeloid cells ameliorated EAE symptoms and suppressed neuroinflammation, as shown by decreased infiltration of T lymphocytes and macrophages and reduced inflammatory gene transcription in the spinal cord at the peak or end stage of EAE. Myeloid deficiency of IKKβ also reduced the transcription of Rorc or Il17 genes in T lymphocytes isolated from lymph nodes, spleen, and spinal cord of EAE mice. Moreover, cultured splenocytes isolated from myeloid IKKβ-deficient EAE mice released less IL-17, interferon-γ, and granulocyte-macrophage colony-stimulating factor after treatment with myelin peptide than splenocytes from IKKβ wild-type EAE mice. Thus, deficiency of myeloid IKKβ attenuates the severity of EAE by inhibiting both the neuroinflammatory activity and the activation of encephalitogenic T lymphocytes. These results suggest IKKβ may be a potential target for MS patients, especially when neuroinflammation is the primary problem. PMID:26968344

  18. A Program of Nutritional Education in Schools Reduced the Prevalence of Iron Deficiency in Students

    PubMed Central

    García-Casal, María Nieves; Landaeta-Jiménez, Maritza; Puche, Rafael; Leets, Irene; Carvajal, Zoila; Patiño, Elijú; Ibarra, Carlos

    2011-01-01

    The objective was to determine the prevalence of iron, folates and retinol deficiencies in school children and to evaluate the changes after an intervention of nutritional education. The project was developed in 17 schools. The sample included 1,301 children (678 males and 623 females). A subsample of 480 individuals, was randomly selected for drawing blood for biochemical determinations before and after the intervention of nutritional education, which included in each school: written pre and post-intervention tests, 6 workshops, 2 participative talks, 5 game activities, 1 cooking course and 1 recipe contest. Anthropometrical and biochemical determinations included weight, height, body-mass index, nutritional status, hematocrit, serum ferritin, retinol and folate concentrations. There was high prevalence of iron (25%), folates (75%) and vitamin A (43%) deficiencies in school children, with a low consumption of fruit and vegetables, high consumption of soft drinks and snacks and almost no physical activity. The nutritional education intervention produced a significant reduction in iron deficiency prevalence (25 to 14%), and showed no effect on vitamin A and folates deficiencies. There was a slight improvement in nutritional status. This study shows, through biochemical determinations, that nutritional education initiatives and programs have an impact improving nutritional health in school children. PMID:21547083

  19. Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1

    PubMed Central

    2014-01-01

    Introduction Defects in the DNA mismatch repair (MMR) protein MLH1 are frequently observed in sporadic and hereditary colorectal cancers (CRC). Affected tumors generate much less metastatic potential than the MLH1 proficient forms. Although MLH1 has been shown to be not only involved in postreplicative MMR but also in several MMR independent processes like cytoskeletal organization, the connection between MLH1 and metastasis remains unclear. We recently identified non-erythroid spectrin αII (SPTAN1), a scaffolding protein involved in cell adhesion and motility, to interact with MLH1. In the current study, the interaction of MLH1 and SPTAN1 and its potential consequences for CRC metastasis was evaluated. Methods Nine cancer cell lines as well as fresh and paraffin embedded colon cancer tissue from 12 patients were used in gene expression studies of SPTAN1 and MLH1. Co-expression of SPTAN1 and MLH1 was analyzed by siRNA knock down of MLH1 in HeLa, HEK293, MLH1 positive HCT116, SW480 and LoVo cells. Effects on cellular motility were determined in MLH1 deficient HCT116 and MLH1 deficient HEK293T compared to their MLH1 proficient sister cells, respectively. Results MLH1 deficiency is clearly associated with SPTAN1 reduction. Moreover, siRNA knock down of MLH1 decreased the mRNA level of SPTAN1 in HeLa, HEK293 as well as in MLH1 positive HCT116 cells, which indicates a co-expression of SPTAN1 by MLH1. In addition, cellular motility of MLH1 deficient HCT116 and MLH1 deficient HEK293T cells was impaired compared to the MLH1 proficient sister clones. Consequently, overexpression of SPTAN1 increased migration of MLH1 deficient cells while knock down of SPTAN1 decreased cellular mobility of MLH1 proficient cells, indicating SPTAN1-dependent migration ability. Conclusions These data suggest that SPTAN1 levels decreased in concordance with MLH1 reduction and impaired cellular mobility in MLH1 deficient colon cancer cells. Therefore, aggressiveness of MLH1-positive CRC might be

  20. Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility

    PubMed Central

    Medina, Indira; Bermudez, Beatriz; Koenen, Rory R.; Sluimer, Judith; Wolfs, Ine; Döring, Yvonne; Herias, Veronica; Gijbels, Marjon; Bot, Ilze; de Jager, Saskia; Weber, Christian; Cleutjens, Jack; van Berkel, Theo J.C.; Sikkink, Kees-Jan; Mócsai, Atilla; Maridonneau-Parini, Isabelle; Soehnlein, Oliver; Biessen, Erik A.L.

    2015-01-01

    Background Leukocyte migration is critical for the infiltration of monocytes and accumulation of monocyte derived macrophages in inflammation. Considering that Hck and Fgr are instrumental in this process, their impact on atherosclerosis and on lesion inflammation and stability was evaluated. Methods and Results Hematopoietic Hck/Fgr–deficient, LDLr−/− chimeras, obtained by bone marrow transplantation, had smaller but, paradoxically, less stable lesions with reduced macrophage content, overt cap thinning, and necrotic core expansion as most prominent features. Despite a Ly6Chigh skewed proinflammatory monocyte phenotype, Hck/Fgr deficiency led to disrupted adhesion of myeloid cells to and transmigration across endothelial monolayers in-vitro and atherosclerotic plaques in–vivo, as assessed by intravital microscopy, flow cytometry and histological examination of atherosclerotic arteries. Moreover, Hck/Fgr deficient macrophages showed blunted podosome formation and mesenchymal migration capacity. In consequence transmigrated dKO macrophages were seen to accumulate in the fibrous cap, potentially promoting its focal erosion, as observed for dKO chimeras. Conclusions Hematopoietic deficiency of Hck and Fgr led to attenuated atherosclerotic plaque formation by abrogating endothelial adhesion and transmigration; paradoxically it also promoted plaque instability by causing monocyte subset imbalance and subendothelial accumulation, raising a note of caution regarding src kinase targeted intervention in plaque inflammation. PMID:26068045

  1. SOD2 deficiency in hematopoietic cells in mice results in reduced red blood cell deformability and increased heme degradation

    PubMed Central

    Mohanty, Joy G.; Nagababu, Enika; Friedman, Jeffrey S.; Rifkind, Joseph M.

    2013-01-01

    Among the three types of super oxide dismutases (SODs) known, SOD2 deficiency is lethal in neonatal mice owing to cardiomyopathy caused by severe oxidative damage. SOD2 is found in red blood cell (RBC) precursors, but not in mature RBCs. To investigate the potential damage to mature RBCs resulting from SOD2 deficiency in precursor cells, we studied RBCs from mice in which fetal liver stem cells deficient in SOD2 were capable of efficiently rescuing lethally irradiated host animals. These transplanted animals lack SOD2 only in hematopoietically generated cells and live longer than SOD2 knockouts. In these mice, approximately 2.8% of their total RBCs in circulation are iron-laden reticulocytes, with numerous siderocytic granules and increased protein oxidation similar to that seen in sideroblastic anemia. We have studied the RBC deformability and oxidative stress in these animals and the control group by measuring them with a microfluidic ektacytometer and assaying fluorescent heme degradation products with a fluorimeter, respectively. In addition, the rate of hemoglobin oxidation in RBCs from these mice and the control group were measured spectrophotometrically. The results show that RBCs from these SOD2-deficient mice have reduced deformability, increased heme degradation products, and an increased rate of hemoglobin oxidation compared with control animals, indicative of increased RBC oxidative stress. PMID:23142655

  2. Marginal Maternal Zinc Deficiency in Lactating Mice Reduces Secretory Capacity and Alters Milk Composition12

    PubMed Central

    Dempsey, Colleen; McCormick, Nicholas H.; Croxford, Thomas P.; Seo, Young Ah; Grider, Arthur; Kelleher, Shannon L.

    2012-01-01

    Dietary analysis predicts that marginal Zn deficiency is common in women of reproductive age. The lack of reliable biomarkers limits the capacity to assess Zn status and consequently understand effects of maternal Zn deficiency. We determined effects of marginal maternal Zn deficiency on mammary gland function, milk secretion, and milk composition in mice. Mice (n = 12/diet) were fed marginal (ZD; 15 mg Zn/kg diet) or adequate (ZA; 30 mg Zn/kg diet) Zn diets for 30 d prior to conception through mid-lactation. Mice fed the ZD had a higher plasma Zn concentration (~20%; P < 0.05) but lower milk Zn concentration (~15%; P < 0.05) compared with mice fed the ZA. ZnT2 abundance was higher (P < 0.05) in mice fed the ZD compared with mice fed the ZA; no effect on ZnT4 abundance was detected. The Zn concentration of mammary gland mitochondria tended to be ~40% greater in mice fed ZD (P = 0.07); this was associated with apoptosis and lower milk secretion (~80%; P < 0.01). Total milk protein was ~25% higher (P < 0.05), although the abundance of the major milk proteins (caseins and whey acidic protein) was lower (P < 0.05) in mice fed the ZD. Proteomic analysis of milk proteins revealed an increase (P < 0.05) in four proteins in mice fed the ZD. These findings illustrate that marginal maternal Zn deficiency compromises mammary gland function and milk secretion and alters milk composition. This suggests that lactating women who consume inadequate Zn may not produce and/or secrete an adequate amount of high quality milk to provide optimal nutrition to their developing infant. PMID:22357740

  3. Reduced early alcohol-induced liver injury in CD14-deficient mice.

    PubMed

    Yin, M; Bradford, B U; Wheeler, M D; Uesugi, T; Froh, M; Goyert, S M; Thurman, R G

    2001-04-01

    Activation of Kupffer cells by gut-derived endotoxin is associated with alcohol-induced liver injury. Recently, it was shown that CD14-deficient mice are more resistant to endotoxin-induced shock than wild-type controls. Therefore, this study was designed to investigate the role of CD14 receptors in early alcohol-induced liver injury using CD14 knockout and wild-type BALB/c mice in a model of enteral ethanol delivery. Animals were given a high-fat liquid diet continuously with ethanol or isocaloric maltose-dextrin as control for 4 wk. The liver to body weight ratio in wild-type mice (5.8 +/- 0.3%) was increased significantly by ethanol (7.3 +/- 0.2%) but was not altered by ethanol in CD14-deficient mice. Ethanol elevated serum alanine aminotransferase levels nearly 3-fold in wild-type mice, but not in CD14-deficient mice. Wild-type and knockout mice given the control high-fat diet had normal liver histology, whereas ethanol caused severe liver injury (steatosis, inflammation, and necrosis; pathology score = 3.8 +/- 0.4). In contrast, CD14-deficient mice given ethanol showed minimal hepatic changes (score = 1.6 +/- 0.3, p < 0.05). Additionally, NF-kappa B, TGF-beta, and TNF-alpha were increased significantly in wild-type mice fed ethanol but not in the CD14 knockout. Thus, chronic ethanol feeding caused more severe liver injury in wild-type than CD14 knockouts, supporting the hypothesis that endotoxin acting via CD14 plays a major role in the development of early alcohol-induced liver injury. PMID:11254735

  4. Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix

    PubMed Central

    Valli, M; Barnes, AM; Gallanti, A; Cabral, WA; Viglio, S; Weis, MA; Makareeva, E; Eyre, D; Leikin, S; Antoniazzi, F; Marini, JC; Mottes, M

    2013-01-01

    Deficiency of any component of the ER-resident collagen prolyl 3-hydroxylation complex causes recessive osteogenesis imperfecta (OI). The complex modifies the α1(I)Pro986 residue and contains cartilage-associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1) and cyclophilin B (CyPB). Fibroblasts normally secrete about 10% of CRTAP. Most CRTAP mutations cause a null allele and lethal type VII OI. We identified a 7-year-old Egyptian boy with non-lethal type VII OI and investigated the effects of his null CRTAP mutation on collagen biochemistry, the prolyl 3-hydroxylation complex, and collagen in extracellular matrix. The proband is homozygous for an insertion/deletion in CRTAP (c.118_133del16insTACCC). His dermal fibroblasts synthesize fully overmodified type I collagen, and 3-hydroxylate only 5% of α1(I)Pro986. CRTAP transcripts are 10% of control. CRTAP protein is absent from proband cells, with residual P3H1 and normal CyPB levels. Dermal collagen fibril diameters are significantly increased. By immunofluorescence of long-term cultures, we identified a severe deficiency (10–15% of control) of collagen deposited in extracellular matrix, with disorganization of the minimal fibrillar network. Quantitative pulse-chase experiments corroborate deficiency of matrix deposition, rather than increased matrix turnover. We conclude that defects of extracellular matrix, as well as intracellular defects in collagen modification, contribute to the pathology of type VII OI. PMID:21955071

  5. Nebulin-deficient mice exhibit shorter thin filament lengths and reduced contractile function in skeletal muscle

    PubMed Central

    Bang, Marie-Louise; Li, Xiaodong; Littlefield, Ryan; Bremner, Shannon; Thor, Andrea; Knowlton, Kirk U.; Lieber, Richard L.; Chen, Ju

    2006-01-01

    Nebulin is a giant modular sarcomeric protein that has been proposed to play critical roles in myofibrillogenesis, thin filament length regulation, and muscle contraction. To investigate the functional role of nebulin in vivo, we generated nebulin-deficient mice by using a Cre knock-in strategy. Lineage studies utilizing this mouse model demonstrated that nebulin is expressed uniformly in all skeletal muscles. Nebulin-deficient mice die within 8–11 d after birth, with symptoms including decreased milk intake and muscle weakness. Although myofibrillogenesis had occurred, skeletal muscle thin filament lengths were up to 25% shorter compared with wild type, and thin filaments were uniform in length both within and between muscle types. Ultrastructural studies also demonstrated a critical role for nebulin in the maintenance of sarcomeric structure in skeletal muscle. The functional importance of nebulin in skeletal muscle function was revealed by isometric contractility assays, which demonstrated a dramatic reduction in force production in nebulin-deficient skeletal muscle. PMID:16769824

  6. Crif1 Deficiency Reduces Adipose OXPHOS Capacity and Triggers Inflammation and Insulin Resistance in Mice

    PubMed Central

    Ryu, Min Jeong; Kim, Soung Jung; Kim, Yong Kyung; Choi, Min Jeong; Tadi, Surendar; Lee, Min Hee; Lee, Seong Eun; Chung, Hyo Kyun; Jung, Saet Byel; Kim, Hyun-Jin; Jo, Young Suk; Kim, Koon Soon; Lee, Sang-Hee; Kim, Jin Man; Kweon, Gi Ryang; Park, Ki Cheol; Lee, Jung Uee; Kong, Young Yun; Lee, Chul-Ho; Chung, Jongkyeong; Shong, Minho

    2013-01-01

    Impaired mitochondrial oxidative phosphorylation (OXPHOS) has been proposed as an etiological mechanism underlying insulin resistance. However, the initiating organ of OXPHOS dysfunction during the development of systemic insulin resistance has yet to be identified. To determine whether adipose OXPHOS deficiency plays an etiological role in systemic insulin resistance, the metabolic phenotype of mice with OXPHOS–deficient adipose tissue was examined. Crif1 is a protein required for the intramitochondrial production of mtDNA–encoded OXPHOS subunits; therefore, Crif1 haploinsufficient deficiency in mice results in a mild, but specific, failure of OXPHOS capacity in vivo. Although adipose-specific Crif1-haploinsufficient mice showed normal growth and development, they became insulin-resistant. Crif1-silenced adipocytes showed higher expression of chemokines, the expression of which is dependent upon stress kinases and antioxidant. Accordingly, examination of adipose tissue from Crif1-haploinsufficient mice revealed increased secretion of MCP1 and TNFα, as well as marked infiltration by macrophages. These findings indicate that the OXPHOS status of adipose tissue determines its metabolic and inflammatory responses, and may cause systemic inflammation and insulin resistance. PMID:23516375

  7. Laminin alpha1 chain reduces muscular dystrophy in laminin alpha2 chain deficient mice.

    PubMed

    Gawlik, Kinga; Miyagoe-Suzuki, Yuko; Ekblom, Peter; Takeda, Shin'ichi; Durbeej, Madeleine

    2004-08-15

    Laminin (LN) alpha2 chain deficiency in humans and mice leads to severe forms of congenital muscular dystrophy (CMD). Here, we investigated whether LNalpha1 chain in mice can compensate for the absence of LNalpha2 chain and prevent the development of muscular dystrophy. We generated mice expressing a LNalpha1 chain transgene in skeletal muscle of LNalpha2 chain deficient mice. LNalpha1 is not normally expressed in muscle, but the transgenically produced LNalpha1 chain was incorporated into muscle basement membranes, and normalized the compensatory changes of expression of certain other laminin chains (alpha4, beta2). In 4-month-old mice, LNalpha1 chain could fully prevent the development of muscular dystrophy in several muscles, and partially in others. The LNalpha1 chain transgene not only reversed the appearance of histopathological features of the disease to a remarkable degree, but also greatly improved health and longevity of the mice. Correction of LNalpha2 chain deficiency by LNalpha1 chain may serve as a paradigm for gene therapy of CMD in patients. PMID:15213105

  8. Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

    PubMed Central

    Langhauser, Friederike; Göb, Eva; Kraft, Peter; Geis, Christian; Schmitt, Joachim; Brede, Marc; Göbel, Kerstin; Helluy, Xavier; Pham, Mirko; Bendszus, Martin; Jakob, Peter; Stoll, Guido; Meuth, Sven G.; Nieswandt, Bernhard; McCrae, Keith R.

    2012-01-01

    Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. High-molecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng−/− mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng−/− mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases. PMID:22936662

  9. Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation.

    PubMed

    Langhauser, Friederike; Göb, Eva; Kraft, Peter; Geis, Christian; Schmitt, Joachim; Brede, Marc; Göbel, Kerstin; Helluy, Xavier; Pham, Mirko; Bendszus, Martin; Jakob, Peter; Stoll, Guido; Meuth, Sven G; Nieswandt, Bernhard; McCrae, Keith R; Kleinschnitz, Christoph

    2012-11-01

    Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. High-molecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng(-/-) mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng(-/-) mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases. PMID:22936662

  10. Severely reduced gravitropism in dark-grown hypocotyls of a starch-deficient mutant of Nicotiana sylvestris

    NASA Technical Reports Server (NTRS)

    Kiss, J. Z.; Sack, F. D.

    1990-01-01

    Gravitropism in dark-grown hypocotyls of the wild type was compared with a starch-deficient Nicotiana sylvestris mutant (NS 458) to test the effects of starch deficiency on gravity sensing. In a time course of curvature measured using infrared video, the response of the mutant was greatly reduced compared to the wild type; 72 hours after reorientation, curvature was about 10 degrees for NS 458 and about 70 degrees for wild type. In dishes maintained in a vertical orientation, wild-type hypocotyls were predominantly vertical, whereas NS 458 hypocotyls were severely disoriented with about 5 times more orientational variability than wild type. Since the growth rates were equal for both genotypes and phototropic curvature was only slightly inhibited in NS 458, the mutation probably affects gravity perception rather than differential growth. Our data suggest that starch deficiency reduces gravitropic sensitivity more in dark-grown hypocotyls than in dark- or light-grown roots in this mutant and support the hypothesis that amyloplasts function as statoliths in shoots as well as roots.

  11. Western blot expression of 5-lipoxygenase in the brain from striped dolphins (stenella coeruleoalba) and bottlenose dolphins (tursiops truncatus) with or without encephalitis/meningo-encephalitis of infectious nature.

    PubMed

    Di Guardo, G; Falconi, A; Di Francesco, A; Mazzariol, S; Centelleghe, C; Casalone, C; Pautasso, A; Cocumelli, C; Eleni, C; Petrella, A; Di Francesco, C E; Sabatucci, A; Leonardi, L; Serroni, A; Marsili, L; Storelli, M M; Giacominelli-Stuffler, R

    2015-01-01

    Dolphin Morbillivirus (DMV), Toxoplasma gondii and Brucella ceti are pathogens of major concern for wild cetaceans. Although a more or less severe encephalitis/meningo-encephalitis may occur in striped dolphins (Stenella coeruleoalba) and bottlenose dolphins (Tursiops truncatus) infected by the aforementioned agents, almost no information is available on the neuropathogenesis of brain lesions, including the neuronal and non-neuronal cells targeted during infection, along with the mechanisms underlying neurodegeneration. We analyzed 5-lipoxygenase (5-LOX) expression in the brain of 11 striped dolphins and 5 bottlenose dolphins, affected or not by encephalitic lesions of various degrees associated with DMV, T. gondii and B. ceti. All the 8 striped dolphins with encephalitis showed a more consistent 5-LOX expression than that observed in the 3 striped dolphins showing no morphologic evidence of brain lesions, with the most prominent band intensity being detected in a B. ceti-infected animal. Similar results were not obtained in T. gondii-infected vs T. gondii-uninfected bottlenose dolphins. Overall, the higher 5-LOX expression found in the brain of the 8 striped dolphins with infectious neuroinflammation is of interest, given that 5-LOX is a putative marker for neurodegeneration in human patients and in experimental animal models. Therefore, further investigation on this challenging issue is also needed in stranded cetaceans affected by central neuropathies. PMID:25864766

  12. Synthesis and biological evaluation of salicylic acid and N-acetyl-2-carboxybenzenesulfonamide regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore: dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity.

    PubMed

    Chowdhury, Morshed A; Abdellatif, Khaled R A; Dong, Ying; Das, Dipankar; Yu, Gang; Velázquez, Carlos A; Suresh, Mavanur R; Knaus, Edward E

    2009-12-15

    A novel class of salicylic acid and N-acetyl-2-carboxybenzenesulfonamide regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore attached to its C-4 or C-5 position was designed for evaluation as anti-inflammatory (AI) agents. Replacement of the 2,4-difluorophenyl ring in diflunisal by the N-difluoromethyl-1,2-dihydropyrid-2-one moiety provided compounds showing dual selective cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activities. AI structure-activity studies showed that the C-4 (14a) and C-5 (14b) salicylate regioisomers were 1.4- and 1.6-fold more potent than aspirin, and the C-5 N-acetyl-2-carboxybenzenesulfonamide regioisomer (22b) was 1.3- and 2.8-fold more potent than ibuprofen and aspirin, respectively. In vivo ulcer index (UI) studies showed that the 4- and 5-(N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl)salicylic acids (14a and 14b) were completely non-ulcerogenic since no gastric lesions were present (UI=0) relative to aspirin (UI=57) at an equivalent mumol/kg oral dose. The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel 5-LOX pharmacophore for the design of cyclic hydroxamic mimetics for exploitation in the development of dual COX-2/5-LOX inhibitory AI drugs. PMID:19884005

  13. XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination

    PubMed Central

    IJspeert, Hanna; Rozmus, Jacob; Schwarz, Klaus; Warren, René L.; van Zessen, David; Holt, Robert A.; Pico-Knijnenburg, Ingrid; Simons, Erik; Jerchel, Isabel; Wawer, Angela; Lorenz, Myriam; Patıroğlu, Turkan; Akar, Himmet Haluk; Leite, Ricardo; Verkaik, Nicole S.; Stubbs, Andrew P.; van Gent, Dik C.; van Dongen, Jacques J. M.

    2016-01-01

    Repair of DNA double-strand breaks (DSBs) by the nonhomologous end-joining pathway (NHEJ) is important not only for repair of spontaneous breaks but also for breaks induced in developing lymphocytes during V(D)J (variable [V], diversity [D], and joining [J] genes) recombination of their antigen receptor loci to create a diverse repertoire. Mutations in the NHEJ factor XLF result in extreme sensitivity for ionizing radiation, microcephaly, and growth retardation comparable to mutations in LIG4 and XRCC4, which together form the NHEJ ligation complex. However, the effect on the immune system is variable (mild to severe immunodeficiency) and less prominent than that seen in deficiencies of NHEJ factors ARTEMIS and DNA-dependent protein kinase catalytic subunit, with defects in the hairpin opening step, which is crucial and unique for V(D)J recombination. Therefore, we aimed to study the role of XLF during V(D)J recombination. We obtained clinical data from 9 XLF-deficient patients and performed immune phenotyping and antigen receptor repertoire analysis of immunoglobulin (Ig) and T-cell receptor (TR) rearrangements, using next-generation sequencing in 6 patients. The results were compared with XRCC4 and LIG4 deficiency. Both Ig and TR rearrangements showed a significant decrease in the number of nontemplated (N) nucleotides inserted by terminal deoxynucleotidyl transferase, which resulted in a decrease of 2 to 3 amino acids in the CDR3. Such a reduction in the number of N-nucleotides has a great effect on the junctional diversity, and thereby on the total diversity of the Ig and TR repertoire. This shows that XLF has an important role during V(D)J recombination in creating diversity of the repertoire by stimulating N-nucleotide insertion. PMID:27281794

  14. XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination.

    PubMed

    IJspeert, Hanna; Rozmus, Jacob; Schwarz, Klaus; Warren, René L; van Zessen, David; Holt, Robert A; Pico-Knijnenburg, Ingrid; Simons, Erik; Jerchel, Isabel; Wawer, Angela; Lorenz, Myriam; Patıroğlu, Turkan; Akar, Himmet Haluk; Leite, Ricardo; Verkaik, Nicole S; Stubbs, Andrew P; van Gent, Dik C; van Dongen, Jacques J M; van der Burg, Mirjam

    2016-08-01

    Repair of DNA double-strand breaks (DSBs) by the nonhomologous end-joining pathway (NHEJ) is important not only for repair of spontaneous breaks but also for breaks induced in developing lymphocytes during V(D)J (variable [V], diversity [D], and joining [J] genes) recombination of their antigen receptor loci to create a diverse repertoire. Mutations in the NHEJ factor XLF result in extreme sensitivity for ionizing radiation, microcephaly, and growth retardation comparable to mutations in LIG4 and XRCC4, which together form the NHEJ ligation complex. However, the effect on the immune system is variable (mild to severe immunodeficiency) and less prominent than that seen in deficiencies of NHEJ factors ARTEMIS and DNA-dependent protein kinase catalytic subunit, with defects in the hairpin opening step, which is crucial and unique for V(D)J recombination. Therefore, we aimed to study the role of XLF during V(D)J recombination. We obtained clinical data from 9 XLF-deficient patients and performed immune phenotyping and antigen receptor repertoire analysis of immunoglobulin (Ig) and T-cell receptor (TR) rearrangements, using next-generation sequencing in 6 patients. The results were compared with XRCC4 and LIG4 deficiency. Both Ig and TR rearrangements showed a significant decrease in the number of nontemplated (N) nucleotides inserted by terminal deoxynucleotidyl transferase, which resulted in a decrease of 2 to 3 amino acids in the CDR3. Such a reduction in the number of N-nucleotides has a great effect on the junctional diversity, and thereby on the total diversity of the Ig and TR repertoire. This shows that XLF has an important role during V(D)J recombination in creating diversity of the repertoire by stimulating N-nucleotide insertion. PMID:27281794

  15. Sphingosine kinase 2 deficient mice exhibit reduced experimental autoimmune encephalomyelitis: Resistance to FTY720 but not ST-968 treatments.

    PubMed

    Imeri, Faik; Schwalm, Stephanie; Lyck, Ruth; Zivkovic, Aleksandra; Stark, Holger; Engelhardt, Britta; Pfeilschifter, Josef; Huwiler, Andrea

    2016-06-01

    The immunomodulatory drug FTY720 is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that requires activation by sphingosine kinase 2 (SK-2) to induce T cell homing to secondary lymphoid tissue. In this study, we have investigated the role of SK-2 in experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. We show that SK-2 deficiency reduced clinical symptoms of EAE. Furthermore, in SK-2-deficient mice, the protective effect of FTY720 on EAE was abolished, while the non-prodrug FTY720-derivative ST-968 was still fully active. Protection was paralleled by reduced numbers of T-lymphocytes in blood and a reduced blood-brain-barrier leakage. This correlated with reduced mRNA expression of ICAM-1, VCAM-1, but enhanced expression of PECAM-1. A similar regulation of permeability and of PECAM-1 was seen in primary cultures of isolated mouse brain vascular endothelial cells and in a human immortalized cell line upon SK-2 knockdown. In summary, these data demonstrated that deletion of SK-2 exerts a protective effect on the pathogenesis of EAE in C57BL/6 mice and that SK-2 is essential for the protective effect of FTY720 but not of ST-968. Thus, ST-968 is a promising novel immunomodulatory compound that may be a valuable alternative to FTY720 under conditions where SK-2 activity is limited. PMID:26808312

  16. Airway-specific recruitment of T cells is reduced in a CD26-deficient F344 rat substrain

    PubMed Central

    Schade, J; Schmiedl, A; Kehlen, A; Veres, T Z; Stephan, M; Pabst, R; von Hörsten, S

    2009-01-01

    Asthma is a chronic inflammatory disease affecting the airways. Increased levels of T cells are found in the lungs after the induction of an allergic-like inflammation in rats, and flow cytometry studies have shown that these levels are reduced in CD26-deficient rats. However, the precise anatomical sites where these newly recruited T cells appear primarily are unknown. Therefore, we quantified the distribution of T cells in lung parenchyma as well as in large, medium and small airways using immunohistochemical stainings combined with morphometric analyses. The number of T cells increased after the induction of an allergic-like inflammation. However, the differences between CD26-deficient and wild-type rats were not attributable to different cell numbers in the lung parenchyma, but the medium- and large-sized bronchi revealed significantly fewer T cells in CD26-deficient rats. These sites of T cell recruitment were screened further using immunohistochemistry and quantitative real-time polymerase chain reaction with regard to two hypotheses: (i) involvement of the nervous system or (ii) expression of chemokines with properties of a T cell attractor. No topographical association was found between nerves and T cells, but a differential transcription of chemokines was revealed in bronchi and parenchyma. Thus, the site-specific recruitment of T cells appears to be a process mediated by chemokines rather than nerve–T cell interactions. In conclusion, this is the first report showing a differential site-specific recruitment of T cells to the bronchi in a CD26-deficient rat substrain during an asthma-like inflammation. PMID:19737240

  17. Reducing health disparities: the role of sleep deficiency and sleep disorders.

    PubMed

    Laposky, Aaron D; Van Cauter, Eve; Diez-Roux, Ana V

    2016-02-01

    Decrements in sleep health, including insufficient sleep duration, irregular timing of sleep, poor sleep quality, and sleep/circadian disorders, are widespread in modern society and are associated with an array of disease risks and outcomes, including those contributing to health disparities (eg, cardiovascular disease, obesity and diabetes, psychiatric illness, and cancer). Recent findings have uncovered racial/ethnic and socioeconomic position differences in sleep health; however, the contribution of sleep deficiency to health disparities remains largely unexplored, and understanding the underlying causes of disparities in sleep health is only beginning to emerge. In 2011, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop, bringing together sleep and health disparities investigators, to identify research gaps and opportunities to advance sleep and health disparities science. This article provides a brief background and rationale for the workshop, and it disseminates the research recommendations and priorities resulting from the working group discussions. PMID:26431756

  18. Vitamin D deficiency causes airway hyperresponsiveness, increases airway smooth muscle mass, and reduces TGF‐β expression in the lungs of female BALB/c mice

    PubMed Central

    Foong, Rachel E.; Shaw, Nicole C.; Berry, Luke J.; Hart, Prue H.; Gorman, Shelley; Zosky, Graeme R.

    2014-01-01

    Abstract Vitamin D deficiency is associated with disease severity in asthma. We tested whether there is a causal association between vitamin D deficiency, airway smooth muscle (ASM) mass, and the development of airway hyperresponsiveness (AHR). A physiologically relevant mouse model of vitamin D deficiency was developed by raising BALB/c mice on vitamin D‐deficient or ‐replete diets. AHR was assessed by measuring lung function responses to increasing doses of inhaled methacholine. Five‐micron sections from formalin‐fixed lungs were used for ASM measurement and assessment of lung structure using stereological methods. Transforming growth factor (TGF)‐β levels were measured in bronchoalveolar lavage fluid (BALF). Lungs were dissected from embryonic day (E) 17.5 vitamin D‐deficient and ‐replete fetal mice for quantification of ASM density and relative gene expression of TGF‐β signaling pathway molecules. Eight‐week‐old adult vitamin D‐deficient female mice had significantly increased airway resistance and ASM in the large airways compared with controls. Vitamin D‐deficient female mice had a smaller lung volume, volume of parenchyma, and alveolar septa. Both vitamin D‐deficient male and female mice had reduced TGF‐β levels in BALF. Vitamin D deficiency did not have an effect on ASM density in E17.5 mice, however, expression of TGF‐β1 and TGF‐β receptor I was downregulated in vitamin D‐deficient female fetal mice. Decreased expression of TGF‐β1 and TGF‐β receptor I during early lung development in vitamin D‐deficient mice may contribute to airway remodeling and AHR in vitamin D‐deficient adult female mice. This study provides a link between vitamin D deficiency and respiratory symptoms in chronic lung disease. PMID:24760528

  19. Impact of 5-lipoxygenase inhibitors on the spatiotemporal distribution of inflammatory cells and neuronal COX-2 expression following experimental traumatic brain injury in rats.

    PubMed

    Härtig, Wolfgang; Michalski, Dominik; Seeger, Gudrun; Voigt, Cornelia; Donat, Cornelius K; Dulin, Julia; Kacza, Johannes; Meixensberger, Jürgen; Arendt, Thomas; Schuhmann, Martin U

    2013-03-01

    The inflammatory response following traumatic brain injury (TBI) contributes to neuronal death with poor outcome. Although anti-inflammatory strategies were beneficial in the experimental TBI, clinical translations mostly failed, probably caused by the complexity of involved cells and mediators. We recently showed in a rat model of controlled cortical impact (CCI) that leukotriene inhibitors (LIs) attenuate contusion growth and improve neuronal survival. This study focuses on spatiotemporal characteristics of macrophages and granulocytes, typically involved in inflammatory processes, and neuronal COX-2 expression. Effects of treatment with LIs (Boscari/MK-886), started prior trauma, were evaluated by quantifying CD68(+), CD43(+) and COX-2(+) cells 24h and 72 h post-CCI in the parietal cortex (PC), CA3 region, dentate gyrus (DG) and visual/auditory cortex (v/aC). Correlations were applied to identify intercellular relationships. At 24h, untreated animals showed granulocyte invasion in all regions, decreasing towards 72 h. Macrophages increased from 24h to 72 h post-CCI in PC and v/aC. COX-2(+) neurones showed no temporal changes, except of an increase in the CA3 region at 72 h. Treatment reduced granulocytes at 24h in the pericontusional zone and hippocampus, and macrophages at 72 h in the PC and v/aC. COX-2 expression remained unaffected by LIs, except of time-specific changes in the DG (increase/decrease at 24/72 h). Interrelations confirmed concomitant cellular reactions beyond the initial trauma site. In conclusion, LIs attenuated the cellular inflammatory response following CCI. Future studies have to clarify region-specific effects and explore the potential of a clinically more relevant therapeutic approach applying LIs after CCI. PMID:23268351

  20. Anti-Inflammatory Effects of Specific Cyclooxygenase 2,5-Lipoxygenase, and Inducible Nitric Oxide Synthase Inhibitors on Experimental Autoimmune Anterior Uveitis (EAAU)

    PubMed Central

    Bora, Nalini S.; Sohn, Jeong-Hyeon; Bora, Puran S.; Kaplan, Henry J.; Kulkarni, Prasad

    2007-01-01

    Purpose Inflammation, in general, causes the release of a variety of inflammatory mediators that in turn induce cyclooxygenase (COX) 2, nitric oxide synthase (iNOS) and 5-lipoxygense (LP) synthesis, producing large amounts of inflammatory prostaglandins (PG), nitric oxide (NO), and leukotriene (LT) B4. Therefore, inhibition of these enzymes may abrogate intraocular inflammation in experimental autoimmune anterior uveitis (EAAU). Methods Lewis rats were immunized with melanin-associated antigen (MAA) isolated from bovine iris and ciliary body. These animals were divided into three groups. The first group of rats received subcutaneous injection of COX 2 inhibitor CS 236 at different time points. The second and third groups of animals received subcutaneous aminoguanidine (AG), an iNOS inhibitor, and nordihydroguaiaretic acid (NDGA), a 5-LP inhibitor, respectively. Control animals received vehicle. Rat eyes were examined daily by slit-lamp biomicroscopy from Day 7 to 30 post injection for uveitis. Animals were also sacrificed at various time points for histologic analysis. Results Control animals developed severe EAAU in both eyes. The disease started in these animals on Day 12 post immunization and lasted for ten days. Interestingly, CS 236, a potent COX 2 inhibitor, completely abrogated EAAU when the animals were treated daily from the Day 0 to 14 or Day 0 to 20 after MAA injection. Furthermore, daily CS 236 treatment after the onset of EAAU (Day 14–20) significantly reduced the severity (both clinical and histologic) of EAAU and shortened the duration of disease. iNOS inhibitor (AG) and 5-LP inhibitor (NDGA) partially attenuated EAAU. Conclusions Our results show that EAAU was partially attenuated by AG and NDGA. Interestingly, CS 236, a potent COX 2 inhibitor, completely inhibited EAAU in male Lewis rats most likely by inhibiting the initial phase and onset of the disease. PMID:16019677

  1. Iron fortification of whole wheat flour reduces iron deficiency and iron deficiency anemia and increases body iron stores in Indian school-aged children.

    PubMed

    Muthayya, Sumithra; Thankachan, Prashanth; Hirve, Siddhivinayak; Amalrajan, Vani; Thomas, Tinku; Lubree, Himangi; Agarwal, Dhiraj; Srinivasan, Krishnamachari; Hurrell, Richard F; Yajnik, Chittaranjan S; Kurpad, Anura V

    2012-11-01

    Wheat is the primary staple food for nearly one-third of the world's population. NaFeEDTA is the only iron (Fe) compound suitable for fortifying high extraction flours. We tested the hypothesis that NaFeEDTA-fortified, whole wheat flour reduces Fe deficiency (ID) and improves body Fe stores (BIS) and cognitive performance in Indian children. In a randomized, double-blind, controlled, school feeding trial, 6- to 15-y-old, Fe-depleted children (n = 401) were randomly assigned to either a daily wheat-based lunch meal fortified with 6 mg of Fe as NaFeEDTA or an otherwise identical unfortified control meal. Hemoglobin (Hb) and Fe status were measured at baseline, 3.5 mo, and 7 mo. Cognitive performance was evaluated at baseline and 7 mo in children (n = 170) at one of the study sites. After 7 mo, the prevalence of ID and ID anemia in the treatment group significantly decreased from 62 to 21% and 18 to 9%, respectively. There was a time x treatment interaction for Hb, serum ferritin, transferrin receptor, zinc protoporphyrin, and BIS (all P < 0.0001). Changes in BIS differed between the groups; it increased in the treatment group (0.04 ± 0.04 mmol/kg body weight) and decreased in the control group (-0.02 ± 0.04 mmol/kg body weight) (P < 0.0001). In sensory tests, NaFeEDTA-fortified flour could not be differentiated from unfortified flour. There were no significant differences in cognitive performance tests between the groups. NaFeEDTA-fortified wheat flour markedly improved BIS and reduced ID in Fe-depleted children. It may be recommended for wider use in national school feeding programs. PMID:23014487

  2. Loss of Acetylcholine Signaling Reduces Cell Clearance Deficiencies in Caenorhabditis elegans

    PubMed Central

    Pinto, Sérgio M.; Almendinger, Johann; Cabello, Juan; Hengartner, Michael O.

    2016-01-01

    The ability to eliminate undesired cells by apoptosis is a key mechanism to maintain organismal health and homeostasis. Failure to clear apoptotic cells efficiently can cause autoimmune diseases in mammals. Genetic studies in Caenorhabditis elegans have greatly helped to decipher the regulation of apoptotic cell clearance. In this study, we show that the loss of levamisole-sensitive acetylcholine receptor, but not of a typical neuronal acetylcholine receptor causes a reduction in the number of persistent cell corpses in worms suffering from an engulfment deficiency. This reduction is not caused by impaired or delayed cell death but rather by a partial restoration of the cell clearance capacity. Mutants in acetylcholine turn-over elicit a similar phenotype, implying that acetylcholine signaling is the process responsible for these observations. Surprisingly, tissue specific RNAi suggests that UNC-38, a major component of the levamisole-sensitive receptor, functions in the dying germ cell to influence engulfment efficiency. Animals with loss of acetylcholine receptor exhibit a higher fraction of cell corpses positive for the “eat-me” signal phosphatidylserine. Our results suggest that modulation by ion channels of ion flow across plasma membrane in dying cells can influence the dynamics of phosphatidylserine exposure and thus clearance efficiency. PMID:26872385

  3. 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.

  4. Natural Forms of Vitamin E and 13′-Carboxychromanol, a Long-Chain Vitamin E Metabolite, Inhibit Leukotriene Generation from Stimulated Neutrophils by Blocking Calcium Influx and Suppressing 5-Lipoxygenase Activity, Respectively

    PubMed Central

    Jiang, Ziying; Yin, Xinmin; Jiang, Qing

    2014-01-01

    Leukotrienes generated by 5-lipoxygenase (5-LOX)–catalyzed reaction are key regulators of inflammation. In ionophore-stimulated (A23187; 1–2.5 μM) human blood neutrophils or differentiated HL-60 cells, vitamin E forms differentially inhibited leukotriene B4 (LTB4) with an IC50 of 5–20 μM for γ-tocopherol, δ-tocopherol (δT), and γ-tocotrienol, but a much higher IC50 for α-tocopherol. 13′-Carboxychromanol, a long-chain metabolite of δT, suppressed neutrophil- and HL-60 cell-generated LTB4 with an IC50 of 4–7 μM and potently inhibited human recombinant 5-LOX activity with an IC50 of 0.5–1 μM. In contrast, vitamin E forms had no effect on human 5-LOX activity but impaired ionophore-induced intracellular calcium increase and calcium influx as well as the subsequent signaling including ERK1/2 phosphorylation and 5-LOX translocation from cytosol to the nucleus, a key event for 5-LOX activation. Further investigation showed that δT suppressed cytosolic Ca2+ increase and/or LTB4 formation triggered by ionophores, sphingosine 1-phosphate, and lysophosphatidic acid but not by fMLP or thapsigargin, whereas 13′-carboxychromanol decreased cellular production of LTB4 regardless of different stimuli, consistent with its strong inhibition of the 5-LOX activity. These observations suggest that δT does not likely affect fMLP receptor-mediated signaling or store depletion-induced calcium entry. Instead, we found that δT prevented ionophore-caused cytoplasmic membrane disruption, which may account for its blocking of calcium influx. These activities by vitamin E forms and long-chain carboxychromanol provide potential molecular bases for the differential anti-inflammatory effects of vitamin E forms in vivo. PMID:21169551

  5. The regulation of human MMP-13 by licofelone, an inhibitor of cyclo-oxygenases and 5-lipoxygenase, in human osteoarthritic chondrocytes is mediated by the inhibition of the p38 MAP kinase signalling pathway

    PubMed Central

    Boileau, C; Pelletier, J; Tardif, G; Fahmi, H; Laufer, S; Lavigne, M; Martel-Pelletier, J

    2005-01-01

    Background: MMP-13 is one of the most important metalloproteases (MMP) involved in osteoarthritis. Licofelone, a novel dual inhibitor of cyclo-oxygenases (COX) and 5-lipoxygenase (5-LOX), can modulate MMP-13 production in human osteoarthritis chondrocytes. Objective: To evaluate the impact of licofelone on MMP-13 expression/production, promoter, and major MAP kinase signalling pathways and transcription factors. Methods: Human osteoarthritis chondrocytes were stimulated by interleukin 1ß (IL1ß) and treated with or without: licofelone (0.3, 1, or 3 µg/ml); NS-398 (10 µM; a specific COX-2 inhibitor); or BayX-1005 (10 µM; a specific 5-LOX inhibitor). MMP-13 synthesis was determined by specific enzyme linked immunosorbent assay, and expression by real time polymerase chain reaction. The effect of licofelone on the MMP-13 promoter was studied through transient transfection; dexamethasone (10–7 M) was used as comparison. The effect on IL1ß induced MMP-13 signalling pathways was determined using specific ELISA for phosphorylated MAP kinases and transcription factors. Results: Licofelone dose dependently inhibited the IL1ß stimulated production and expression of MMP-13. NS-398 and BayX-1005 had very little effect. Licofelone also inhibited MMP-13 transcription on each of the promoter constructs used. The licofelone inhibition was comparable to that obtained with dexamethasone. Licofelone had no effect on phosphorylated p44/42 or JNK1/2; however, it decreased phosphorylated c-jun and inhibited phosphorylated p38, CREB, and AP-1 activity. Conclusions: Licofelone inhibited MMP-13 production under proinflammatory conditions on human osteoarthritis chondrocytes, through inhibition of the p38/AP-1 pathway and the transcription factor CREB. This may explain some of the mechanisms whereby licofelone exerts its positive effect on osteoarthritic changes. PMID:15498796

  6. Investigation for the amorphous state of ER-34122, a dual 5-lipoxygenase/cyclooxygenase inhibitor with poor aqueous solubility, in HPMC solid dispersion prepared by the solvent evaporation method.

    PubMed

    Kushida, Ikuo; Gotoda, Masaharu

    2013-10-01

    ER-34122, a poorly water-soluble dual 5-lipoxygenase/cyclooxygenase inhibitor, exists as a crystalline form. According to an Oak Ridge thermal ellipsoid plot drawing, carbonyl oxygen O (5) makes an intermolecular hydrogen bond with the hydrogen bonded to N (3) in the crystal structure. The FTIR and the solid-state ¹³C NMR spectra suggest that the network is spread out in the amorphous state and the hydrogen bonding gets weaker than that in the crystalline phase, because the carbonyl signals significantly shift in both spectra. When amorphous ER-34122 was heated, crystallization occurred at around 140°C. Similar crystallization happened in the solid dispersion; however, the degree of crystallization was much lower than that observed in the pure amorphous material. Also, the DSC thermogram of the solid dispersion did not show any exothermic peaks implying crystallization. The heat of fusion (ΔHf) determined in the pure amorphous material was nearly equal to that for the crystalline form, whereas the ΔHf value obtained in the solid dispersion was less than a third of them. These data prove that crystallization of the amorphous form is dramatically restrained in the solid dispersion system. The carbonyl wavenumber shifts in the FTIR spectra indicate that the average hydrogen bond in the solid dispersion is lower than that in the pure amorphous material. Therefore, HPMC will suppress formation of the intermolecular network observed in ER-34122 crystal and preserve the amorphous state, which is thermodynamically less stable, in the solid dispersed system. PMID:22519663

  7. Reduced locomotor activity and exploratory behavior in CC chemokine receptor 4 deficient mice.

    PubMed

    Ambrée, Oliver; Klassen, Irene; Förster, Irmgard; Arolt, Volker; Scheu, Stefanie; Alferink, Judith

    2016-11-01

    Chemokines and their receptors are key regulators of immune cell trafficking and activation. Recent findings suggest that they may also play pathophysiological roles in psychiatric diseases like depression and anxiety disorders. The CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are functionally involved in neuroinflammation as well as anti-infectious and autoimmune responses. However, their influence on behavior remains unknown. Here we characterized the functional role of the CCR4-CCL17 chemokine-receptor axis in the modulation of anxiety-related behavior, locomotor activity, and object exploration and recognition. Additionally, we investigated social exploration of CCR4 and CCL17 knockout mice and wild type (WT) controls. CCR4 knockout (CCR4(-/-)) mice exhibited fewer anxiety-related behaviors in the elevated plus-maze, diminished locomotor activity, exploratory behavior, and social exploration, while their recognition memory was not affected. In contrast, CCL17 deficient mice did not show an altered behavior compared to WT mice regarding locomotor activity, anxiety-related behavior, social exploration, and object recognition memory. In the dark-light and object recognition tests, CCL17(-/-) mice even covered longer distances than WT mice. These data demonstrate a mechanistic or developmental role of CCR4 in the regulation of locomotor and exploratory behaviors, whereas the ligand CCL17 appears not to be involved in the behaviors measured here. Thus, either CCL17 and the alternative ligand CCL22 may be redundant, or CCL22 is the main activator of CCR4 in these processes. Taken together, these findings contribute to the growing evidence regarding the involvement of chemokines and their receptors in the regulation of behavior. PMID:27469058

  8. Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency

    PubMed Central

    Mochel, Fanny; Hainque, Elodie; Gras, Domitille; Adanyeguh, Isaac M; Caillet, Samantha; Héron, Bénédicte; Roubertie, Agathe; Kaphan, Elsa; Valabregue, Romain; Rinaldi, Daisy; Vuillaumier, Sandrine; Schiffmann, Raphael; Ottolenghi, Chris; Hogrel, Jean-Yves; Servais, Laurent; Roze, Emmanuel

    2016-01-01

    Objective On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. Methods We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7–47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional 31P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. Results Patients with GLUT1-DS experienced a mean of 30.8 (±27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (±2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (±21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when triheptanoin was withdrawn. Conclusions Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS. Trial registration number NCT02014883. PMID:26536893

  9. Reduced glutathione biosynthesis in Drosophila melanogaster causes neuronal defects linked to copper deficiency.

    PubMed

    Mercer, Stephen W; La Fontaine, Sharon; Warr, Coral G; Burke, Richard

    2016-05-01

    Glutathione (GSH) is a tripeptide often considered to be the master antioxidant in cells. GSH plays an integral role in cellular redox regulation and is also known to have a role in mammalian copper homeostasis. In vitro evidence suggests that GSH is involved in copper uptake, sequestration and efflux. This study was undertaken to further investigate the roles that GSH plays in neuronal copper homeostasis in vivo, using the model organism Drosophila melanogaster. RNA interference-mediated knockdown of the Glutamate-cysteine ligase catalytic subunit gene (Gclc) that encodes the rate-limiting enzyme in GSH biosynthesis was utilised to genetically deplete GSH levels. When Gclc was knocked down in all neurons, this caused lethality, which was partially rescued by copper supplementation and was exacerbated by additional knockdown of the copper uptake transporter Ctr1A, or over-expression of the copper efflux transporter ATP7. Furthermore, when Gclc was knocked down in a subset of neuropeptide-producing cells, this resulted in adult progeny with unexpanded wings, a phenotype previously associated with copper dyshomeostasis. In these cells, Gclc suppression caused a decrease in axon branching, a phenotype further enhanced by ATP7 over-expression. Therefore, we conclude that GSH may play an important role in regulating neuronal copper levels and that reduction in GSH may lead to functional copper deficiency in neurons in vivo. We provide genetic evidence that glutathione (GSH) levels influence Cu content or distribution in vivo, in Drosophila neurons. GSH could be required for binding Cu imported by Ctr1A and distributing it to chaperones, such as Mtn, CCS and Atox1. Alternatively, GSH could modify the copper-binding and transport activities of Atox1 and the ATP7 efflux protein via glutathionylation of copper-binding cysteines. PMID:26851457

  10. Reducing Incapacitating Symptoms during Space Flight: is Postural Deficiency Syndrome an Applicable Model?

    PubMed Central

    Souvestre, P A; Landrock, C K; Blaber, A P

    2008-01-01

    Severe and prolonged unmitigated SAS and SMS related symptoms have been thoroughly described in Astronauts during adaptation periods for orbital flight and post orbital flight. It has recently been shown that there is a strong correlation between these symptoms most often suffered by astronauts to that of the symptoms of patients suffering from Postural Deficiency Syndrome (PDS) on Earth that have been successfully assessed, diagnosed and treated. International peer-reviewed literature identifies PDS as a trauma induced medical condition which originates from central neural dysregulation of sensory-motor and cognitive controls; these dysfunctions can be accurately identified, measured, and monitored via a specific ocular-vestibular-postural monitoring system along with relevant clinical data. This higher level of understanding is necessary in order to reach the next stage of success for humans living and working in Space. Central sensory-motor and cognitive controls dysfunction underlie symptoms that can adversely impact and reflect alteration of eye-hand coordination, fine tuned dexterity, body positioning in space, space projection and trajectory control, perception of environment/obstacles, orientation in space and time, sensory motor and cognitive aspects of decision making, sensory-motor/cognitive error proneness. All of these factors are necessary for Astronaut's mission capabilities, while both carrying out operations in Space and performing the tasks required during and after re-entry. The objective of this paper is to elucidate how PDS related medical conditions are currently assessed, identified and monitored, and how these methodologies and technologies translate into a potential for better understanding of astronauts' potential incapacitation during space flight operations. PMID:19048092

  11. Complement C1q Reduces Early Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

    PubMed Central

    Bhatia, Vinay K.; Yun, Sheng; Leung, Viola; Grimsditch, David C.; Benson, G. Martin; Botto, Marina B.; Boyle, Joseph J.; Haskard, Dorian O.

    2007-01-01

    We explored the role of the classic complement pathway in atherogenesis by intercrossing C1q-deficient mice (C1qa−/−) with low-density lipoprotein receptor knockout mice (Ldlr−/−). Mice were fed a normal rodent diet until 22 weeks of age. Aortic root lesions were threefold larger in C1qa−/−/Ldlr−/− mice compared with Ldlr−/− mice (3.72 ± 1.0% aortic root versus 1.1 ± 0.4%; mean ± SEM, P < 0.001). Furthermore, the cellular composition of lesions in C1qa−/−/Ldlr−/− was more complex, with an increase in vascular smooth muscle cells. The greater aortic root lesion size in C1qa−/−/Ldlr−/− mice occurred despite a significant reduction in C5b-9 deposition per lesion unit area, suggesting the critical importance of proximal pathway activity. Apoptotic cells were readily detectable by cleaved caspase-3 staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electron microscopy in C1qa−/−/Ldlr−/−, whereas apoptotic cells were not detected in Ldlr−/− mice. This is the first direct demonstration of a role for the classic complement pathway in atherogenesis. The greater lesion size in C1qa−/−/Ldlr−/− mice is consistent with the emerging homeostatic role for C1q in the disposal of dying cells. This study suggests the importance of effective apoptotic cell removal for containing the size and complexity of early lesions in atherosclerosis. PMID:17200212

  12. Reduced light and moderate water deficiency sustain nitrogen assimilation and sucrose degradation at low temperature in durum wheat.

    PubMed

    Majláth, Imre; Darko, Eva; Palla, Balázs; Nagy, Zoltán; Janda, Tibor; Szalai, Gabriella

    2016-02-01

    The rate of carbon and nitrogen assimilation is highly sensitive to stress factors, such as low temperature and drought. Little is known about the role of light in the simultaneous effect of cold and drought. The present study thus focused on the combined effect of mild water deficiency and different light intensities during the early cold hardening in durum wheat (Triticum turgidum ssp. durum L.) cultivars with different levels of cold sensitivity. The results showed that reduced illumination decreased the undesirable effects of photoinhibition in the case of net photosynthesis and nitrate reduction, which may help to sustain these processes at low temperature. Mild water deficiency also had a slight positive effect on the effective quantum efficiency of PSII and the nitrate reductase activity in the cold. Glutamine synthesis was affected by light rather than by water deprivation during cold stress. The invertase activity increased to a greater extent by water deprivation, but an increase in illumination also had a facilitating effect on this enzyme. This suggests that both moderate water deficiency and light have an influence on nitrogen metabolism and sucrose degradation during cold hardening. A possible rise in the soluble sugar content caused by the invertase may compensate for the decline in photosynthetic carbon assimilation indicated by the decrease in net photosynthesis. The changes in the osmotic potential can be also correlated to the enhanced level of invertase activity. Both of them were regulated by light at normal water supply, but not at water deprivation in the cold. However, changes in the metabolic enzyme activities and osmotic adjustment could not be directly contributed to the different levels of cold tolerance of the cultivars in the early acclimation period. PMID:26788956

  13. Deficiency of angiotensin type 1a receptors in adipocytes reduces differentiation and promotes hypertrophy of adipocytes in lean mice.

    PubMed

    Putnam, Kelly; Batifoulier-Yiannikouris, Frederique; Bharadwaj, Kalyani G; Lewis, Eboni; Karounos, Michael; Daugherty, Alan; Cassis, Lisa A

    2012-10-01

    Adipocytes express angiotensin receptors, but the direct effects of angiotensin II (AngII) stimulating this cell type are undefined. Adipocytes express angiotensin type 1a receptor (AT1aR) and AT2R, both of which have been implicated in obesity. In this study, we determined the effects of adipocyte AT1aR deficiency on adipocyte differentiation and the development of obesity in mice fed low-fat (LF) or high-fat (HF) diets. Mice expressing Cre recombinase under the control of the aP2 promoter were bred with AT1aR-floxed mice to generate mice with adipocyte AT1aR deficiency (AT1aR(aP2)). AT1aR mRNA abundance was reduced significantly in both white and brown adipose tissue from AT1aR(aP2) mice compared with nontransgenic littermates (AT1aR(fl/fl)). Adipocyte AT1aR deficiency did not influence body weight, glucose tolerance, or blood pressure in mice fed either LF or high-fat diets. However, LF-fed AT1aR(aP2) mice exhibited striking adipocyte hypertrophy even though total fat mass was not different between genotypes. Stromal vascular cells from AT1aR(aP2) mice differentiated to a lesser extent to adipocytes compared with controls. Conversely, incubation of 3T3-L1 adipocytes with AngII increased Oil Red O staining and increased mRNA abundance of peroxisome proliferator-activated receptor γ (PPARγ) via AT1R stimulation. These results suggest that reductions in adipocyte differentiation in LF-fed AT1aR(aP2) mice resulted in increased lipid storage and hypertrophy of remaining adipocytes. These results demonstrate that AngII regulates adipocyte differentiation and morphology through the adipocyte AT1aR in lean mice. PMID:22919058

  14. Reduced susceptibility to azoxymethane-induced aberrant crypt foci formation and colon cancer in growth hormone deficient rats

    PubMed Central

    Carroll, Robert E.; Goodlad, Robert A.; Poole, Aleksandra J.; Tyner, Angela L.; Robey, R. Brooks; Swanson, Steven M.; Unterman, Terry G.

    2010-01-01

    Objectives To evaluate the role of GH in colon carcinogenesis, we examined the formation of aberrant crypt foci (ACFs) and tumor development in wild type (WT) and GH-deficient, spontaneous dwarf rats (SDRs) exposed to the carcinogen azoxymethane (AOM). Design ACF were quantified by stereomicroscopy and tumor number and weights were recorded for each animal. Cell proliferation was measured by vincristine metaphase arrest, flow cytometry, and bromode-oxyuridine (BrdU) incorporation. Apoptosis was measured by TUNEL staining and cleaved caspase-3 immunohistochemistry. IGF-I was measured by radioimmunoassay (RIA). Hexokinase activity was measured by spectrophotometric assay. PARP cleavage, and IGF-IR, and p27kip/cip expression were measured by Western blotting. Results ACFs detected by stereomicroscopy were markedly reduced (~85%) in SDRs vs. WT rats at 10, 25, and 28 weeks after AOM. Tumor incidence, number, and weight also were reduced in SDR vs. WT animals. AOM treatment increased cell proliferation in the distal colon (where tumors occur) of WT rats but not SDRs, and these changes corresponded to increased ACF and tumor formation. Apoptosis rates were similar in AOM-treated WT and SDRs. Alterations in serum IGF-I levels may contribute to differences in the proliferative response to AOM and decreased ACF formation in SDR vs. WT rats. Conclusions We conclude that early neoplastic lesions (ACFs) were reduced in GH-deficient animals. This effect corresponds with differences in AOM-induced proliferation, but not apoptosis. These data indicate that GH is required for the full effect of AOM on colon ACF and tumor development, and that the SDR rat is a promising model for studies regarding the role of GH/IGF system in the initiation and promotion of colon cancer. PMID:19406679

  15. Xpa deficiency reduces CAG trinucleotide repeat instability in neuronal tissues in a mouse model of SCA1

    PubMed Central

    Hubert, Leroy; Lin, Yunfu; Dion, Vincent; Wilson, John H.

    2011-01-01

    Expansion of trinucleotide repeats (TNRs) is responsible for a number of human neurodegenerative disorders. The molecular mechanisms that underlie TNR instability in humans are not clear. Based on results from model systems, several mechanisms for instability have been proposed, all of which focus on the ability of TNRs to form alternative structures during normal DNA transactions, including replication, DNA repair and transcription. These abnormal structures are thought to trigger changes in TNR length. We have previously shown that transcription-induced TNR instability in cultured human cells depends on several genes known to be involved in transcription-coupled nucleotide excision repair (NER). We hypothesized that NER normally functions to destabilize expanded TNRs. To test this hypothesis, we bred an Xpa null allele, which eliminates NER, into the TNR mouse model for spinocerebellar ataxia type 1 (SCA1), which carries an expanded CAG repeat tract at the endogenous mouse Sca1 locus. We find that Xpa deficiency does not substantially affect TNR instability in either the male or female germline; however, it dramatically reduces CAG repeat instability in neuronal tissues—striatum, hippocampus and cerebral cortex—but does not alter CAG instability in kidney or liver. The tissue-specific effect of Xpa deficiency represents a novel finding; it suggests that tissue-to-tissue variation in CAG repeat instability arises, in part, by different underlying mechanisms. These results validate our original findings in cultured human cells and suggest that transcription may induce NER-dependent TNR instability in neuronal tissues in humans. PMID:21926083

  16. Deletion of UCP2 in iNOS Deficient Mice Reduces the Severity of the Disease during Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Aheng, Caroline; Ly, Nathalie; Kelly, Mairead; Ibrahim, Saleh; Ricquier, Daniel; Alves-Guerra, Marie-Clotilde; Miroux, Bruno

    2011-01-01

    Uncoupling protein 2 is a member of the mitochondrial anion carrier family that is widely expressed in neurons and the immune cells of humans. Deletion of Ucp2 gene in mice pre-activates the immune system leading to higher resistance toward infection and to an increased susceptibility to develop chronic inflammatory diseases as previously exemplified with the Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for multiple sclerosis. Given that oxidative stress is enhanced in Ucp2−/− mice and that nitric oxide (NO) also plays a critical function in redox balance and in chronic inflammation, we generated mice deficient for both Ucp2 and iNos genes and submitted them to EAE. Mice lacking iNos gene exhibited the highest clinical score (3.4+/−0.5 p<0.05). Surprisingly, mice deficient for both genes developed milder disease with reduced immune cell infiltration, cytokines and ROS production as compared to iNos−/− mice. PMID:21857957

  17. Deficiency of prolyl oligopeptidase in mice disturbs synaptic plasticity and reduces anxiety-like behaviour, body weight, and brain volume.

    PubMed

    Höfling, Corinna; Kulesskaya, Natalia; Jaako, Külli; Peltonen, Iida; Männistö, Pekka T; Nurmi, Antti; Vartiainen, Nina; Morawski, Markus; Zharkovsky, Alexander; Võikar, Vootele; Roßner, Steffen; García-Horsman, J Arturo

    2016-06-01

    Prolyl oligopeptidase (PREP) has been implicated in neurodegeneration and neuroinflammation and has been considered a drug target to enhance memory in dementia. However, the true physiological role of PREP is not yet understood. In this paper, we report the phenotyping of a mouse line where the PREP gene has been knocked out. This work indicates that the lack of PREP in mice causes reduced anxiety but also hyperactivity. The cortical volumes of PREP knockout mice were smaller than those of wild type littermates. Additionally, we found increased expression of diazepam binding inhibitor protein in the cortex and of the somatostatin receptor-2 in the hippocampus of PREP knockout mice. Furthermore, immunohistochemistry and tail suspension test revealed lack of response of PREP knockout mice to lipopolysaccharide insult. Further analysis revealed significantly increased levels of polysialylated-neural cell adhesion molecule in PREP deficient mice. These findings might be explained as possible alteration in brain plasticity caused by PREP deficiency, which in turn affect behaviour and brain development. PMID:26996375

  18. Numerical evaluation of the use of granulated coal ash to reduce an oxygen-deficient water mass.

    PubMed

    Yamamoto, Hironori; Yamamoto, Tamiji; Mito, Yugo; Asaoka, Satoshi

    2016-06-15

    Granulated coal ash (GCA), which is a by-product of coal thermal electric power stations, effectively decreases phosphate and hydrogen sulfide (H2S) concentrations in the pore water of coastal marine sediments. In this study, we developed a pelagic-benthic coupled ecosystem model to evaluate the effectiveness of GCA for diminishing the oxygen-deficient water mass formed in coastal bottom water of Hiroshima Bay in Japan. Numerical experiments revealed the application of GCA was effective for reducing the oxygen-deficient water masses, showing alleviation of the DO depletion in summer increased by 0.4-3mgl(-1). The effect of H2S adsorption onto the GCA lasted for 5.25years in the case in which GCA was mixed with the sediment in a volume ratio of 1:1. The application of this new GCA-based environmental restoration technique could also make a substantial contribution to form a recycling-oriented society. PMID:27143344

  19. Extracellular superoxide dismutase deficiency impairs wound healing in advanced age by reducing neovascularization and fibroblast function

    PubMed Central

    Fujiwara, Toshihiro; Duscher, Dominik; Rustad, Kristine C.; Kosaraju, Revanth; Rodrigues, Melanie; Whittam, Alexander J.; Januszyk, Michael; Maan, Zeshaan N.; Gurtner, Geoffrey C.

    2016-01-01

    Advanced age is characterized by impairments in wound healing, and evidence is accumulating that this may be due in part to a concomitant increase in oxidative stress. Extended exposure to reactive oxygen species (ROS) is thought to lead to cellular dysfunction and organismal death via the destructive oxidation of intra-cellular proteins, lipids and nucleic acids. Extracellular superoxide dismutase (ecSOD/SOD3) is a prime antioxidant enzyme in the extracellular space that eliminates ROS. Here, we demonstrate that reduced SOD3 levels contribute to healing impairments in aged mice. These impairments include delayed wound closure, reduced neovascularization, impaired fibroblast proliferation and increased neutrophil recruitment. We further establish that SOD3 KO and aged fibroblasts both display reduced production of TGF-β1, leading to decreased differentiation of fibroblasts into myofibroblasts. Taken together, these results suggest that wound healing impairments in ageing are associated with increased levels of ROS, decreased SOD3 expression and impaired extracellular oxidative stress regulation. Our results identify SOD3 as a possible target to correct age-related cellular dysfunction in wound healing. PMID:26663425

  20. Prmt7 Deficiency Causes Reduced Skeletal Muscle Oxidative Metabolism and Age-Related Obesity.

    PubMed

    Jeong, Hyeon-Ju; Lee, Hye-Jin; Vuong, Tuan Anh; Choi, Kyu-Sil; Choi, Dahee; Koo, Sung-Hoi; Cho, Sung Chun; Cho, Hana; Kang, Jong-Sun

    2016-07-01

    Maintenance of skeletal muscle function is critical for metabolic health and the disruption of which exacerbates many chronic diseases such as obesity and diabetes. Skeletal muscle responds to exercise or metabolic demands by a fiber-type switch regulated by signaling-transcription networks that remains to be fully defined. Here, we report that protein arginine methyltransferase 7 (Prmt7) is a key regulator for skeletal muscle oxidative metabolism. Prmt7 is expressed at the highest levels in skeletal muscle and decreased in skeletal muscles with age or obesity. Prmt7(-/-) muscles exhibit decreased oxidative metabolism with decreased expression of genes involved in muscle oxidative metabolism, including PGC-1α. Consistently, Prmt7(-/-) mice exhibited significantly reduced endurance exercise capacities. Furthermore, Prmt7(-/-) mice exhibit decreased energy expenditure, which might contribute to the exacerbated age-related obesity of Prmt7(-/-) mice. Similarly to Prmt7(-/-) muscles, Prmt7 depletion in myoblasts also reduces PGC-1α expression and PGC-1α-promoter driven reporter activities. Prmt7 regulates PGC-1α expression through interaction with and activation of p38 mitogen-activated protein kinase (p38MAPK), which in turn activates ATF2, an upstream transcriptional activator for PGC-1α. Taken together, Prmt7 is a novel regulator for muscle oxidative metabolism via activation of p38MAPK/ATF2/PGC-1α. PMID:27207521

  1. Reduced gravitropism in hypocotyls of starch-deficient mutants of Arabidopsis

    NASA Technical Reports Server (NTRS)

    Kiss, J. Z.; Guisinger, M. M.; Miller, A. J.; Stackhouse, K. S.

    1997-01-01

    Gravitropism was examined in dark- and light-grown hypocotyls of wild-type (WT), two reduced starch mutants (ACG 20 and ACG 27), and a starchless mutant (ACG 21) of Arabidopsis. In addition, the starch content of these four strains was studied with light and electron microscopy. Based on time course of curvature and orientation studies, the graviresponse in hypocotyls is proportional to the amount of starch in a genotype. Furthermore, starch mutations seem to primarily affect gravitropism rather than differential growth since both phototropic curvature and growth rates among the four genotypes are approximately equal. Our results suggest that gravity perception may require a greater plastid mass in hypocotyls compared to roots. The kinetics of gravitropic curvature also was compared following reorientation at 45 degrees, 90 degrees, and 135 degrees. As has been reported for other plant species, the optimal angle of reorientation is 135 degrees for WT Arabidopsis and the two reduced starch mutants, but the magnitude of curvature of the starchless mutant appears to be independent of the initial angle of displacement. Taken together, the results of the present study and our previous experiments with roots of the same four genotypes [Kiss et al. (1996) Physiol. Plant. 97: 237] support a plastid-based hypothesis for gravity perception in plants.

  2. B cell VLA-4-deficiency reduces leukocyte recruitment and susceptibility to central nervous system autoimmunity

    PubMed Central

    Lehmann-Horn, Klaus; Sagan, Sharon A.; Bernard, Claude C.A.; Sobel, Raymond A.; Zamvil, Scott S.

    2015-01-01

    Natalizumab, which binds very late antigen-4 (VLA-4), is a potent therapy for multiple sclerosis (MS). Studies have focused primarily upon its capacity to interfere with T cell-migration into the central nervous system (CNS). B cells are important in MS pathogenesis and express high levels of VLA-4. Here, we report that the selective inhibition of VLA-4-expression on B cells impedes CNS accumulation of B cells, recruitment of Th17 cells and macrophages, and reduces susceptibility to experimental autoimmune encephalomyelitis (EAE). These results underscore the importance of B cell VLA-4-expression in pathogenesis of CNS autoimmunity and provide insight regarding mechanisms that may contribute to the benefit of natalizumab in MS, as well as candidate therapeutics that selectively target B cells. PMID:25712734

  3. CTRP3 deficiency reduces liver size and alters IL-6 and TGFβ levels in obese mice.

    PubMed

    Wolf, Risa M; Lei, Xia; Yang, Zhi-Chun; Nyandjo, Maeva; Tan, Stefanie Y; Wong, G William

    2016-03-01

    C1q/TNF-related protein 3 (CTRP3) is a secreted metabolic regulator whose circulating levels are reduced in human and rodent models of obesity and diabetes. Previously, we showed that CTRP3 infusion lowers blood glucose by suppressing gluconeogenesis and that transgenic overexpression of CTRP3 protects mice against diet-induced hepatic steatosis. Here, we used a genetic loss-of-function mouse model to further address whether CTRP3 is indeed required for metabolic homeostasis under normal and obese states. Both male and female mice lacking CTRP3 had similar weight gain when fed a control low-fat (LFD) or high-fat diet (HFD). Regardless of diet, no differences were observed in adiposity, food intake, metabolic rate, energy expenditure, or physical activity levels between wild-type (WT) and Ctrp3-knockout (KO) animals of either sex. Contrary to expectations, loss of CTRP3 in LFD- or HFD-fed male and female mice also had minimal or no impact on whole body glucose metabolism, insulin sensitivity, and fasting-induced hepatic gluconeogenesis. Unexpectedly, the liver sizes of HFD-fed Ctrp3-KO male mice were markedly reduced despite a modest increase in triglyceride content. Furthermore, liver expression of fat oxidation genes was upregulated in the Ctrp3-KO mice. Whereas the liver and adipose expression of profibrotic TGFβ1, as well as its serum levels, was suppressed in HFD-fed KO mice, circulating proinflammatory IL-6 levels were markedly increased; these changes, however, were insufficient to affect systemic metabolic outcome. We conclude that, although it is dispensable for physiological control of energy balance, CTRP3 plays a previously unsuspected role in modulating liver size and circulating cytokine levels in response to obesity. PMID:26670485

  4. Reduced gravitropic sensitivity in roots of a starch-deficient mutant of Nicotiana sylvestris

    NASA Technical Reports Server (NTRS)

    Kiss, J. Z.; Sack, F. D.

    1989-01-01

    Gravitropism was studied in seedlings of Nicotiana sylvestris Speg. et Comes wild-type (WT) and mutant NS 458 which has a defective plastid phosphoglucomutase (EC 2.7.5.1.). Starch was greatly reduced in NS 458 compared to the WT, but small amounts of starch were detected in rootcap columella cells in NS 458 by light and electron microscopy. The roots of WT are more sensitive to gravity than mutant NS 458 roots since: (1) in mutant roots, curvature was reduced and delayed in the time course of curvature; (2) curvature of mutant roots was 24-56% that of WT roots over the range of induction periods tested; (3) in intermittent-stimulation experiments, curvature of mutant roots was 37% or less than that of WT roots in all treatments tested. The perception time, determined by intermittent-stimulation experiments, was < or = 5 s for WT roots and 30-60 s for mutant roots. The growth rates for WT and NS 458 roots were essentially equal. These results and our previous results with WT and starchless mutant Arabidopsis roots (Kiss et al. 1989, Planta 177, 198-206) support the conclusions that a full complement of starch is necessary for full gravitropic sensitivity and that amyloplasts function in gravity perception. Since a presumed relatively small increase in plastid buoyant mass (N. sylvestris mutant versus Arabidopsis mutant) significantly improves the orientation of the N. sylvestris mutant roots, we suggest that plastids are the likeliest candidates to be triggering gravity perception in roots of both mutants.

  5. Pitavastatin Reduces Inflammation in Atherosclerotic Plaques in Apolipoprotein E-Deficient Mice with Late Stage Renal Disease

    PubMed Central

    Figueiredo, Jose-Luiz; New, Sophie E. P.; Quillard, Thibaut; Goettsch, Claudia; Koga, Jun-ichiro; Sonoki, Hiroyuki; Matsumoto, Jiro; Aikawa, Masanori; Aikawa, Elena

    2015-01-01

    Objectives Chronic renal disease (CRD) accelerates atherosclerosis and cardiovascular calcification. Statins reduce low-density lipoprotein-cholesterol levels in patients with CRD, however, the benefits of statins on cardiovascular disease in CRD remain unclear. This study has determined the effects of pitavastatin, the newest statin, on arterial inflammation and calcification in atherogenic mice with CRD. Methods and Results CRD was induced by 5/6 nephrectomy in cholesterol-fed apolipoprotein E-deficient mice. Mice were randomized into three groups: control mice, CRD mice, and CRD mice treated with pitavastatin. Ultrasonography showed that pitavastatin treatment significantly attenuated luminal stenosis in brachiocephalic arteries of CRD mice. Near-infrared molecular imaging and correlative Mac3 immunostaining demonstrated a significant reduction in macrophage accumulation in pitavastatin-treated CRD mice. Pitavastatin treatment reduced levels of osteopontin in plasma and atherosclerotic lesions in CRD mice, but did not produce a significant reduction in calcification in atherosclerotic plaques as assesses by histology. CRD mice had significantly higher levels of phosphate in plasma than did control mice, which did not change by pitavastatin. In vitro, pitavastatin suppressed the expression of osteopontin in peritoneal macrophages stimulated with phosphate or calcium/phosphate in concentrations similar to those found in human patients with CRD. Conclusion Our study provides in vivo evidence that pitavastatin reduces inflammation within atherosclerotic lesions in CRD mice. PMID:26367531

  6. Grape powder polyphenols attenuate atherosclerosis development in apolipoprotein E deficient (E0) mice and reduce macrophage atherogenicity.

    PubMed

    Fuhrman, Bianca; Volkova, Nina; Coleman, Raymond; Aviram, Michael

    2005-04-01

    The beneficial health effects of red wine have been attributed to the antioxidant activity of its polyphenols. The present study investigated the effects of a standardized freeze-dried powder made from fresh grapes, rich in grape-specific polyphenols and free of alcohol, on oxidative stress, atherogenicity of macrophages, and the development of atherosclerotic lesions in apolipoprotein E deficient (E(0)) mice. Thirty E(0) mice were assigned to 3 groups. Mice consumed water alone (control), 150 mug total polyphenols/d in the form of grape powder (grape powder), or the equivalent amount of glucose and fructose (placebo) in drinking water for 10 wk. Consumption of grape powder reduced the atherosclerotic lesion area by 41% (P < 0.0002) compared to the control or placebo mice. The antiatherosclerotic effect was at least partly due to a significant 8% reduction in serum oxidative stress, an up to 22% increase in serum antioxidant capacity, a significant 33% reduction in macrophage uptake of oxidized LDL, and a 25% decrease in macrophage-mediated oxidation of LDL relative to controls. Grape powder directly protected both plasma LDL and macrophages from oxidative stress in vitro. We conclude that polyphenols from fresh grape powder directly affect macrophage atherogenicity by reducing macrophage-mediated oxidation of LDL and cellular uptake of oxidized LDL. Both of these processes can eventually reduce macrophage cholesterol accumulation and foam cell formation and hence attenuate atherosclerosis development. PMID:15795424

  7. Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

    PubMed Central

    Magrini, Elena; Villa, Alessandra; Angiolini, Francesca; Doni, Andrea; Mazzarol, Giovanni; Rudini, Noemi; Maddaluno, Luigi; Komuta, Mina; Topal, Baki; Prenen, Hans; Schachner, Melitta; Confalonieri, Stefano; Dejana, Elisabetta; Bianchi, Fabrizio; Mazzone, Massimiliano; Cavallaro, Ugo

    2014-01-01

    While tumor blood vessels share many characteristics with normal vasculature, they also exhibit morphological and functional aberrancies. For example, the neural adhesion molecule L1, which mediates neurite outgrowth, fasciculation, and pathfinding, is expressed on tumor vasculature. Here, using an orthotopic mouse model of pancreatic carcinoma, we evaluated L1 functionality in cancer vessels. Tumor-bearing mice specifically lacking L1 in endothelial cells or treated with anti-L1 antibodies exhibited decreased angiogenesis and improved vascular stabilization, leading to reduced tumor growth and metastasis. In line with these dramatic effects of L1 on tumor vasculature, the ectopic expression of L1 in cultured endothelial cells (ECs) promoted phenotypical and functional alterations, including proliferation, migration, tubulogenesis, enhanced vascular permeability, and endothelial-to-mesenchymal transition. L1 induced global changes in the EC transcriptome, altering several regulatory networks that underlie endothelial pathophysiology, including JAK/STAT-mediated pathways. In particular, L1 induced IL-6–mediated STAT3 phosphorylation, and inhibition of the IL-6/JAK/STAT signaling axis prevented L1-induced EC proliferation and migration. Evaluation of patient samples revealed that, compared with that in noncancerous tissue, L1 expression is specifically enhanced in blood vessels of human pancreatic carcinomas and in vessels of other tumor types. Together, these data indicate that endothelial L1 orchestrates multiple cancer vessel functions and represents a potential target for tumor vascular-specific therapies. PMID:25157817

  8. Dystrophin-deficient mdx mice display a reduced life span and are susceptible to spontaneous rhabdomyosarcoma.

    PubMed

    Chamberlain, Jeffrey S; Metzger, Joseph; Reyes, Morayma; Townsend, DeWayne; Faulkner, John A

    2007-07-01

    Duchenne muscular dystrophy (DMD) is the most common, lethal genetic disorder of children. A number of animal models of muscular dystrophy exist, but the most effective model for characterizing the structural and functional properties of dystrophin and therapeutic interventions has been the mdx mouse. Despite the approximately 20 years of investigations of the mdx mouse, the impact of the disease on the life span of mdx mice and the cause of death remain unresolved. Consequently, a life span study of the mdx mouse was designed that included cohorts of male and female mdx and wild-type C57BL/10 mice housed under specific pathogen-free conditions with deaths restricted to natural causes and with examination of the carcasses for pathology. Compared with wild-type mice, both mdx male and female mice had reduced life spans and displayed a progressively dystrophic muscle histopathology. Surprisingly, old mdx mice were prone to develop muscle tumors that resembled the human form of alveolar rhabdomyosarcoma, a cancer associated with poor prognosis. Rhabdomyosarcomas have not been observed previously in nontransgenic mice. The results substantiate the mdx mouse as an important model system for studies of the pathogenesis of and potential remedies for DMD. PMID:17360850

  9. Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice.

    PubMed

    De Bundel, Dimitri; Gangarossa, Giuseppe; Biever, Anne; Bonnefont, Xavier; Valjent, Emmanuel

    2013-01-01

    The circadian clock comprises a set of genes involved in cell-autonomous transcriptional feedback loops that orchestrate the expression of a range of downstream genes, driving circadian patterns of behavior. Cognitive dysfunction, mood disorders, anxiety disorders, and substance abuse disorders have been associated with disruptions in circadian rhythm and circadian clock genes, but the causal relationship of these associations is still poorly understood. In the present study, we investigate the effect of genetic disruption of the circadian clock, through deletion of both paralogs of the core gene cryptochrome (Cry1 and Cry2). Mice lacking Cry1 and Cry2 (Cry1(-/-)Cry2(-/-) ) displayed attenuated dark phase and novelty-induced locomotor activity. Moreover, they showed impaired recognition memory but intact fear memory. Depression-related behaviors in the forced swim test or sucrose preference tests were unaffected but Cry1(-/-)Cry2(-/-) mice displayed increased anxiety in the open field and elevated plus maze tests. Finally, hyperlocomotion and striatal phosphorylation of extracellular signal-regulated kinase (ERK) induced by a single cocaine administration are strongly reduced in Cry1(-/-)Cry2(-/-) mice. Interestingly, only some behavioral measures were affected in mice lacking either Cry1 or Cry2. Notably, recognition memory was impaired in both Cry1(-/-)Cry2(+/+) and Cry1(+/+)Cry2(-/-) mice. Moreover, we further observed elevated anxiety in Cry1(-/-)Cry2(+/+) and Cry1(+/+)Cry2(-/-) mice. Our data indicate that beyond their role in the control of circadian rhythm, cryptochrome genes have a direct influence in cognitive function, anxiety-related behaviors and sensitivity to psychostimulant drugs. PMID:24187535

  10. Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects

    SciTech Connect

    Desai, Jayashree; Shannon, Mark E.; Johnson, Mahlon D.; Ruff, David W.; Hughes, Lori A; Kerley, Marilyn K; Carpenter, D A; Johnson, Dabney K; Rinchik, Eugene M.; Culiat, Cymbeline T

    2006-01-01

    The mammalian Nell1 gene encodes a protein kinase C-b1 (PKC-b1) binding protein that belongs to a new class of cell-signaling molecules controlling cell growth and differentiation. Over-expression of Nell1 in the developing cranial sutures in both human and mouse induces craniosynostosis, the premature fusion of the growing cranial bone fronts. Here, we report the generation, positional cloning and characterization of Nell16R, a recessive, neonatal-lethal point mutation in the mouse Nell1 gene, induced by N-ethyl-N-nitrosourea. Nell16R has a T!A base change that converts a codon for cysteine into a premature stop codon [Cys(502)Ter], resulting in severe truncation of the predicted protein product and marked reduction in steady-state levels of the transcript. In addition to the expected alteration of cranial morphology, Nell16R mutants manifest skeletal defects in the vertebral column and ribcage, revealing a hitherto undefined role for Nell1 in signal transduction in endochondral ossification. Real-time quantitative reverse transcription-PCR assays of 219 genes showed an association between the loss of Nell1 function and reduced expression of genes for extracellular matrix (ECM) proteins critical for chondrogenesis and osteogenesis. Several affected genes are involved in the human cartilage disorder Ehlers-Danlos Syndrome and other disorders associated with spinal curvature anomalies. Nell16R mutant mice are a new tool for elucidating basic mechanisms in osteoblast and chrondrocyte differentiation in the developing skull and vertebral column and understanding how perturbations in the production of ECM proteins can lead to anomalies in these structures.

  11. Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice

    PubMed Central

    De Bundel, Dimitri; Gangarossa, Giuseppe; Biever, Anne; Bonnefont, Xavier; Valjent, Emmanuel

    2013-01-01

    The circadian clock comprises a set of genes involved in cell-autonomous transcriptional feedback loops that orchestrate the expression of a range of downstream genes, driving circadian patterns of behavior. Cognitive dysfunction, mood disorders, anxiety disorders, and substance abuse disorders have been associated with disruptions in circadian rhythm and circadian clock genes, but the causal relationship of these associations is still poorly understood. In the present study, we investigate the effect of genetic disruption of the circadian clock, through deletion of both paralogs of the core gene cryptochrome (Cry1 and Cry2). Mice lacking Cry1 and Cry2 (Cry1−/−Cry2−/−) displayed attenuated dark phase and novelty-induced locomotor activity. Moreover, they showed impaired recognition memory but intact fear memory. Depression-related behaviors in the forced swim test or sucrose preference tests were unaffected but Cry1−/−Cry2−/− mice displayed increased anxiety in the open field and elevated plus maze tests. Finally, hyperlocomotion and striatal phosphorylation of extracellular signal-regulated kinase (ERK) induced by a single cocaine administration are strongly reduced in Cry1−/−Cry2−/− mice. Interestingly, only some behavioral measures were affected in mice lacking either Cry1 or Cry2. Notably, recognition memory was impaired in both Cry1−/−Cry2+/+ and Cry1+/+Cry2−/− mice. Moreover, we further observed elevated anxiety in Cry1−/−Cry2+/+ and Cry1+/+Cry2−/− mice. Our data indicate that beyond their role in the control of circadian rhythm, cryptochrome genes have a direct influence in cognitive function, anxiety-related behaviors and sensitivity to psychostimulant drugs. PMID:24187535

  12. Reduced oncotic necrosis in Fas receptor-deficient C57BL/6J-lpr mice after bile duct ligation.

    PubMed

    Gujral, Jaspreet S; Liu, Jie; Farhood, Anwar; Jaeschke, Hartmut

    2004-10-01

    Neutrophils aggravate cholestatic liver injury after bile duct ligation (BDL). Recently, it was suggested that hepatocellular apoptosis might be critical for liver injury in this model. To test the hypothesis that apoptosis could be a signal for neutrophil extravasation and injury, we assessed parameters of apoptosis and inflammation after BDL using 2 different approaches: (1) wild-type and Fas receptor-deficient lpr mice of the C57BL/6J or C3H/HeJ strains, and (2) treatment with the pancaspase inhibitor z-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk)in C3HeB/FeJ mice. After BDL for 3 days, total cell death was estimated to be between 10% and 50% of all cells evaluated. However, less than 0.1% of hepatocytes showed apoptotic morphology in all 3 strains. Processing of procaspase-3, caspase-3 enzyme activities, and immunohistochemical staining for cytokeratin 18 cleavage products indicated no activation of caspases. Real-time reverse-transcriptase polymerase chain reaction analysis revealed increased expression of many inflammatory mediators but no effect on proapoptotic genes. More than 50% of all accumulated neutrophils were extravasated and colocalized with foci of oncotic hepatocytes and chlorotyrosine adducts. z-VAD-fmk treatment had no effect on apoptosis or liver injury after BDL but eliminated apoptosis after galactosamine/endotoxin in C3HeB/FeJ mice. In Fas receptor-deficient lpr mice (C57BL/6J), expression of inflammatory mediators, neutrophil accumulation and extravasation, chlorotyrosine adduct formation, and liver injury were reduced. This protection was not observed in lpr mice of the endotoxin-resistant C3H/HeJ strain. In conclusion, liver injury (oncotic necrosis) after BDL correlated with the severity of the inflammatory response. The minimal amount of apoptosis had no effect on inflammation or on the overall injury. PMID:15382126

  13. CD4+ T Cell Migration into the Cornea is Reduced in CXCL9 Deficient but not CXCL10 Deficient Mice following Herpes Simplex Virus Type 1 Infection1

    PubMed Central

    Wuest, Todd; Farber, Joshua; Luster, Andrew; Carr, Daniel J. J.

    2007-01-01

    The role of CXCL9 and CXCL10 in the ocular immune response to herpes simplex virus type 1 (HSV-1) infection was investigated using mice deficient in either CXCL9 or CXCL10. CXCL10 but not CXCL9 deficient mice showed an increase in sensitivity to ocular virus infection as measured by an elevation in virus titer recovered in the tear film and corneal tissue. The increase in virus was associated with an increase in the expression of the chemokine CCL2 but no significant change in the infiltration of CD4+ T cells or NK cells into the corneal stroma. In contrast, a significant reduction in CD4+ T cell infiltration into the cornea was found in CXCL9 deficient mice following HSV-1 infection consistent with the absence of CXCL9 expression and reduction in expression of other chemokines including CCL3, CCL5, CXCL1, and CXCL10. Collectively, the results suggest a non-redundant role for CXCL9 and CXCL10 in response to ocular HSV-1 infection in terms of controlling virus replication and recruitment of CD4+ T cells into the cornea. PMID:17296171

  14. Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse

    PubMed Central

    de Greef, Jessica C.; Hamlyn, Rebecca; Jensen, Braden S.; O'Campo Landa, Raul; Levy, Jennifer R.; Kobuke, Kazuhiro; Campbell, Kevin P.

    2016-01-01

    Muscular dystrophy is characterized by progressive skeletal muscle weakness and dystrophic muscle exhibits degeneration and regeneration of muscle cells, inflammation and fibrosis. Skeletal muscle fibrosis is an excessive deposition of components of the extracellular matrix including an accumulation of Collagen VI. We hypothesized that a reduction of Collagen VI in a muscular dystrophy model that presents with fibrosis would result in reduced muscle pathology and improved muscle function. To test this hypothesis, we crossed γ-sarcoglycan-null mice, a model of limb-girdle muscular dystrophy type 2C, with a Col6a2-deficient mouse model. We found that the resulting γ-sarcoglycan-null/Col6a2Δex5 mice indeed exhibit reduced muscle pathology compared with γ-sarcoglycan-null mice. Specifically, fewer muscle fibers are degenerating, fiber size varies less, Evans blue dye uptake is reduced and serum creatine kinase levels are lower. Surprisingly, in spite of this reduction in muscle pathology, muscle function is not significantly improved. In fact, grip strength and maximum isometric tetanic force are even lower in γ-sarcoglycan-null/Col6a2Δex5 mice than in γ-sarcoglycan-null mice. In conclusion, our results reveal that Collagen VI-mediated fibrosis contributes to skeletal muscle pathology in γ-sarcoglycan-null mice. Importantly, however, our data also demonstrate that a reduction in skeletal muscle pathology does not necessarily lead to an improvement of skeletal muscle function, and this should be considered in future translational studies. PMID:26908621

  15. Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse.

    PubMed

    de Greef, Jessica C; Hamlyn, Rebecca; Jensen, Braden S; O'Campo Landa, Raul; Levy, Jennifer R; Kobuke, Kazuhiro; Campbell, Kevin P

    2016-04-01

    Muscular dystrophy is characterized by progressive skeletal muscle weakness and dystrophic muscle exhibits degeneration and regeneration of muscle cells, inflammation and fibrosis. Skeletal muscle fibrosis is an excessive deposition of components of the extracellular matrix including an accumulation of Collagen VI. We hypothesized that a reduction of Collagen VI in a muscular dystrophy model that presents with fibrosis would result in reduced muscle pathology and improved muscle function. To test this hypothesis, we crossed γ-sarcoglycan-null mice, a model of limb-girdle muscular dystrophy type 2C, with a Col6a2-deficient mouse model. We found that the resulting γ-sarcoglycan-null/Col6a2Δex5 mice indeed exhibit reduced muscle pathology compared with γ-sarcoglycan-null mice. Specifically, fewer muscle fibers are degenerating, fiber size varies less, Evans blue dye uptake is reduced and serum creatine kinase levels are lower. Surprisingly, in spite of this reduction in muscle pathology, muscle function is not significantly improved. In fact, grip strength and maximum isometric tetanic force are even lower in γ-sarcoglycan-null/Col6a2Δex5 mice than in γ-sarcoglycan-null mice. In conclusion, our results reveal that Collagen VI-mediated fibrosis contributes to skeletal muscle pathology in γ-sarcoglycan-null mice. Importantly, however, our data also demonstrate that a reduction in skeletal muscle pathology does not necessarily lead to an improvement of skeletal muscle function, and this should be considered in future translational studies. PMID:26908621

  16. Mecp2 Deficiency Decreases Bone Formation and Reduces Bone Volume in a Rodent Model of Rett Syndrome

    PubMed Central

    O’Connor, R.D.; Zayzafoon, M.; Farach-Carson, M.C.; Schanen, N.C.

    2009-01-01

    Rett Syndrome (RTT), a neurological disorder characterized by neurological impairment and a high frequency of osteopenia which often manifests early in childhood, most often is caused by inactivating mutations in the X-linked gene encoding a regulator of epigenetic gene expression, methyl CpG binding protein, MeCP2. Clinical data show that, along with neurological defects, females with RTT frequently have marked decreases in Bone Mineral Density (BMD) beyond that expected from disuse atrophy. To investigate the relationship between loss of Mecp2 and reduced BMD, we used a Mecp2 null mouse model, Mecp2−/yBIRD, for our histological and biochemical studies. Mecp2−/yBIRD mice have significantly shorter femurs and an overall reduced skeletal size compared to wild-type mice by post-natal day 60 (P60). Histological and histomorphometric studies identified growth plate abnormalities as well as decreased cortical and trabecular bone in P21 and especially in P60 Mecp2−/yBIRD mice. Dynamic histomorphometry revealed decreased Mineral Apposition Rates (MAR) in Mecp2 null femoral trabecular bone as well as in calvarial bone samples. While changes in MAR of cortical bone were not significant, loss of Mecp2 significantly reduced cortical, trabecular and calvarial bone volume compared with age-matched wild-type animals. These differences indicate that Mecp2 deficiency leads to osteoblast dysfunction, which translates into reduced osteoid deposition accounting for the reduced bone volume phenotype. While individual variations were observed in OPG and Rankl concentrations, molar ratios of OPG:Rankl at P21 and P60 were comparable between wild-type and Mecp2−/yBIRD mice and showed a consistent excess of OPG. In tibial sections, TRAP staining demonstrated equivalent osteoclast number per bone surface measurements between wild-type and null animals. Our work with a Mecp2 null mouse model suggests epigenetic regulation of bone in the Mecp2−/yBIRD mice which is associated with

  17. SPECC1L deficiency results in increased adherens junction stability and reduced cranial neural crest cell delamination

    PubMed Central

    Wilson, Nathan R.; Olm-Shipman, Adam J.; Acevedo, Diana S.; Palaniyandi, Kanagaraj; Hall, Everett G.; Kosa, Edina; Stumpff, Kelly M.; Smith, Guerin J.; Pitstick, Lenore; Liao, Eric C.; Bjork, Bryan C.; Czirok, Andras; Saadi, Irfan

    2016-01-01

    Cranial neural crest cells (CNCCs) delaminate from embryonic neural folds and migrate to pharyngeal arches, which give rise to most mid-facial structures. CNCC dysfunction plays a prominent role in the etiology of orofacial clefts, a frequent birth malformation. Heterozygous mutations in SPECC1L have been identified in patients with atypical and syndromic clefts. Here, we report that in SPECC1L-knockdown cultured cells, staining of canonical adherens junction (AJ) components, β-catenin and E-cadherin, was increased, and electron micrographs revealed an apico-basal diffusion of AJs. To understand the role of SPECC1L in craniofacial morphogenesis, we generated a mouse model of Specc1l deficiency. Homozygous mutants were embryonic lethal and showed impaired neural tube closure and CNCC delamination. Staining of AJ proteins was increased in the mutant neural folds. This AJ defect is consistent with impaired CNCC delamination, which requires AJ dissolution. Further, PI3K-AKT signaling was reduced and apoptosis was increased in Specc1l mutants. In vitro, moderate inhibition of PI3K-AKT signaling in wildtype cells was sufficient to cause AJ alterations. Importantly, AJ changes induced by SPECC1L-knockdown were rescued by activating the PI3K-AKT pathway. Together, these data indicate SPECC1L as a novel modulator of PI3K-AKT signaling and AJ biology, required for neural tube closure and CNCC delamination. PMID:26787558

  18. Selling Sprinkles micronutrient powder reduces anemia, iron deficiency, and vitamin A deficiency in young children in Western Kenya: a cluster-randomized controlled trial2, 3

    PubMed Central

    Suchdev, Parminder S; Ruth, Laird J; Woodruff, Bradley A; Mbakaya, Charles; Mandava, Usha; Flores-Ayala, Rafael; Jefferds, Maria Elena D; Quick, Robert

    2015-01-01

    Background Although the efficacy of micronutrient powders [MNPs; eg, Sprinkles MNP (Sprinkles Global Health Initiative)] in the reduction of anemia has been established, the effectiveness of these powders in real-world programs has seldom been assessed. Objective In this study, we evaluated the effect of community-based marketing and distribution of Sprinkles MNP on childhood rates of anemia and iron and vitamin A deficiency. Design In a cluster-randomized trial in children aged 6–35 mo in Western Kenya, 60 villages were randomly assigned to either intervention or control groups. Community vendors marketed and sold sachets of Sprinkles MNP in intervention villages. Biweekly household visits monitored the use of Sprinkles MNP. Hemoglobin, ferritin, retinol binding protein, malaria, and anthropometric measures were assessed at baseline (n = 1063) and 12 mo of follow-up (n = 862). Data were analyzed by using an intention-to-treat analysis and generalized linear mixed models. Results On average, 33% of households in intervention villages purchased Sprinkles MNP; the average weekly intake per child was 0.9 sachets (~11.3 mg Fe and ~328 μg vitamin A). Compared with control subjects, intervention children had greater improvements in hemoglobin concentrations (increase of 0.9 compared with 0.6 g/dL, respectively; P = 0.02), iron deficiency (decrease of 19.3% compared with 5.3%, respectively; P = 0.001), and vitamin A deficiency (decrease of 7.5% compared with an increase 2.5% increase, respectively; P = 0.01). Results adjusted for age, sex, socioeconomic status, and maternal education showed a significant association between the hemoglobin, iron, and vitamin A concentrations of children and the number of Sprinkles MNP sachets the children consumed. The prevalence of malaria, wasting, and stunting did not change significantly in either group. Conclusion Even with relatively low and infrequent use, Sprinkles MNP sales through community vendors were associated with

  19. Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict.

    PubMed

    Li, Chunlu; Yan, Yixiu; Cheng, Jingjing; Xiao, Gang; Gu, Jueqing; Zhang, Luqi; Yuan, Siyu; Wang, Junlu; Shen, Yi; Zhou, Yu-Dong

    2016-04-01

    Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine (DA) system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4 (TLR4), an important pattern-recognition receptor in the innate immune system, can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient (TLR4(-/-)) and wild-type (WT) mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed, large spaces. We found that TLR4(-/-) mice exhibited reduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4(-/-) mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approach-avoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4(-/-) mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly, the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell (NAcSh) in TLR4(-/-) mice than in WT mice. Partially inactivating the NAcSh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4(-/-) mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAcSh may contribute to this phenomenon. PMID:26898297

  20. Fgf8-Deficient Mice Compensate for Reduced GnRH Neuronal Population and Exhibit Normal Testicular Function

    PubMed Central

    Zhang, Wei; Johnson, Joshua I.; Tsai, Pei-San

    2015-01-01

    Gonadotropin-releasing hormone (GnRH) is critical for the onset and maintenance of reproduction in vertebrates. The development of GnRH neurons is highly dependent on fibroblast growth factor (Fgf) signaling. Mice with a hypomorphic Fgf8 allele (Fgf8 Het) exhibited a ~50% reduction in GnRH neuron number at birth. Female Fgf8 Het mice were fertile but showed significantly delayed puberty. However, it was unclear if these mice suffered additional loss of GnRH neurons after birth, and if male Fgf8 Het mice had normal pubertal transition and testicular function. In this study, we examined postnatal GnRH neuron number and hypothalamic GnRH content in Fgf8 Het mice from birth to 120 days of age. Further, we examined seminal vesicle and testicular growth, testicular histology, and circulating luteinizing hormone (LH) around and after pubertal transition. Our results showed that GnRH neuron numbers were significantly and consistently reduced in Fgf8 Het mice of both sexes in all ages examined, suggesting these animals were born with an inherently defective GnRH system, and no further postnatal loss of GnRH neurons had occurred. Despite an innately compromised GnRH system, male and female Fgf8 mice exhibited normal levels of immunoassayable hypothalamic GnRH peptide at all ages examined except on 60 days of age, suggesting increased GnRH synthesis or reduced turnover as a compensatory mechanism. Fgf8 Het males also had normal seminal vesicle and testicular mass/body mass ratios, testicular histology, and circulating LH. Overall, our data speak to the extraordinary ability of a GnRH system permanently compromised by developmental defect to overcome pre-existing deficiencies to ensure pubertal progression and reproduction. PMID:26441841

  1. The effects of oral Cardax (disodium disuccinate astaxanthin) on multiple independent oxidative stress markers in a mouse peritoneal inflammation model: influence on 5-lipoxygenase in vitro and in vivo.

    PubMed

    Lockwood, Samuel F; Penn, Marc S; Hazen, Stanley L; Bikádi, Zsolt; Zsila, Ferenc

    2006-06-01

    observed at time points two and five. When normalized to the concentration of the oxidative substrates, statistically significant reductions of 8-isoprostane-F(2alpha) (8-iso-F(2alpha)) at time point three (maximal neutrophil recruitment/activation), and 5-HETE, 5-oxo-EET, 11-HETE, 9-HODE, and PGF(2alpha) at time point five (maximal monocyte/macrophage recruitment/activation) were observed. Subsequently, the direct interaction of the optically inactive stereoisomer of Cardax (meso-dAST) with human 5-lipoxygenase (5-LOX) was evaluated in vitro with circular dichroism (CD) and electronic absorption (UV/Vis) spectroscopy, and subsequent molecular docking calculations were made using mammalian 15-LOX as a surrogate (for which XRC data has been reported). The results suggested that the meso-compound was capable of interaction with, and binding to, the solvent-exposed surface of the enzyme. These preliminary studies provide the foundation for more detailed evaluation of the therapeutic effects of this compound on the 5-LOX enzyme, important in chronic diseases such as atherosclerosis, asthma, and prostate cancer in humans. PMID:16466747

  2. Plasminogen activator inhibitor with very long half-life (VLHL PAI-1) can reduce bleeding in PAI-1-deficient patients.

    PubMed

    Jankun, Jerzy; Skrzypczak-Jankun, Ewa

    2013-08-01

    This review summarizes our current knowledge of plasminogen activator inhibitor (PAI-1) deficiency and proposes some novel treatments for this condition. PAI-1 is a fast acting inhibitor of tissue and urokinase plasminogen activators (tPA and uPA). PAI-1 controls/slows clot lysis triggered by tPA activated plasminogen. PAI-1 deficiency was once considered to be an extremely rare disorder characterized by frequent and prolonged bleeding episodes. PAI-1 deficiency is now thought to be more frequent than initially reported and is known to be caused by mutations in the PAI-1 gene that produce a dysfunctional PAI-1 protein or slow the secretion of PAI-1 into the circulation. PAI-1 deficiency is characterized by hyperfibrinolysis that results in frequent bleeding episodes. Patients with this condition form normal blood clots that are quickly lysed by unopposed tPA-activated plasmin. Spontaneous bleeding is rare in PAI-1 deficient patients, but moderate hemorrhaging of the knees, elbows, nose, and gums can be triggered by mild trauma. Additionally, prolonged bleeding after surgery is common and menstrual bleeding may be severe. Moderate PAI-1 deficiency is associated with a lifelong bleeding tendency, but severe deficiencies can be life-threatening. The diagnosis of this disorder remains challenging due to the lack of a clear definition of PAI-1 deficiency as well as a lack of standardized tests. Patients with mild PAI-1 deficiency may be treated with antifibrinolytic agents (ε-aminocaproic acid or tranexamic acid); however, not all patients respond well to these treatments. These patients may be treated with wild-type PAI-1; however, this molecule quickly converts into its inactive form. We propose to use PAI-1 with an extended half-life to treat these patients. PMID:23988002

  3. Prenatal Iron Supplementation Reduces Maternal Anemia, Iron Deficiency, and Iron Deficiency Anemia in a Randomized Clinical Trial in Rural China, but Iron Deficiency Remains Widespread in Mothers and Neonates123

    PubMed Central

    Zhao, Gengli; Xu, Guobin; Zhou, Min; Jiang, Yaping; Richards, Blair; Clark, Katy M; Kaciroti, Niko; Georgieff, Michael K; Zhang, Zhixiang; Tardif, Twila; Li, Ming; Lozoff, Betsy

    2015-01-01

    Background: Previous trials of prenatal iron supplementation had limited measures of maternal or neonatal iron status. Objective: The purpose was to assess effects of prenatal iron-folate supplementation on maternal and neonatal iron status. Methods: Enrollment occurred June 2009 through December 2011 in Hebei, China. Women with uncomplicated singleton pregnancies at ≤20 wk gestation, aged ≥18 y, and with hemoglobin ≥100 g/L were randomly assigned 1:1 to receive daily iron (300 mg ferrous sulfate) or placebo + 0.40 mg folate from enrollment to birth. Iron status was assessed in maternal venous blood (at enrollment and at or near term) and cord blood. Primary outcomes were as follows: 1) maternal iron deficiency (ID) defined in 2 ways as serum ferritin (SF) <15 μg/L and body iron (BI) <0 mg/kg; 2) maternal ID anemia [ID + anemia (IDA); hemoglobin <110 g/L]; and 3) neonatal ID (cord blood ferritin <75 μg/L or zinc protoporphyrin/heme >118 μmol/mol). Results: A total of 2371 women were randomly assigned, with outcomes for 1632 women or neonates (809 placebo/folate, 823 iron/folate; 1579 mother-newborn pairs, 37 mothers, 16 neonates). Most infants (97%) were born at term. At or near term, maternal hemoglobin was significantly higher (+5.56 g/L) for iron vs. placebo groups. Anemia risk was reduced (RR: 0.53; 95% CI: 0.43, 0.66), as were risks of ID (RR: 0.74; 95% CI: 0.69, 0.79 by SF; RR: 0.65; 95% CI: 0.59, 0.71 by BI) and IDA (RR: 0.49; 95% CI: 0.38, 0.62 by SF; RR: 0.51; 95% CI: 0.40, 0.65 by BI). Most women still had ID (66.8% by SF, 54.7% by BI). Adverse effects, all minor, were similar by group. There were no differences in cord blood iron measures; >45% of neonates in each group had ID. However, dose-response analyses showed higher cord SF with more maternal iron capsules reported being consumed (β per 10 capsules = 2.60, P < 0.05). Conclusions: Prenatal iron supplementation reduced anemia, ID, and IDA in pregnant women in rural China, but most women

  4. Decreased sucrase and lactase activity in iron deficiency is accompanied by reduced gene expression and upregulation of the transcriptional repressor PDX-1.

    PubMed

    West, Adrian R; Oates, Phillip S

    2005-12-01

    Disaccharidases are important digestive enzymes whose activities can be reduced by iron deficiency. We hypothesise that this is due to reduced gene expression, either by impairment to enterocyte differentiation or by iron-sensitive mechanisms that regulate mRNA levels in enterocytes. Iron-deficient Wistar rats were generated by dietary means. The enzyme activities and kinetics of sucrase and lactase were tested as well as the activity of intestinal alkaline phosphatase (IAP)-II because it is unrelated to carbohydrate digestion. mRNA levels of beta-actin, sucrase, lactase, and the associated transcription factors pancreatic duodenal homeobox (PDX)-1, caudal-related homeobox (CDX)-2, GATA-binding protein (GATA)-4, and hepatocyte nuclear factor (HNF)-1 were measured by real-time PCR. Spatial patterns of protein and gene expression were assessed by immunofluorescence and in situ hybridization, respectively. It was found that iron-deficient rats had significantly lower sucrase (19.5% lower) and lactase (56.8% lower) but not IAP-II activity than control rats. Kinetic properties of both enzymes remained unchanged from controls, suggesting a decrease in the quantity of enzyme present. Sucrase and lactase mRNA levels were reduced by 44.5% and 67.9%, respectively, by iron deficiency, suggesting that enzyme activity is controlled primarily by gene expression. Iron deficiency did not affect the pattern of protein and gene expression along the crypt to villus axis. Expression of PDX-1, a repressor of sucrase and lactase promoters, was 4.5-fold higher in iron deficiency, whereas CDX-2, GATA-4, and HNF-1 levels were not significantly different. These data suggest that decreases in sucrase and lactase activities result from a reduction in gene expression, following from increased levels of the transcriptional repressor PDX-1. PMID:16081762

  5. Methylmalonic semialdehyde dehydrogenase deficiency: demonstration of defective valine and beta-alanine metabolism and reduced malonic semialdehyde dehydrogenase activity in cultured fibroblasts

    SciTech Connect

    Gray, R.G.; Pollitt, R.J.; Webley, J.

    1987-08-01

    Intact cultured fibroblasts from a child with a new metabolic disorder, thought to be due to a deficiency of methylmalonic semialdehyde dehydrogenase, produced labeled CO/sub 2/ normally from (1-/sup 14/C)valine but not from (2-/sup 14/C)valine. CO/sub 2/ production from labeled beta-alanine was also much reduced, confirming the suspicion that malonic semialdehyde dehydrogenase is also deficient in this condition. An assay for malonic semialdehyde dehydrogenase in cell homogenates showed low activity but it was impossible to assess the degree of reduction.

  6. Deficiency in Cardiolipin Reduces Doxorubicin-Induced Oxidative Stress and Mitochondrial Damage in Human B-Lymphocytes

    PubMed Central

    Aryal, Baikuntha; Rao, V. Ashutosh

    2016-01-01

    Cardiolipin (CL) is an inner mitochondrial membrane phospholipid which plays an important role in mitochondrial function. Perturbation in CL biosynthesis alters mitochondrial bioenergetics causing a severe genetic disorder commonly known as Barth syndrome. Barth syndrome patients are known to have a reduced concentration and altered composition of CL. Cardiolipin is also known to have a high affinity for the chemotherapeutic agent doxorubicin (Dox), resulting in an extensive mitochondrial accumulation of the drug. Our results indicate that B-lymphocytes from healthy individuals are more sensitive to Dox-induced oxidative stress and cellular toxicity compared to the B-lymphocytes from Barth syndrome as indicated by greater cell death and greater level of cleaved caspase-3 following Dox treatment. Barth lymphocytes, when compared to healthy lymphocytes, showed a greater basal level of mitochondrial reactive oxygen species (mito-ROS), yet exhibited a lower level of induced mito-ROS production in response to Dox. Significantly less ATP content and slightly greater OXPHOS protein levels were detected in healthy cells compared to Barth cells after Dox treatment. Consistent with greater mitochondrial ROS, treatment with Dox induced a higher level of lipid peroxidation and protein carbonylation in healthy lymphocytes compared to Barth lymphocytes. The final remodeling of CL during CL synthesis is catalyzed by the tafazzin protein. Knockdown of tafazzin gene in H9c2 cardiomyocytes using siRNA showed decreased oxidant-induced damage, as observed in Barth lymphocytes. Our findings demonstrate that a deficiency in CL might provide a therapeutic advantage in favor of oxidant-induced anticancer activities. PMID:27434059

  7. Corticosteroid-binding globulin cleavage is paradoxically reduced in alpha-1 antitrypsin deficiency: Implications for cortisol homeostasis.

    PubMed

    Nenke, Marni A; Holmes, Mark; Rankin, Wayne; Lewis, John G; Torpy, David J

    2016-01-15

    High-affinity corticosteroid-binding globulin (haCBG) is cleaved by neutrophil elastase (NE) resulting in permanent transition to the low cortisol-binding affinity form (laCBG), thereby increasing cortisol availability at inflammatory sites. Alpha-1 antitrypsin (AAT) is the major inhibitor of NE. AAT deficiency (AATD) predisposes patients to early-onset emphysema due to increased proteolytic destruction from the inherent proteinase-antiproteinase imbalance. We hypothesized that AATD may result in increased CBG cleavage in vivo. We collected demographic data and blood samples from 10 patients with AATD and 28 healthy controls measuring total CBG and haCBG levels by parallel in-house ELISAs, as well as AAT, total and free cortisol levels. haCBG was higher (median [range]); 329 [210-551] vs. 250 [175-365] nmol/L; P<0.005, and laCBG lower; 174 [68-229] vs. 220 [119-348] nmol/L; P=0.016 in the AATD group, compared with controls. The ratio of haCBG:total CBG was also higher in AATD; 72 [53-83] vs. 54 [41-72] %; P=0.0001). There was a negative correlation between haCBG:total CBG and AAT levels (P<0.05, R=-0.64). Paradoxically, proteolytic cleavage of CBG was reduced in AATD, despite the recognized increase in NE activity. This implies that NE activity is not the mechanism for systemic CBG cleavage in basal, low inflammatory conditions. Relatively low levels of laCBG may have implications for cortisol action in AATD. PMID:26522656

  8. Dietary repletion can replenish reduced T cell subset numbers and lymphoid organ weight in zinc-deficient and energy-restricted rats.

    PubMed

    Hosea, Heather J; Rector, Edward S; Taylor, Carla G

    2004-05-01

    The objective of the present study was to investigate the time course for recovery of lymphoid tissue and T cell subset numbers when Zn-deficient (ZD) or energy-restricted (ER) rats were repleted with control diet; in a second experiment, the link between the stress axis and lymphoid organs was explored. During the deficiency phase, rats were fed a ZD (<1 mg Zn/kg) or control diet (30 mg Zn/kg, nutritionally complete) either as pair-fed controls (ER) or ad libitum-fed controls (CTL) for 3 weeks. During the repletion phase, all rats were fed control diet ad libitum for 3, 7 or 23 d. After the deficiency phase, ZD and ER had lower T cell subset numbers in the thymus compared with CTL, and ZD had reduced T cell subset numbers in the spleen compared with both ER and CTL. T cell subset numbers and lymphoid organ weights recovered from dietary Zn deficiency and energy restriction by 7 d of repletion (except 23 d for thymus weight in ZD), while body weight required more than 23 d for recovery. At the end of the deficiency phase, ZD and ER had higher circulating corticosterone concentrations compared with CTL; plasma TNFalpha was not detectable and there were no differences in plasma haptoglobin, an acute-phase protein. In conclusion, Zn deficiency and energy restriction elevated circulating corticosterone and reduced T cell subset numbers in the thymus and spleen of growing rats. Repletion with a nutritionally complete diet allowed recovery of T cell subset numbers and lymphoid organ weight. PMID:15137926

  9. Iron deficiency.

    PubMed

    Scrimshaw, N S

    1991-10-01

    The world's leading nutritional problem is iron deficiency. 66% of children and women aged 15-44 years in developing countries have it. Further, 10-20% of women of childbearing age in developed countries are anemic. Iron deficiency is identified with often irreversible impairment of a child's learning ability. It is also associated with low capacity for adults to work which reduces productivity. In addition, it impairs the immune system which reduces the body's ability to fight infection. Iron deficiency also lowers the metabolic rate and the body temperature when exposed to cold. Hemoglobin contains nearly 73% of the body's iron. This iron is always being recycled as more red blood cells are made. The rest of the needed iron does important tasks for the body, such as binds to molecules that are reservoirs of oxygen for muscle cells. This iron comes from our diet, especially meat. Even though some plants, such as spinach, are high in iron, the body can only absorb 1.4-7% of the iron in plants whereas it can absorb 20% of the iron in red meat. In many developing countries, the common vegetarian diets contribute to high rates of iron deficiency. Parasitic diseases and abnormal uterine bleeding also promote iron deficiency. Iron therapy in anemic children can often, but not always, improve behavior and cognitive performance. Iron deficiency during pregnancy often contributes to maternal and perinatal mortality. Yet treatment, if given to a child in time, can lead to normal growth and hinder infections. However, excess iron can be damaging. Too much supplemental iron in a malnourished child promotes fatal infections since the excess iron is available for the pathogens use. Many countries do not have an effective system for diagnosing, treating, and preventing iron deficiency. Therefore a concerted international effort is needed to eliminate iron deficiency in the world. PMID:1745900

  10. Maternal vitamin C deficiency does not reduce hippocampal volume and β-tubulin III intensity in prenatal Guinea pigs.

    PubMed

    Hansen, Stine N; Schjoldager, Janne G; Paidi, Maya D; Lykkesfeldt, Jens; Tveden-Nyborg, Pernille

    2016-07-01

    Marginal vitamin C (vitC) deficiency affects 5% to 10% of adults including subpopulations such as pregnant women and newborns. Animal studies link vitC deficiency to deleterious effects on the developing brain, but exactly how the brain adapts to vitC deficiency and the mechanisms behind the observed deficits remain largely unknown. We hypothesized that vitC deficiency in utero may lead to a decreased neuronal maturation and increased cellular death giving rise to alterations of the hippocampal morphology in a guinea pig model. Brains from prenatal guinea pig pups (n=9-10 in each group) subjected to either a sufficient (918mg vitC/kg feed) or deficient (100mg vitC/kg feed) maternal dietary regimen were assessed with regards to hippocampal volume and β-tubulin isotype III staining intensity at 2 gestational time points (45 and 56). We found a distinct differential regional growth pattern of the hippocampus with a clear effect of gestational age, whereas vitC status did not affect either investigated parameters. Within hippocampal subdivisions, the overall expansion of the hippocampus from gestational day 45 to 56 was found to reside in the dentate gyrus. In conclusion, the present study found that hippocampal volume and β-tubulin isotype III intensity in the prenatal guinea pig were influenced by gestational day but not by maternal vitC intake. PMID:27333961

  11. Monocyte chemotactic protein-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is a risk factor for cancer. Adipose tissue produces pro-inflammatory adipokines that contribute obesity-related malignant progression. This study investigated the effects of monocyte chemotactic protein-1 (MCP-1) deficiency on pulmonary metastasis of Lewis lung carcinoma (LLC) in male C57...

  12. Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair

    SciTech Connect

    Sun, Xi; Zhou, Xixi; Du, Libo; Liu, Wenlan; Liu, Yang; Hudson, Laurie G.; Liu, Ke Jian

    2014-01-15

    Inhibition of DNA repair is a recognized mechanism for arsenic enhancement of ultraviolet radiation-induced DNA damage and carcinogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger DNA repair protein, has been identified as a sensitive molecular target for arsenic. The zinc finger domains of PARP-1 protein function as a critical structure in DNA recognition and binding. Since cellular poly(ADP-ribosyl)ation capacity has been positively correlated with zinc status in cells, we hypothesize that arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair. To test this hypothesis, we compared the effects of arsenite exposure with zinc deficiency, created by using the membrane-permeable zinc chelator TPEN, on 8-OHdG formation, PARP-1 activity and zinc binding to PARP-1 in HaCat cells. Our results show that arsenite exposure and zinc deficiency had similar effects on PARP-1 protein, whereas supplemental zinc reversed these effects. To investigate the molecular mechanism of zinc loss induced by arsenite, ICP-AES, near UV spectroscopy, fluorescence, and circular dichroism spectroscopy were utilized to examine arsenite binding and occupation of a peptide representing the first zinc finger of PARP-1. We found that arsenite binding as well as zinc loss altered the conformation of zinc finger structure which functionally leads to PARP-1 inhibition. These findings suggest that arsenite binding to PARP-1 protein created similar adverse biological effects as zinc deficiency, which establishes the molecular mechanism for zinc supplementation as a potentially effective treatment to reverse the detrimental outcomes of arsenic exposure. - Highlights: • Arsenite binding is equivalent to zinc deficiency in reducing PARP-1 function. • Zinc reverses arsenic inhibition of PARP-1 activity and enhancement of DNA damage. • Arsenite binding and zinc loss alter the conformation of zinc finger

  13. NLRP3 Deficiency Reduces Macrophage Interleukin-10 Production and Enhances the Susceptibility to Doxorubicin-induced Cardiotoxicity.

    PubMed

    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

  14. Synthesis, SAR, and series evolution of novel oxadiazole-containing 5-lipoxygenase activating protein inhibitors: discovery of 2-[4-(3-{(r)-1-[4-(2-amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]-N,N-dimethyl-acetamide (BI 665915).

    PubMed

    Takahashi, Hidenori; Riether, Doris; Bartolozzi, Alessandra; Bosanac, Todd; Berger, Valentina; Binetti, Ralph; Broadwater, John; Chen, Zhidong; Crux, Rebecca; De Lombaert, Stéphane; Dave, Rajvee; Dines, Jonathon A; Fadra-Khan, Tazmeen; Flegg, Adam; Garrigou, Michael; Hao, Ming-Hong; Huber, John; Hutzler, J Matthew; Kerr, Steven; Kotey, Adrian; Liu, Weimin; Lo, Ho Yin; Loke, Pui Leng; Mahaney, Paige E; Morwick, Tina M; Napier, Spencer; Olague, Alan; Pack, Edward; Padyana, Anil K; Thomson, David S; Tye, Heather; Wu, Lifen; Zindell, Renee M; Abeywardane, Asitha; Simpson, Thomas

    2015-02-26

    The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production. PMID:25671290

  15. A modified choline-deficient, ethionine-supplemented diet reduces morbidity and retains a liver progenitor cell response in mice

    PubMed Central

    Passman, Adam M.; Strauss, Robyn P.; McSpadden, Sarah B.; Finch-Edmondson, Megan L.; Woo, Ken H.; Diepeveen, Luke A.; London, Roslyn; Callus, Bernard A.; Yeoh, George C.

    2015-01-01

    ABSTRACT The choline-deficient, ethionine-supplemented (CDE) dietary model induces chronic liver damage, and stimulates liver progenitor cell (LPC)-mediated repair. Long-term CDE administration leads to hepatocellular carcinoma in rodents and lineage-tracing studies show that LPCs differentiate into functional hepatocytes in this model. The CDE diet was first modified for mice by our laboratory by separately administering choline-deficient chow and ethionine in the drinking water (CD+E diet). Although this CD+E diet is widely used, concerns with variability in weight loss, morbidity, mortality and LPC response have been raised by researchers who have adopted this model. We propose that these inconsistencies are due to differential consumption of chow and ethionine in the drinking water, and that incorporating ethionine in the choline-deficient chow, and altering the strength, will achieve better outcomes. Therefore, C57Bl/6 mice, 5 and 6 weeks of age, were fed an all-inclusive CDE diet of various strengths (67% to 100%) for 3 weeks. The LPC response was quantitated and cell lines were derived. We found that animal survival, LPC response and liver damage are correlated with CDE diet strength. The 67% and 75% CDE diet administered to mice older than 5 weeks and greater than 18 g provides a consistent and acceptable level of animal welfare and induces a substantial LPC response, permitting their isolation and establishment of cell lines. This study shows that an all-inclusive CDE diet for mice reproducibly induces an LPC response conducive to in vivo studies and isolation, whilst minimizing morbidity and mortality. PMID:26496771

  16. 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

  17. ACE2 deficiency reduces β-cell mass and impairs β-cell proliferation in obese C57BL/6 mice.

    PubMed

    Shoemaker, Robin; Yiannikouris, Frederique; Thatcher, Sean; Cassis, Lisa

    2015-10-01

    Drugs that inhibit the renin-angiotensin system (RAS) decrease the onset of type 2 diabetes (T2D). Pancreatic islets express RAS components, including angiotensin-converting enzyme 2 (ACE2), which cleaves angiotensin II (Ang II) to angiotensin-(1-7) [Ang-(1-7)]. Overexpression of ACE2 in pancreas of diabetic mice improved glucose homeostasis. The purpose of this study was to determine if deficiency of endogenous ACE2 contributes to islet dysfunction and T2D. We hypothesized that ACE2 deficiency potentiates the decline in β-cell function and augments the development of diet-induced T2D. Male Ace2(+/y) or Ace2(-/y) mice were fed a low-fat (LF) or high-fat (HF) diet for 1 or 4 mo. A subset of 1-mo HF-fed mice were infused with Sal (Sal), losartan (Los), or Ang-(1-7). At 4 mo, while both genotypes of HF-fed mice developed a similar level of insulin resistance, adaptive hyperinsulinemia was reduced in Ace2(-/y) vs. Ace2(+/y) mice. Similarly, in vivo glucose-stimulated insulin secretion (GSIS) was reduced in 1-mo HF-fed Ace2(-/y) compared with Ace2(+/y) mice, resulting in augmented hyperglycemia. The average islet area was significantly smaller in both LF- and HF-fed Ace2(-/y) vs. Ace2(+/y) mice. Additionally, β-cell mass and proliferation were reduced significantly in HF-fed Ace2(-/y) vs. Ace2(+/y) mice. Neither infusion of Los nor Ang-(1-7) was able to correct impaired in vivo GSIS of HF-fed ACE2-deficient mice. These results demonstrate a critical role for endogenous ACE2 in the adaptive β-cell hyperinsulinemic response to HF feeding through regulation of β-cell proliferation and growth. PMID:26389599

  18. Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair.

    PubMed

    Sun, Xi; Zhou, Xixi; Du, Libo; Liu, Wenlan; Liu, Yang; Hudson, Laurie G; Liu, Ke Jian

    2014-01-15

    Inhibition of DNA repair is a recognized mechanism for arsenic enhancement of ultraviolet radiation-induced DNA damage and carcinogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger DNA repair protein, has been identified as a sensitive molecular target for arsenic. The zinc finger domains of PARP-1 protein function as a critical structure in DNA recognition and binding. Since cellular poly(ADP-ribosyl)ation capacity has been positively correlated with zinc status in cells, we hypothesize that arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair. To test this hypothesis, we compared the effects of arsenite exposure with zinc deficiency, created by using the membrane-permeable zinc chelator TPEN, on 8-OHdG formation, PARP-1 activity and zinc binding to PARP-1 in HaCat cells. Our results show that arsenite exposure and zinc deficiency had similar effects on PARP-1 protein, whereas supplemental zinc reversed these effects. To investigate the molecular mechanism of zinc loss induced by arsenite, ICP-AES, near UV spectroscopy, fluorescence, and circular dichroism spectroscopy were utilized to examine arsenite binding and occupation of a peptide representing the first zinc finger of PARP-1. We found that arsenite binding as well as zinc loss altered the conformation of zinc finger structure which functionally leads to PARP-1 inhibition. These findings suggest that arsenite binding to PARP-1 protein created similar adverse biological effects as zinc deficiency, which establishes the molecular mechanism for zinc supplementation as a potentially effective treatment to reverse the detrimental outcomes of arsenic exposure. PMID:24275069

  19. Relation between increased anxiety and reduced expression of alpha1 and alpha2 subunits of GABA(A) receptors in Wfs1-deficient mice.

    PubMed

    Raud, Sirli; Sütt, Silva; Luuk, Hendrik; Plaas, Mario; Innos, Jürgen; Kõks, Sulev; Vasar, Eero

    2009-08-28

    Mutations in the coding region of the WFS1 gene cause Wolfram syndrome, a rare multisystem neurodegenerative disorder of autosomal recessive inheritance. In clinical studies a relation between mutations in the Wfs1 gene and increased susceptibility for mood disorders has been established. According to our previous studies, mice lacking Wfs1 gene displayed increased anxiety in stressful environment. As the GABA-ergic system plays a significant role in the regulation of anxiety, we analyzed the expression of GABA-related genes in the forebrain structures of wild-type and Wfs1-deficient mice. Experimentally naïve Wfs1-deficient animals displayed a significant down-regulation of alpha1 (Gabra1) and alpha2 (Gabra2) subunits of GABA(A) receptors in the temporal lobe and frontal cortex. Exposure of wild-type mice to the elevated plus-maze decreased levels of Gabra1 and Gabra2 genes in the temporal lobe. A similar tendency was also established in the frontal cortex of wild-type animals exposed to behavioral test. In Wfs1-deficient mice the elevated plus-maze exposure did not induce further changes in the expression of Gabra1 and Gabra2 genes. By contrast, the expression of Gad1 and Gad2 genes, enzymes responsible for the synthesis of GABA, was not significantly affected by the exposure of mice to the elevated plus-maze or by the invalidation of Wfs1 gene. Altogether, the present study demonstrates that increased anxiety of Wfs1-deficient mice is probably linked to reduced expression of Gabra1 and Gabra2 genes in the frontal cortex and temporal lobe. PMID:19477223

  20. Repin1 deficiency improves insulin sensitivity and glucose metabolism in db/db mice by reducing adipose tissue mass and inflammation.

    PubMed

    Kunath, Anne; Hesselbarth, Nico; Gericke, Martin; Kern, Matthias; Dommel, Sebastian; Kovacs, Peter; Stumvoll, Michael; Blüher, Matthias; Klöting, Nora

    2016-09-01

    Replication initiator 1 (Repin1) is a zinc finger protein playing a role in insulin sensitivity, body fat mass and lipid metabolism by regulating the expression key genes of glucose and lipid metabolism. Here, we tested the hypothesis that introgression of a Repin1 deletion into db/db mice improves glucose metabolism in vivo. We generated a whole body Repin1 deficient db/db double knockout mouse (Rep1(-/-)x db/db) and systematically characterized the consequences of Repin1 deficiency on insulin sensitivity, glucose and lipid metabolism parameters and fat mass. Hyperinsulinemic-euglycemic clamp studies revealed significantly improved insulin sensitivity in Rep1(-/-)x db/db mice, which are also characterized by lower HbA1c, lower body fat mass and reduced adipose tissue (AT) inflammation area. Our study provides evidence that loss of Repin1 in db/db mice improves insulin sensitivity and reduces chronic hyperglycemia most likely by reducing fat mass and AT inflammation. PMID:27402271

  1. NADPH oxidase 4 deficiency leads to impaired wound repair and reduced dityrosine-crosslinking, but does not affect myofibroblast formation.

    PubMed

    Lévigne, Dominik; Modarressi, Ali; Krause, Karl-Heinz; Pittet-Cuénod, Brigitte

    2016-07-01

    NADPH oxidases (NOX) mediate redox signaling by generating superoxide and/or hydrogen peroxide, which are involved in biosynthetic pathways, e.g. thyroid hormone generation, dityrosine crosslinking, as well as bacterial killing. Data investigating the role of NOX enzymes in cutaneous wound repair is limited and specifically their function in skin myofibroblast expression is unknown. The isoform NOX4 was recently shown to be a pre-requisite for the differentiation of cardiac and pulmonary myofibroblasts. In this study we investigate the role of NOX4 in wound repair using a wound model in NOX4 knockout mice (n=16) and wildtype mice (n=16). Wounds were photographed daily until complete wound closure. Mice were sacrificed at day 3, 7, 14; wound tissue was harvested. NOX4-deficient mice healed significantly slower (22 days, SD=1.9) than wild-type mice (17 days, SD=1.4, p<0.005). However, there was no difference in myofibroblast expression. Strong dityrosine formation was observed, but was significantly weaker in NOX4-/- mice (p<0.05). NOX2, HIF1α and CD31 expression was significantly weaker in NOX4-/- mice (p<0.05). In this study we show for the first time that NOX4 plays a role in cutaneous wound repair. Our data suggests that NOX4 mediates HIF1α expression and neoangiogenesis during wound repair. NOX4 deletion led to a decreased expression of NOX2, implying a role of NOX4 in phagocytic cell recruitment. NOX4 was required for effective wound contraction but not myofibroblast expression. We suggest that myofibroblast contraction in NOX4-deficient mice is less effective in contracting the wound because of insufficient dityrosine-crosslinking of the ECM, providing the first indication for a physiological function of dityrosine crosslinking in higher animals. PMID:27140231

  2. Resveratrol protects against diet-induced atherosclerosis by reducing low-density lipoprotein cholesterol and inhibiting inflammation in apolipoprotein E-deficient mice

    PubMed Central

    Chang, Geng-Ruei; Chen, Po-Lin; Hou, Po-Hsun; Mao, Frank Chiahung

    2015-01-01

    Objective(s): Resveratrol (RES) is a polyphenol compound that has been shown a promising cardioprotective effect. However, some reports have yielded conflicting findings. Herein, we investigated the anti-atherosclerotic effects of RES in apolipoprotein E (apo E)-deficient mice on a high cholesterol diet. Materials and Methods: Firstly, atherosclerosis was induced by feeding a high cholesterol diet to apo E-deficient mice. Then, we examined its effects on weight control, and serum interleukin-6 (IL-6) levels and used histopathological methods to analyze morphology and inflammatory marker of atherosclerotic lesions in mice orally supplemented with high (25 mg/kg/day) and low (5 mg/kg/day) doses of RES for 8 weeks. Results: Mice with high dose of RES had reduced epididymal fat pads, and lower serum IL-6 levels compared with those of control mice. Moreover, RES in high doses also decreased the low-density lipoprotein cholesterol (LDL-C) levels and atherogenic index (LDL-C/HDL-C) in the mice. Dissection of high-dose RES-treated mice revealed a marked reduction in fat deposition, percentage of mice with atherosclerotic lesion, and intima/media ratio in the aortic areas. The expressions of macrophage-specific marker F4/80 and cardiovascular inflammatory marker NF-κB in atherosclerotic vessels were both diminished in the atherosclerotic vessels of high-dose RES-supplementated apo E-deficient mice. Conclusion: These results suggest that RES prevented the effects of a high cholesterol diet on the rate of accretion in atherosclerosis progression by reducing the LDL-C levels and suppressing atherosclerotic inflammation. RES can therefore be valuable in the development of new anti-atherosclerotic agents. PMID:26949492

  3. Reducing Iron Deficiency in 18-36-months-old US Children: Is the Solution Less Calcium?

    PubMed

    Kerling, Elizabeth H; Souther, Laura M; Gajewski, Byron J; Sullivan, Debra K; Georgieff, Michael K; Carlson, Susan E

    2016-09-01

    Objectives National surveys consistently identify iron deficiency (ID) in US children between 1 and 3 years of age, when the brain is rapidly developing and vulnerable to the effects of ID. However, controversy remains as to how best to recognize and prevent ID in young children, in part because of the multiple potential etiologies. The objective of this project was to assess ID in children and identify potential individual dietary predictors of status. Methods We examined three biomarkers of ID [soluble transferrin receptor (sTfR) and serum ferritin (SF), and body iron (calculated from sTfR and SF)] against parent-provided dietary calcium and iron intake for eight-three 18-36 month old children from middle class families. Results Using literature-based cutoffs, fourteen children (16.9 %) had at least one indicator of ID: low SF(<10 μg/l, 7.2 %), negative body iron (<0 mg/kg, 7.2 %) or elevated sTfR (>8.4 μg/ml, 13.2 %). All children consumed more than the Dietary Reference Intake (DRI) Estimated Average Requirement of 3 mg/d iron. The mean iron intake of children identified with ID approximated the Recommended Dietary Allowance of 7 mg/d. Most children (81 %) consumed above the DRI Adequate Intake of 500 mg/d of calcium. Calcium intakes were generally high and predicted lower body iron (p = 0.0005), lower SF (p = 0.0086) and higher sTfR (p = 0.0176). Conclusions for Practice We found rates of ID similar to US national averages. Dietary calcium intake predicted lower iron status more than deficits in iron intake. Teaching parents to balance calcium and iron intake in toddlers could be a strategy to prevent ID. PMID:26987860

  4. Carrageenan-Induced Colonic Inflammation Is Reduced in Bcl10 Null Mice and Increased in IL-10-Deficient Mice

    PubMed Central

    Bhattacharyya, Sumit; Xue, Liquan; Devkota, Suzanne; Chang, Eugene; Morris, Stephan; Tobacman, Joanne K.

    2013-01-01

    The common food additive carrageenan is a known activator of inflammation in mammalian tissues and stimulates both the canonical and noncanonical pathways of NF-κB activation. Exposure to low concentrations of carrageenan (10 μg/mL in the water supply) has produced glucose intolerance, insulin resistance, and impaired insulin signaling in C57BL/6 mice. B-cell leukemia/lymphoma 10 (Bcl10) is a mediator of inflammatory signals from Toll-like receptor (TLR) 4 in myeloid and epithelial cells. Since the TLR4 signaling pathway is activated in diabetes and by carrageenan, we addressed systemic and intestinal inflammatory responses following carrageenan exposure in Bcl10 wild type, heterozygous, and null mice. Fecal calprotectin and circulating keratinocyte chemokine (KC), nuclear RelA and RelB, phospho(Thr559)-NF-κB-inducing kinase (NIK), and phospho(Ser36)-IκBα in the colonic epithelial cells were significantly less (P < 0.001) in the carrageenan-treated Bcl10 null mice than in controls. IL-10-deficient mice exposed to carrageenan in a germ-free environment showed an increase in activation of the canonical pathway of NF-κB (RelA) activation, but without increase in RelB or phospho-Bcl10, and exogenous IL-10 inhibited only the canonical pathway of NF-κB activation in cultured colonic cells. These findings demonstrate a Bcl10 requirement for maximum development of carrageenan-induced inflammation and lack of complete suppression by IL-10 of carrageenan-induced inflammation. PMID:23766559

  5. Reduced GM1 ganglioside in CFTR-deficient human airway cells results in decreased β1-integrin signaling and delayed wound repair

    PubMed Central

    Itokazu, Yutaka; Pagano, Richard E.; Schroeder, Andreas S.; O'Grady, Scott M.; Limper, Andrew H.

    2014-01-01

    Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function reduces chloride secretion and increases sodium uptake, but it is not clear why CFTR mutation also results in progressive lung inflammation and infection. We previously demonstrated that CFTR-silenced airway cells migrate more slowly during wound repair than CFTR-expressing controls. In addition, CFTR-deficient cells and mouse models have been reported to have altered sphingolipid levels. Here, we investigated the hypothesis that reduced migration in CFTR-deficient airway epithelial cells results from altered sphingolipid composition. We used cell lines derived from a human airway epithelial cell line (Calu-3) stably transfected with CFTR short hairpin RNA (CFTR-silenced) or nontargeting short hairpin RNA (controls). Cell migration was measured by electric cell substrate impedance sensing (ECIS). Lipid analyses, addition of exogenous glycosphingolipids, and immunoblotting were performed. We found that levels of the glycosphingolipid, GM1 ganglioside, were ∼60% lower in CFTR-silenced cells than in controls. CFTR-silenced cells exhibited reduced levels of activated β1-integrin, phosphorylated tyrosine 576 of focal adhesion kinase (pFAK), and phosphorylation of Crk-associated substrate (pCAS). Addition of GM1 (but not GM3) ganglioside to CFTR-silenced cells restored activated β1-integrin, pFAK, and pCAS to near control levels and partially restored (∼40%) cell migration. Our results suggest that decreased GM1 in CFTR-silenced cells depresses β1-integrin signaling, which contributes to the delayed wound repair observed in these cells. These findings have implications for the pathology of cystic fibrosis, where altered sphingolipid levels in airway epithelial cells could result in a diminished capacity for wound repair after injury. PMID:24500283

  6. Irsogladine Maleate Prevents Colitis in Interleukin-10 Gene-Deficient Mice by Reducing Interleukin-12 and -23 Production.

    PubMed

    Nakagawa, Tomoo; Katsuno, Tatsuro; Noguchi, Yoshiko; Mandai, Yasushi; Yoshihama, Sayuri; Saito, Keiko; Maruoka, Daisuke; Matsumura, Tomoaki; Arai, Makoto; Yokosuka, Osamu

    2015-01-01

    Irsogladine maleate (2,4-diamino-6-[2,5-dichlorophenyl]-s-triazine maleate; IM), an anti-peptic ulcer drug, may have a protective effect on the gastrointestinal mucosa. This study investigated the effects of IM on spontaneous colitis in interleukin-10 gene-deficient (IL-10(-/-)) mice. Five-week-old IL-10(-/-) mice were fed a control diet or one containing 100 ppm of IM for 10 weeks. Colonic tissues were evaluated morphologically and histologically. J774A.1 murine monocyte/macrophage cells were incubated with IM after lipopolysaccharide stimulation. mRNA expression was assessed by quantitative polymerase chain reaction (PCR) and protein concentration by enzyme-linked immunosorbent assay (ELISA). Colonic length, weight, and histological scores clearly demonstrated that spontaneous colitis was prevented in IL-10(-/-) mice fed a diet containing IM compared with those fed control diet. Levels of tumor necrosis factor-alpha (TNF-α) (-2.5-fold), IL-1β (-5.4), interferon-gamma (IFN-γ) (-4.5), IL-17 (-113.0), IL-12p35 (-21.0), IL-12p40 (-3.4), and IL-23p19 (-4.2) mRNA expression were significantly decreased in the colonic tissues of IM-treated animals, suggesting that oral treatment with IM suppressed the T-helper (Th)1/Th17 immune response in the colonic mucosa. An in vitro study using monocyte/macrophage cells to clarify the pharmacological action of IM indicated that IL-12p40 and IL-23p19 mRNA expression levels were dose-dependently decreased by IM treatment. ELISA showed that IL-12p40 and IL-23 protein secretion were significantly decreased by IM in a dose-dependent manner. Oral treatment with IM prevented spontaneous colitis in IL-10(-/-) mice by suppressing the colonic mucosal Th1/Th17 immune response through inhibition of IL-12 and -23 production in monocyte/macrophage cells. PMID:26521820

  7. Deficiency of the iron-sulfur clusters of mitochondrial reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase (complex I) in an infant with congenital lactic acidosis.

    PubMed

    Moreadith, R W; Batshaw, M L; Ohnishi, T; Kerr, D; Knox, B; Jackson, D; Hruban, R; Olson, J; Reynafarje, B; Lehninger, A L

    1984-09-01

    We report the case of an infant with hypoglycemia, progressive lactic acidosis, an increased serum lactate/pyruvate ratio, and elevated plasma alanine, who had a moderate to profound decrease in the ability of mitochondria from four organs to oxidize pyruvate, malate plus glutamate, citrate, and other NAD+-linked respiratory substrates. The capacity to oxidize the flavin adenine dinucleotide-linked substrate, succinate, was normal. The most pronounced deficiency was in skeletal muscle, the least in kidney mitochondria. Enzymatic assays on isolated mitochondria ruled out defects in complexes II, III, and IV of the respiratory chain. Further studies showed that the defect was localized in the inner membrane mitochondrial NADH-ubiquinone oxidoreductase (complex I). When ferricyanide was used as an artificial electron acceptor, complex I activity was normal, indicating that electrons from NADH could reduce the flavin mononucleotide cofactor. However, electron paramagnetic resonance spectroscopy performed on liver submitochondrial particles showed an almost total loss of the iron-sulfur clusters characteristic of complex I, whereas normal signals were noted for other mitochondrial iron-sulfur clusters. This infant is presented as the first reported case of congenital lactic acidosis caused by a deficiency of the iron-sulfur clusters of complex I of the mitochondrial electron transport chain. PMID:6432847

  8. Ezetimibe potently reduces vascular inflammation and arteriosclerosis in eNOS deficient ApoE ko mice

    PubMed Central

    Kuhlencordt, Peter J.; Padmapriya, P.; Rützel, S.; Schödel, J.; Hu, K.; Schäfer, A.; Huang, P.L.; Ertl, G.; Bauersachs, J.

    2013-01-01

    Objective Hypercholesterolemia is associated with decreased vascular nitric oxide bioavailability and deletion of endothelial nitric oxide synthase (eNOS) markedly accelerates atherosclerosis development in apolipoprotein E knockout (apoE ko) mice. The current study tests whether atheroprotection provided by a lipid lowering therapy with Ezetimibe depends on eNOS. Methods/Results ApoE ko and apoE/eNOS double ko (dko) mice received a high fat diet with or without 0.05% Ezetimibe. Ezetimibe significantly reduced plasma cholesterol concentrations and atherogenic lipoproteins in both genotypes to a similar extent. Moreover, the drug reduced vascular inflammation, as it significantly reduced Vascular Cell Adhesion Molecule-1 (VCAM-1) expression and vascular CD14 expression, a marker for mononuclear cell infiltration, in both genotypes. Neither NOS protein expression nor vascular reactivity of aortic rings were changed in apoE ko mice following Ezetimibe treatment. Significant lesion reduction was seen in Ezetimibe treated male and female apoE ko and apoE/eNOS dko animals (p≤0.05). Interestingly, the drug mediated additional atheroprotection in male apoE ko, compared to male eNOS dko mice, suggesting that lipid lowering does provide additional eNOS dependent atheroprotection in this experimental group. Conclusion Lipid lowering with Ezetimibe potently reduces atherosclerosis and vascular inflammation independent of eNOS. Moreover, Ezetimibe did not exert any effects on eNOS protein expression or enzyme activity. However, additional atheroprotection by Ezetimibe was observed in eNOS competent apoE ko mice, suggesting that some of the drug's antiatherosclerotic effects are mediated by the eNOS pathway. PMID:18479686

  9. Myeloid Acyl-CoA:Cholesterol Acyltransferase 1 Deficiency Reduces Lesion Macrophage Content and Suppresses Atherosclerosis Progression.

    PubMed

    Huang, Li-Hao; Melton, Elaina M; Li, Haibo; Sohn, Paul; Rogers, Maximillian A; Mulligan-Kehoe, Mary Jo; Fiering, Steven N; Hickey, William F; Chang, Catherine C Y; Chang, Ta-Yuan

    2016-03-18

    Acyl-CoA:cholesterol acyltransferase 1 (Acat1) converts cellular cholesterol to cholesteryl esters and is considered a drug target for treating atherosclerosis. However, in mouse models for atherosclerosis, global Acat1 knockout (Acat1(-/-)) did not prevent lesion development. Acat1(-/-) increased apoptosis within lesions and led to several additional undesirable phenotypes, including hair loss, dry eye, leukocytosis, xanthomatosis, and a reduced life span. To determine the roles of Acat1 in monocytes/macrophages in atherosclerosis, we produced a myeloid-specific Acat1 knockout (Acat1(-M/-M)) mouse and showed that, in the Apoe knockout (Apoe(-/-)) mouse model for atherosclerosis, Acat1(-M/-M) decreased the plaque area and reduced lesion size without causing leukocytosis, dry eye, hair loss, or a reduced life span. Acat1(-M/-M) enhanced xanthomatosis in apoe(-/-) mice, a skin disease that is not associated with diet-induced atherosclerosis in humans. Analyses of atherosclerotic lesions showed that Acat1(-M/-M) reduced macrophage numbers and diminished the cholesterol and cholesteryl ester load without causing detectable apoptotic cell death. Leukocyte migration analysis in vivo showed that Acat1(-M/-M) caused much fewer leukocytes to appear at the activated endothelium. Studies in inflammatory (Ly6C(hi)-positive) monocytes and in cultured macrophages showed that inhibiting ACAT1 by gene knockout or by pharmacological inhibition caused a significant decrease in integrin β 1 (CD29) expression in activated monocytes/macrophages. The sparse presence of lesion macrophages without Acat1 can therefore, in part, be attributed to decreased interaction between inflammatory monocytes/macrophages lacking Acat1 and the activated endothelium. We conclude that targeting ACAT1 in a myeloid cell lineage suppresses atherosclerosis progression while avoiding many of the undesirable side effects caused by global Acat1 inhibition. PMID:26801614

  10. Increased Bacterial Load and Expression of Antimicrobial Peptides in Skin of Barrier-Deficient Mice with Reduced Cancer Susceptibility.

    PubMed

    Natsuga, Ken; Cipolat, Sara; Watt, Fiona M

    2016-01-01

    Mice lacking three epidermal barrier proteins-envoplakin, periplakin, and involucrin (EPI-/- mice)-have a defective cornified layer, reduced epidermal γδ T cells, and increased dermal CD4(+) T cells. They are also resistant to developing skin tumors. The tumor-protective mechanism involves signaling between Rae-1 expressing keratinocytes and the natural killer group 2D receptor on immune cells, which also plays a role in host defenses against infection. Given the emerging link between bacteria and cancer, we investigated whether EPI-/- mice have an altered skin microbiota. The bacterial phyla were similar in wild-type and EPI-/- skin. However, bacteria were threefold more abundant in EPI-/- skin and penetrated deeper into the epidermis. The major epithelial defense mechanism against bacteria is production of antimicrobial proteins (AMPs). EPI-/- skin exhibited enhanced expression of antimicrobial peptides. However, reducing the bacterial load by antibiotic treatment or breeding mice under specific pathogen-free conditions did not reduce AMP expression or alleviate the abnormalities in T-cell populations. We conclude that the atopic characteristics of EPI-/- skin are a consequence of the defective barrier rather than a response to the increased bacterial load. It is therefore unlikely that the increase in skin microbiota contributes directly to the observed cancer resistance. PMID:26763429

  11. Increased Bacterial Load and Expression of Antimicrobial Peptides in Skin of Barrier-Deficient Mice with Reduced Cancer Susceptibility

    PubMed Central

    Natsuga, Ken; Cipolat, Sara; Watt, Fiona M.

    2016-01-01

    Mice lacking three epidermal barrier proteins—envoplakin, periplakin, and involucrin (EPI-/- mice)—have a defective cornified layer, reduced epidermal γδ T cells, and increased dermal CD4+ T cells. They are also resistant to developing skin tumors. The tumor-protective mechanism involves signaling between Rae-1 expressing keratinocytes and the natural killer group 2D receptor on immune cells, which also plays a role in host defenses against infection. Given the emerging link between bacteria and cancer, we investigated whether EPI-/- mice have an altered skin microbiota. The bacterial phyla were similar in wild-type and EPI-/- skin. However, bacteria were threefold more abundant in EPI-/- skin and penetrated deeper into the epidermis. The major epithelial defense mechanism against bacteria is production of antimicrobial proteins (AMPs). EPI-/- skin exhibited enhanced expression of antimicrobial peptides. However, reducing the bacterial load by antibiotic treatment or breeding mice under specific pathogen-free conditions did not reduce AMP expression or alleviate the abnormalities in T-cell populations. We conclude that the atopic characteristics of EPI-/- skin are a consequence of the defective barrier rather than a response to the increased bacterial load. It is therefore unlikely that the increase in skin microbiota contributes directly to the observed cancer resistance. PMID:26763429

  12. Reduced junctional Na+/Ca2+-exchanger activity contributes to sarcoplasmic reticulum Ca2+ leak in junctophilin-2-deficient mice

    PubMed Central

    Wang, Wei; Landstrom, Andrew P.; Wang, Qiongling; Munro, Michelle L.; Beavers, David; Ackerman, Michael J.; Soeller, Christian

    2014-01-01

    Expression silencing of junctophilin-2 (JPH2) in mouse heart leads to ryanodine receptor type 2 (RyR2)-mediated sarcoplasmic reticulum (SR) Ca2+ leak and rapid development of heart failure. The mechanism and physiological significance of JPH2 in regulating RyR2-mediated SR Ca2+ leak remains elusive. We sought to elucidate the role of JPH2 in regulating RyR2-mediated SR Ca2+ release in the setting of cardiac failure. Cardiac myocytes isolated from tamoxifen-inducible conditional knockdown mice of JPH2 (MCM-shJPH2) were subjected to confocal Ca2+ imaging. MCM-shJPH2 cardiomyocytes exhibited an increased spark frequency width with altered spark morphology, which caused increased SR Ca2+ leakage. Single channel studies identified an increased RyR2 open probability in MCM-shJPH2 mice. The increase in spark frequency and width was observed only in MCM-shJPH2 and not found in mice with increased RyR2 open probability with native JPH2 expression. Na+/Ca2+-exchanger (NCX) activity was reduced by 50% in MCM-shJPH2 with no detectable change in NCX expression. Additionally, 50% inhibition of NCX through Cd2+ administration alone was sufficient to increase spark width in myocytes obtained from wild-type mice. Additionally, superresolution analysis of RyR2 and NCX colocalization showed a reduced overlap between RyR2 and NCX in MCM-shJPH2 mice. In conclusion, decreased JPH2 expression causes increased SR Ca2+ leakage by directly increasing open probability of RyR2 and by indirectly reducing junctional NCX activity through increased dyadic cleft Ca2+. This demonstrates two novel and independent cellular mechanisms by which JPH2 regulates RyR2-mediated SR Ca2+ leak and heart failure development. PMID:25193470

  13. Carrier Screening is a Deficient Strategy for Determining Sperm Donor Eligibility and Reducing Risk of Disease in Recipient Children

    PubMed Central

    Silver, Ari J.; Larson, Jessica L.; Silver, Maxwell J.; Lim, Regine M.; Borroto, Carlos; Spurrier, Brett; Morriss, Anne

    2016-01-01

    Aims: DNA-based carrier screening is a standard component of donor eligibility protocols practiced by U.S. sperm banks. Applicants who test positive for carrying a recessive disease mutation are typically disqualified. The aim of our study was to examine the utility of a range of screening panels adopted by the industry and the effectiveness of the screening paradigm in reducing a future child's risk of inheriting disease. Methods: A cohort of 27 donor applicants, who tested negative on an initial cystic fibrosis carrier test, was further screened with three expanded commercial carrier testing panels. These results were then compared to a systematic analysis of the applicants' DNA using next-generation sequencing (NGS) data. Results: The carrier panels detected serious pediatric disease mutations in one, four, or six donor applicants. Because each panel screens distinct regions of the genome, no single donor was uniformly identified as carrier positive by all three panels. In contrast, systematic NGS analysis identified all donors as carriers of one or more mutations associated with severe monogenic pediatric disease. These included 30 variants classified as “pathogenic” based on clinical observation and 66 with a high likelihood of causing gene dysfunction. Conclusion: Despite tremendous advances in variant identification, understanding, and analysis, the vast majority of disease-causing mutation combinations remain undetected by commercial carrier screening panels, which cover a narrow, and often distinct, subset of genes and mutations. The biological reality is that all donors and recipients carry serious recessive disease mutations. This challenges the utility of any screening protocol that anchors donor eligibility to carrier status. A more effective approach to reducing recessive disease risk would consider joint comprehensive analysis of both donor and recipient disease mutations. This type of high-resolution recessive disease risk analysis is now

  14. Performance of phalangeal quantitative ultrasound parameters in the evaluation of reduced bone mineral density assessed by DX in patients with 21 hydroxylase deficiency.

    PubMed

    Gonçalves, Ezequiel M; Sewaybricker, Leticia E; Baptista, Fatima; Silva, Analiza M; Carvalho, Wellington R G; Santos, Allan O; de Mello, Maricilda P; Lemos-Marini, Sofia H V; Guerra, Gil

    2014-07-01

    The purpose of this study was to verify the performance of quantitative ultrasound (QUS) parameters of proximal phalanges in the evaluation of reduced bone mineral density (BMD) in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21 OHD). Seventy patients with 21 OHD (41 females and 29 males), aged between 6-27 y were assessed. The QUS measurements, amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), and ultrasound bone profile index (UBPI) were obtained using the BMD Sonic device (IGEA, Carpi, Italy) on the last four proximal phalanges in the non-dominant hand. BMD was determined by dual energy X-ray (DXA) across the total body and lumbar spine (LS). Total body and LS BMD were positively correlated to UBPI, BTT and AD-SoS (correlation coefficients ranged from 0.59-0.72, p < 0.001). In contrast, when comparing patients with normal and low (Z-score < -2) BMD, no differences were found in the QUS parameters. Furthermore, UBPI, BTT and AD-SoS measurements were not effective for diagnosing patients with reduced BMD by receiver operator characteristic curve parameters. Although the AD-SoS, BTT and UBPI showed significant correlations with the data obtained by DXA, they were not effective for diagnosing reduced bone mass in patients with 21 OHD. PMID:24726797

  15. Iron deficiency in cyanobacteria causes monomerization of photosystem I trimers and reduces the capacity for state transitions and the effective absorption cross section of photosystem I in vivo.

    PubMed

    Ivanov, Alexander G; Krol, Marianna; Sveshnikov, Dmitry; Selstam, Eva; Sandström, Stefan; Koochek, Maryam; Park, Youn-Il; Vasil'ev, Sergej; Bruce, Doug; Oquist, Gunnar; Huner, Norman P A

    2006-08-01

    The induction of the isiA (CP43') protein in iron-stressed cyanobacteria is accompanied by the formation of a ring of 18 CP43' proteins around the photosystem I (PSI) trimer and is thought to increase the absorption cross section of PSI within the CP43'-PSI supercomplex. In contrast to these in vitro studies, our in vivo measurements failed to demonstrate any increase of the PSI absorption cross section in two strains (Synechococcus sp. PCC 7942 and Synechocystis sp. PCC 6803) of iron-stressed cells. We report that iron-stressed cells exhibited a reduced capacity for state transitions and limited dark reduction of the plastoquinone pool, which accounts for the increase in PSII-related 685 nm chlorophyll fluorescence under iron deficiency. This was accompanied by lower abundance of the NADP-dehydrogenase complex and the PSI-associated subunit PsaL, as well as a reduced amount of phosphatidylglycerol. Nondenaturating polyacrylamide gel electrophoresis separation of the chlorophyll-protein complexes indicated that the monomeric form of PSI is favored over the trimeric form of PSI under iron stress. Thus, we demonstrate that the induction of CP43' does not increase the PSI functional absorption cross section of whole cells in vivo, but rather, induces monomerization of PSI trimers and reduces the capacity for state transitions. We discuss the role of CP43' as an effective energy quencher to photoprotect PSII and PSI under unfavorable environmental conditions in cyanobacteria in vivo. PMID:16798943

  16. Deficiency of the oxidative damage-specific DNA glycosylase NEIL1 leads to reduced germinal center B cell expansion

    PubMed Central

    Mori, Hiromi; Ouchida, Rika; Hijikata, Atsushi; Kitamura, Hiroshi; Ohara, Osamu; Li, Yingqian; Gao, Xiang; Yasui, Akira; Lloyd, R. Stephen; Wang, Ji-Yang

    2016-01-01

    Mammalian cells possess multiple DNA glycosylases, including OGG1, NTH1, NEIL1, NEIL2 and NEIL3, for the repair of oxidative DNA damage. Among these, NEIL1 and NEIL2 are able to excise oxidized bases on single stranded or bubble-structured DNA and has been implicated in repair of oxidative damage associated with DNA replication or transcription. We found that Neil1 was highly constitutively expressed in the germinal center (GC) B cells, a rapidly dividing cell population that is undergoing immunoglobulin (Ig) gene hypermutation and isotype switching. While Neil1−/− mice exhibited normal B and T cell development and maturation, these mice contained a significantly lower frequency of GC B cells than did WT mice after immunization with a T-dependent antigen. Consistent with the reduced expansion of GC B cells, Neil1−/− mice had a decreased frequency of Ig gene hypermutation and produced less antibody against a T-dependent antigen during both primary and secondary immune responses. These results suggest that repair of endogenous oxidative DNA damage by NEIL1 is important for the rapid expansion of GC B cells and efficient induction of humoral immune responses. PMID:19782007

  17. Activin-β(c) reduces reproductive tumour progression and abolishes cancer-associated cachexia in inhibin-deficient mice.

    PubMed

    Gold, Elspeth; Marino, Francesco Elia; Harrison, Craig; Makanji, Yogeshwar; Risbridger, Gail

    2013-03-01

    Activins are involved in the regulation of a diverse range of physiological processes including development, reproduction, and fertility, and have been implicated in the progression of cancers. Bioactivity is regulated by the inhibin α-subunit and by an activin-binding protein, follistatin. The activin-β(C) subunit was not considered functionally significant in this regard due to an absence of phenotype in knockout mice. However, activin-β(C) forms heterodimers with activin-β(A) and activin-C antagonizes activin-A in vitro. Thus, it is proposed that overexpression, rather than loss of activin-β(C) , regulates activin-A bioactivity. In order to prove biological efficacy, inhibin α-subunit knockout mice (α-KO) were crossed with mice overexpressing activin-β(C) (ActC++). Deletion of inhibin leads to Sertoli and granulosa cell tumours, increased activin-A, and cancer-associated cachexia. Therefore, cachexia and reproductive tumour development should be modulated in α-KO/ActC++ mice, where excessive activin-A is the underlying cause. Accordingly, a reduction in activin-A, no significant weight loss, and reduced incidence of reproductive tumours were evident in α-KO/ActC++ mice. Overexpression of activin-β(C) antagonized the activin signalling cascade; thus, the tumourigenic effects of activin-A were abrogated. This study provides proof of the biological relevance of activin-β(C) . Being a regulator of activin-A, it is able to abolish cachexia and modulate reproductive tumour development in α-KO mice. PMID:23180294

  18. Efficacy of a low-dose ferric-EDTA in reducing iron deficiency anaemia among underfive children living in malaria-holoendemic district of Mvomero, Tanzania.

    PubMed

    Mosha, Theobald C E; Laswai, Henry H; Assey, John; Bennink, Maurice R

    2014-04-01

    Iron deficiency anaemia is a public health problem in Tanzania especially among children under the age of five years. In malaria holoendemic areas, control of anaemia by supplementation with iron has been reported to increase serious adverse events. The World Health Organization recommends that, programs to control anaemia in such areas should go concurrently with malaria control programmes. The objectives of the study were to: (i) to determine if a supplement providing 2.5 mg of iron as ferric EDTA and 2.5 mg of iron as ferrous lactate (low dose) is as effective in correcting anaemia as a supplement providing the standard 10 mg of iron as ferrous lactate (high dose); and ii) determine if iron supplementation increased the risk of malaria. This study was carried out in Mvomero District of east-central Tanzania. Two groups (69 and 70 subjects per treatment) of moderately anaemic children (7.0-9.1 g of Hb/dl), received one of the two micronutrient supplements differing only in iron content for a period of 60 days. Results showed that, the average haemoglobin (Hb) concentration improved from 8.30 ± 0.60 g/dl to 11.08 ± 1.25 g/dl. The average weight-for-age for all children increased from 16.0 to 20.6% while their weight-for-height increased from 4.0 to 13.3%. The incidence of asymptomatic and symptomatic malaria ranged from 10.0 to 10.4% at all time points with no apparent increase in malaria severity due to iron supplementation. Overall, there was a significant reduction in anaemia during the 60 day supplementation period. This study demonstrated that, micronutrient supplements containing low-dose ferric-EDTA is just as effective as the high dose iron in reducing anaemia and can be safely utilized in malaria holoendemic areas to control iron deficiency anaemia. It is recommended that, a large study should be conducted to affirm the effectiveness of the low-dose ferric-EDTA in controlling iron deficiency anaemia among underfive children. PMID:26875300

  19. Whole cowpea meal fortified with NaFeEDTA reduces iron deficiency among Ghanaian school children in a malaria endemic area.

    PubMed

    Abizari, Abdul-Razak; Moretti, Diego; Zimmermann, Michael B; Armar-Klemesu, Margaret; Brouwer, Inge D

    2012-10-01

    Cowpeas, like other legumes, contain high amounts of native iron but are rich in phytic acid (PA) and polyphenols (PP) that inhibit iron absorption. NaFeEDTA may overcome the combined inhibitory effect of PA and PP. Our objective was to test the efficacy of NaFeEDTA-fortified cowpea meal in improving iron status of school children in a malaria endemic area. We conducted a double-blind, controlled trial with 5- to 12-y-old school children from 2 rural communities in northern Ghana (n = 241). Eligible children were randomly assigned to 2 treatment groups to receive either cowpea meal fortified with 10 mg Fe/meal as NaFeEDTA, or an identical but nonfortified cowpea meal. Meals were provided 3 d/wk for a period of ~7 mo under strict supervision. Mass deworming and malaria antigenemia screening and treatment were carried out at baseline and 3.5 mo into the trial. Consumption of cowpea flour fortified with NaFeEDTA resulted in improvement of hemoglobin (P < 0.05), serum ferritin (P < 0.001), and body iron stores (P < 0.001) and reduction of transferrin receptor (P < 0.001) compared with nonfortified flour. Fortification resulted in a 30 and 47% reduction in the prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) (P < 0.05), respectively. The results indicate that fortification of cowpea flour with NaFeEDTA overcomes the combined inhibitory effect of PA and PP and, when used for targeted school-based fortification of cowpea flour, is effective in reducing the prevalence of ID and IDA among school children in malaria endemic rural northern Ghana. PMID:22915294

  20. Loss of Slc26a9 anion transporter alters intestinal electrolyte and HCO3(-) transport and reduces survival in CFTR-deficient mice.

    PubMed

    Liu, Xuemei; Li, Taolang; Riederer, Brigitte; Lenzen, Henrike; Ludolph, Lisa; Yeruva, Sunil; Tuo, Biguang; Soleimani, Manoocher; Seidler, Ursula

    2015-06-01

    Slc26a9 is an anion transporter that is strongly expressed in the stomach and lung. Slc26a9 variants were recently found associated with a higher incidence of meconium ileus in cystic fibrosis (CF) infants, raising the question whether Slc26a9 is expressed in the intestine and what its functional role is. Slc26a9 messenger RNA (mRNA) was found highly expressed in the mucosae of the murine and human upper gastrointestinal tract, with an abrupt decrease in expression levels beyond the duodenum. Absence of SLC26a9 expression strongly increased the intestinally related mortality in cystic fibrosis transmembrane conductance regulator (CFTR)-deficient mice. Proximal duodenal JHCO3(-) and fluid secretion were reduced in the absence of Slc26a9 expression. In the proximal duodenum of young Slc26a9 KO mice, the glands and villi/crypts were elongated and proliferation was enhanced. This difference was lost with ageing, as were the alterations in fluid movement, whereas the reduction in JHCO3(-) remained. Laser dissection followed by qPCR suggested Slc26a9 expression to be crypt-predominant in the duodenum. In summary, deletion of Slc26a9 caused bicarbonate secretory and fluid absorptive changes in the proximal duodenal mucosa and increased the postweaning death rates in CFTR-deficient mice. Functional alterations in the duodenum were most prominent at young ages. We assume that the association of meconium ileus and Slc26a9 variants may be related to maldigestion and impaired downstream signaling caused by loss of upper GI tract digestive functions, aggravating the situation of lack of secretion and sticky mucus at the site of obstruction in CF intestine. PMID:24965066

  1. T-type calcium channel Cav3.2 deficient mice show elevated anxiety, impaired memory and reduced sensitivity to psychostimulants.

    PubMed

    Gangarossa, Giuseppe; Laffray, Sophie; Bourinet, Emmanuel; Valjent, Emmanuel

    2014-01-01

    The fine-tuning of neuronal excitability relies on a tight control of Ca(2+) homeostasis. The low voltage-activated (LVA) T-type calcium channels (Cav3.1, Cav3.2 and Cav3.3 isoforms) play a critical role in regulating these processes. Despite their wide expression throughout the central nervous system, the implication of T-type Cav3.2 isoform in brain functions is still poorly characterized. Here, we investigate the effect of genetic ablation of this isoform in affective disorders, including anxiety, cognitive functions as well as sensitivity to drugs of abuse. Using a wide range of behavioral assays we show that genetic ablation of the cacna1h gene results in an anxiety-like phenotype, whereas novelty-induced locomotor activity is unaffected. Deletion of the T-type channel Cav3.2 also triggers impairment of hippocampus-dependent recognition memories. Acute and sensitized hyperlocomotion induced by d-amphetamine and cocaine are dramatically reduced in T-type Cav3.2 deficient mice. In addition, the administration of the T-type blocker TTA-A2 prevented the expression of locomotor sensitization observed in wildtype mice. In conclusion, our data reveal that physiological activity of this specific Ca(2+) channel is required for affective and cognitive behaviors. Moreover, our work highlights the interest of T-type channel blockers as therapeutic strategies to reverse drug-associated alterations. PMID:24672455

  2. PAK1-deficiency/down-regulation reduces brood size, activates HSP16.2 gene and extends lifespan in Caenorhabditis elegans.

    PubMed

    Yanase, S; Luo, Y; Maruta, H

    2013-02-01

    There is an increasing evidence that the oncogenic kinase PAK1 is responsible not only for malignant transformation, but also for several other diseases such as inflammatory diseases (asthma and arthritis), infectious diseases including malaria, AIDS, and flu, as well as a series of neuronal diseases/disorders (neurofibromatosis, tuberous sclerosis, Alzheimer's diseases, Huntington's disease, epilepsy, depression, learning deficit, etc.) which often cause premature death. Interestingly, a few natural PAK1-blockers such as curcumin, caffeic acid (CA) and rosmarinic acid (RA) extend the lifespan of the nematode Caenorhabditis elegans or fruit flies. Here, to explore the possibility that C. elegans could provide us with a quick and inexpensive in vivo screening system for a series of more potent but safe (non-toxic) PAK1-blocking therapeutics, we examined the effects of PAK1-deficiency or down-regulation on a few selected functions of this worm, including reproduction, expression of HSP16.2 gene, and lifespan. In short, we found that PAK1 promotes reproduction, whereas it inactivates HSP16.2 gene and shortens lifespan, as do PI-3 kinase (AGE-1), TOR, and insulin-like signalling /ILS (Daf-2) in this worm. These findings not only support the "trade-off" theory on reproduction versus lifespan, but also suggest the possibility that the reduced reproduction (or HSP16.2 gene activation) of this worm could be used as the first indicator of extended lifespan for a quick in vivo screening for PAK1-blockers. PMID:23524941

  3. T-type calcium channel Cav3.2 deficient mice show elevated anxiety, impaired memory and reduced sensitivity to psychostimulants

    PubMed Central

    Gangarossa, Giuseppe; Laffray, Sophie; Bourinet, Emmanuel; Valjent, Emmanuel

    2014-01-01

    The fine-tuning of neuronal excitability relies on a tight control of Ca2+ homeostasis. The low voltage-activated (LVA) T-type calcium channels (Cav3.1, Cav3.2 and Cav3.3 isoforms) play a critical role in regulating these processes. Despite their wide expression throughout the central nervous system, the implication of T-type Cav3.2 isoform in brain functions is still poorly characterized. Here, we investigate the effect of genetic ablation of this isoform in affective disorders, including anxiety, cognitive functions as well as sensitivity to drugs of abuse. Using a wide range of behavioral assays we show that genetic ablation of the cacna1h gene results in an anxiety-like phenotype, whereas novelty-induced locomotor activity is unaffected. Deletion of the T-type channel Cav3.2 also triggers impairment of hippocampus-dependent recognition memories. Acute and sensitized hyperlocomotion induced by d-amphetamine and cocaine are dramatically reduced in T-type Cav3.2 deficient mice. In addition, the administration of the T-type blocker TTA-A2 prevented the expression of locomotor sensitization observed in wildtype mice. In conclusion, our data reveal that physiological activity of this specific Ca2+ channel is required for affective and cognitive behaviors. Moreover, our work highlights the interest of T-type channel blockers as therapeutic strategies to reverse drug-associated alterations. PMID:24672455

  4. Phycobilisome-Deficient Strains of Synechocystis sp. PCC 6803 Have Reduced Size and Require Carbon-Limiting Conditions to Exhibit Enhanced Productivity1[W][OPEN

    PubMed Central

    Lea-Smith, David J.; Bombelli, Paolo; Dennis, John S.; Scott, Stuart A.; Smith, Alison G.; Howe, Christopher J.

    2014-01-01

    Reducing excessive light harvesting in photosynthetic organisms may increase biomass yields by limiting photoinhibition and increasing light penetration in dense cultures. The cyanobacterium Synechocystis sp. PCC 6803 harvests light via the phycobilisome, which consists of an allophycocyanin core and six radiating rods, each with three phycocyanin (PC) discs. Via targeted gene disruption and alterations to the promoter region, three mutants with two (pcpcT→C) and one (ΔCpcC1C2:pcpcT→C) PC discs per rod or lacking PC (olive) were generated. Photoinhibition and chlorophyll levels decreased upon phycobilisome reduction, although greater penetration of white light was observed only in the PC-deficient mutant. In all strains cultured at high cell densities, most light was absorbed by the first 2 cm of the culture. Photosynthesis and respiration rates were also reduced in the ΔCpcC1C2:pcpcT→C and olive mutants. Cell size was smaller in the pcpcT→C and olive strains. Growth and biomass accumulation were similar between the wild-type and pcpcT→C under a variety of conditions. Growth and biomass accumulation of the olive mutant were poorer in carbon-saturated cultures but improved in carbon-limited cultures at higher light intensities, as they did in the ΔCpcC1C2:pcpcT→C mutant. This study shows that one PC disc per rod is sufficient for maximal light harvesting and biomass accumulation, except under conditions of high light and carbon limitation, and two or more are sufficient for maximal oxygen evolution. To our knowledge, this study is the first to measure light penetration in bulk cultures of cyanobacteria and offers important insights into photobioreactor design. PMID:24760817

  5. Cost-Effectiveness of Price Subsidies on Fortified Packaged Infant Cereals in Reducing Iron Deficiency Anemia in 6-23-Month-Old-Children in Urban India

    PubMed Central

    Plessow, Rafael; Arora, Narendra Kumar; Brunner, Beatrice

    2016-01-01

    Introduction Iron deficiency anaemia (IDA) is a major public health problem in India and especially harmful in early childhood due to its impact on cognitive development and increased all-cause mortality. We estimate the cost-effectiveness of price subsidies on fortified packaged infant cereals (F-PICs) in reducing IDA in 6-23-monthold children in urban India. Materials and Methods Cost-effectiveness is estimated by comparing the net social cost of price subsidies with the disability-adjusted life-years (DALYs) averted with price subsidies. The net social costs correspond to the cost of the subsidy minus the monetary costs saved by reducing IDA. The estimation proceeds in three steps: 1) the current lifetime costs of IDA are assessed with a health economic model combining the prevalence of anemia, derived from a large population survey, with information on the health consequences of IDA and their costs in terms of mortality, morbidity, and DALYs. 2) The effects of price subsidies on the demand for F-PICs are assessed with a market survey among 4801 households in 12 large Indian cities. 3) The cost-effectiveness is calculated by combining the findings of the first two steps with the results of a systematic review on the effectiveness of F-PICs in reducing IDA. We compare the cost-effectiveness of interventions that differ in the level of the subsidy and in the socio-economic strata (SES) eligible for the subsidy. Results The lifetime social costs of IDA in 6-23-month-old children in large Indian cities amount to production losses of 3222 USD and to 726,000 DALYs. Poor households incur the highest costs, yet even wealthier households suffer substantial losses. The market survey reveals that few households currently buy F-PICs, with the share ranging from 14% to 36%. Wealthier households are generally more likely to buy FPICs. The costs of the subsidies per DALY averted range from 909 to 3649 USD. Interventions targeted at poorer households are most effective. Almost

  6. Deficiency of Rac1 Blocks NADPH Oxidase Activation, Inhibits Endoplasmic Reticulum Stress, and Reduces Myocardial Remodeling in a Mouse Model of Type 1 Diabetes

    PubMed Central

    Li, Jianmin; Zhu, Huaqing; Shen, E; Wan, Li; Arnold, J. Malcolm O.; Peng, Tianqing

    2010-01-01

    OBJECTIVE Our recent study demonstrated that Rac1 and NADPH oxidase activation contributes to cardiomyocyte apoptosis in short-term diabetes. This study was undertaken to investigate if disruption of Rac1 and inhibition of NADPH oxidase would prevent myocardial remodeling in chronic diabetes. RESEARCH DESIGN AND METHODS Diabetes was induced by injection of streptozotocin in mice with cardiomyocyte-specific Rac1 knockout and their wild-type littermates. In a separate experiment, wild-type diabetic mice were treated with vehicle or apocynin in drinking water. Myocardial hypertrophy, fibrosis, endoplasmic reticulum (ER) stress, inflammatory response, and myocardial function were investigated after 2 months of diabetes. Isolated adult rat cardiomyocytes were cultured and stimulated with high glucose. RESULTS In diabetic hearts, NADPH oxidase activation, its subunits' expression, and reactive oxygen species production were inhibited by Rac1 knockout or apocynin treatment. Myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly increased in diabetic mice, which were accompanied by elevated expression of pro-fibrotic genes and hypertrophic genes. Deficiency of Rac1 or apocynin administration reduced myocardial fibrosis and hypertrophy, resulting in improved myocardial function. These effects were associated with a normalization of ER stress markers' expression and inflammatory response in diabetic hearts. In cultured cardiomyocytes, high glucose–induced ER stress was inhibited by blocking Rac1 or NADPH oxidase. CONCLUSIONS Rac1 via NADPH oxidase activation induces myocardial remodeling and dysfunction in diabetic mice. The role of Rac1 signaling may be associated with ER stress and inflammation. Thus, targeting inhibition of Rac1 and NADPH oxidase may be a therapeutic approach for diabetic cardiomyopathy. PMID:20522592

  7. Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells.

    PubMed

    Del Rio, Maria-Luisa; Fernandez-Renedo, Carlos; Chaloin, Olivier; Scheu, Stefanie; Pfeffer, Klaus; Shintani, Yasushi; Perez-Simon, Jose-Antonio; Schneider, Pascal; Rodriguez-Barbosa, Jose-Ignacio

    2016-04-01

    Tumor necrosis factor (TNF)/TNF receptor (TNFR) superfamily members play essential roles in the development of the different phases of the immune response. Mouse LIGHT (TNFSF14) is a type II transmembrane protein with a C-terminus extracellular TNF homology domain (THD) that assembles in homotrimers and regulates the course of the immune responses by signaling through 2 receptors, the herpes virus entry mediator (HVEM, TNFSFR14) and the lymphotoxin β receptor (LTβR, TNFSFR3). LIGHT is a membrane-bound protein transiently expressed on activated T cells, natural killer (NK) cells and immature dendritic cells that can be proteolytically cleaved by a metalloprotease and released to the extracellular milieu. The immunotherapeutic potential of LIGHT blockade was evaluated in vivo. Administration of an antagonist of LIGHT interaction with its receptors attenuated the course of graft-versus-host reaction and recapitulated the reduced cytotoxic activity of LIGHT-deficient T cells adoptively transferred into non-irradiated semiallogeneic recipients. The lack of LIGHT expression on donor T cells or blockade of LIGHT interaction with its receptors slowed down the rate of T cell proliferation and decreased the frequency of precursor alloreactive T cells, retarding T cell differentiation toward effector T cells. The blockade of LIGHT/LTβR/HVEM pathway was associated with delayed downregulation of interleukin-7Rα and delayed upregulation of inducible costimulatory molecule expression on donor alloreactive CD8 T cells that are typical features of impaired T cell differentiation. These results expose the relevance of LIGHT/LTβR/HVEM interaction for the potential therapeutic control of the allogeneic immune responses mediated by alloreactive CD8 T cells that can contribute to prolong allograft survival. PMID:26752542

  8. The efficacy of micronutrient supplementation in reducing the prevalence of anaemia and deficiencies of zinc and iron among adolescents in Sri Lanka

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: To determine the effectiveness of combined iron and zinc over the iron- or zinc-only supplementation in correcting deficiency and possible interactive effects in a group of adolescent school children. Subjects and methods: Schoolchildren (n=821) of 12–16 years of age were randomized into ...

  9. Impact of fortification of flours with iron to reduce the prevalence of anemia and iron deficiency among schoolchildren in Caracas, Venezuela: a follow-up.

    PubMed

    Layrisse, Miguel; García-Casal, María Nieves; Méndez-Castellano, Hernán; Jiménez, Maritza; Henry, Olavarría; Chávez, José E; González, Eglis

    2002-12-01

    In Venezuela, a severe economic crisis starting in 1983 provoked a progressive reduction in the quantity and quality of food consumed by people from the low socioeconomic strata of the population. This situation resulted in a continuous increase in the prevalence of iron deficiency in the 1980s and 1990s. In 1993, an iron-fortification program was started, in which precooked corn and white wheat flours were enriched with iron, vitamin A, thiamine, niacin, and riboflavin. White wheat flour was enriched with the same nutrients, except for vitamin A. In 1996 we published the results of the impact of fortification of precooked corn and white wheat flours on the prevalence of anemia and iron deficiency in the population. A survey carried out in Caracas in 307 children aged 7, 11, and 15 years showed that the prevalence of iron deficiency measured by serum ferritin concentration dropped from 37% in 1992 to 16% in 1994, only one year after the iron-fortification program began. The prevalence of anemia, as measured by the hemoglobin concentration, diminished from 19% to 10% during the same period. This article reports the results of three other surveys carried out in 1997, 1998, and 1999 on children of the same age and socioeconomic groups that were evaluated in 1990, 1992, and 1994. There were no significant differences in anemia or iron deficiency among the last three surveys. The prevalence results from the last seven years seem to indicate that, after a dramatic reduction in 1994, iron deficiency tended to stabilize, while the prevalence of anemia increased to the same level found in 1992, before the fortification program started. PMID:16619746

  10. Iron deficiency in Europe.

    PubMed

    Hercberg, S; Preziosi, P; Galan, P

    2001-04-01

    In Europe, iron deficiency is considered to be one of the main nutritional deficiency disorders affecting large fractions of the population, particularly such physiological groups as children, menstruating women and pregnant women. Some factors such as type of contraception in women, blood donation or minor pathological blood loss (haemorrhoids, gynaecological bleeding...) considerably increase the difficulty of covering iron needs. Moreover, women, especially adolescents consuming low-energy diets, vegetarians and vegans are at high risk of iron deficiency. Although there is no evidence that an absence of iron stores has any adverse consequences, it does indicate that iron nutrition is borderline, since any further reduction in body iron is associated with a decrease in the level of functional compounds such as haemoglobin. The prevalence of iron-deficient anaemia has slightly decreased in infants and menstruating women. Some positive factors may have contributed to reducing the prevalence of iron-deficiency anaemia in some groups of population: the use of iron-fortified formulas and iron-fortified cereals; the use of oral contraceptives and increased enrichment of iron in several countries; and the use of iron supplements during pregnancy in some European countries. It is possible to prevent and control iron deficiency by counseling individuals and families about sound iron nutrition during infancy and beyond, and about iron supplementation during pregnancy, by screening persons on the basis of their risk for iron deficiency, and by treating and following up persons with presumptive iron deficiency. This may help to reduce manifestations of iron deficiency and thus improve public health. Evidence linking iron status with risk of cardiovascular disease or cancer is unconvincing and does not justify changes in food fortification or medical practice, particularly because the benefits of assuring adequate iron intake during growth and development are well established

  11. Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency

    PubMed Central

    Valayannopoulos, Vassili; Malinova, Vera; Honzík, Tomas; Balwani, Manisha; Breen, Catherine; Deegan, Patrick B.; Enns, Gregory M.; Jones, Simon A.; Kane, John P.; Stock, Eveline O.; Tripuraneni, Radhika; Eckert, Stephen; Schneider, Eugene; Hamilton, Gavin; Middleton, Michael S.; Sirlin, Claude; Kessler, Bruce; Bourdon, Christopher; Boyadjiev, Simeon A.; Sharma, Reena; Twelves, Chris; Whitley, Chester B.; Quinn, Anthony G.

    2014-01-01

    Background and aims Lysosomal Acid Lipase Deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. Methods Sebelipase alfa (1 mg/kg or 3 mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. Results 216 infusions were administered to eight adult subjects through Week 52 during LAL-CL04. At Week 52, mean alanine aminotransferase and aspartate aminotransferase were normal with mean change from baseline of −58% and −40%. Mean change for low density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were −60%, −39%, −36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. Conclusions Long-term dosing with sebelipase alfa in Lysosomal Acid Lipase-Deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184). PMID:24993530

  12. Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE

    PubMed Central

    Battaglia-Hsu, Shyue-fang; Akchiche, Nassila; Noel, Nicole; Alberto, Jean-Marc; Jeannesson, Elise; Orozco-Barrios, Carlos Enrique; Martinez-Fong, Daniel; Daval, Jean-Luc; Guéant, Jean-Louis

    2009-01-01

    Vitamin B12 (cobalamin, Cbl) is indispensable for proper brain development and functioning, suggesting that it has neurotrophic effects beside its well-known importance in metabolism. The molecular basis of these effects remains hypothetical, one of the reasons being that no efficient cell model has been made available for investigating the consequences of B12 cellular deficiency in neuronal cells. Here, we designed an approach by stable transfection of NIE115 neuroblastoma cells to impose the anchorage of a chimeric B12-binding protein, transcobalamin-oleosin (TO) to the intracellular membrane. This model produced an intracellular sequestration of B12 evidenced by decreased methyl-Cbl and S-adenosylmethionine and increased homocysteine and methylmalonic acid concentrations. B12 deficiency affected the proliferation of NIE115 cells through an overall increase in catalytic protein phosphatase 2A (PP2A), despite its demethylation. It promoted cellular differentiation by improving initial outgrowth of neurites and, at the molecular level, by augmenting the levels of proNGF and p75NTR. The up-regulation of PP2A and pro-nerve growth factor (NGF) triggered changes in ERK1/2 and Akt, two signaling pathways that influence the balance between proliferation and neurite outgrowth. Compared with control cells, a 2-fold increase of p75NTR-regulated intramembraneous proteolysis (RIP) was observed in proliferating TO cells (P < 0.0001) that was associated with an increased expression of two tumor necrosis factor (TNF)-α converting enzyme (TACE) secretase enzymes, Adam 10 and Adam 17. In conclusion, our data show that B12 cellular deficiency produces a slower proliferation and a speedier differentiation of neuroblastoma cells through interacting signaling pathways that are related with increased expression of PP2A, proNGF, and TACE. PMID:19959661

  13. Urate Crystal Induced Inflammation and Joint Pain Are Reduced in Transient Receptor Potential Ankyrin 1 Deficient Mice – Potential Role for Transient Receptor Potential Ankyrin 1 in Gout

    PubMed Central

    Moilanen, Lauri J.; Hämäläinen, Mari; Lehtimäki, Lauri; Nieminen, Riina M.; Moilanen, Eeva

    2015-01-01

    Introduction In gout, monosodium urate (MSU) crystals deposit intra-articularly and cause painful arthritis. In the present study we tested the hypothesis that Transient Receptor Poten-tial Ankyrin 1 (TRPA1), an ion channel mediating nociceptive signals and neurogenic in-flammation, is involved in MSU crystal-induced responses in gout by utilizing three experi-mental murine models. Methods The effects of selective pharmacological inhibition (by HC-030031) and genetic depletion of TRPA1 were studied in MSU crystal-induced inflammation and pain by using 1) spontaneous weight-bearing test to assess MSU crystal-induced joint pain, 2) subcutaneous air-pouch model resembling joint inflammation to measure MSU crystal-induced cytokine production and inflammatory cell accumulation, and 3) MSU crystal-induced paw edema to assess acute vascular inflammatory responses and swelling. Results Intra-articularly injected MSU crystals provoked spontaneous weight shift off from the affected limb in wild type but not in TRPA1 knock-out mice referring alleviated joint pain in TRPA1 deficient animals. MSU crystal-induced inflammatory cell infiltration and accumulation of cytokines MCP-1, IL-6, IL-1beta, MPO, MIP-1alpha and MIP-2 into subcu-taneous air-pouch (resembling joint cavity) was attenuated in TRPA1 deficient mice and in mice treated with the selective TRPA1 inhibitor HC-030031 as compared to control animals. Further, HC-030031 treated and TRPA1 deficient mice developed tempered inflammatory edema when MSU crystals were injected into the paw. Conclusions TRPA1 mediates MSU crystal-induced inflammation and pain in experimental models supporting the role of TRPA1 as a potential mediator and a drug target in gout flare. PMID:25658427

  14. High-dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV-1 replication in urban Southern Africans

    NASA Astrophysics Data System (ADS)

    Coussens, Anna K.; Naude, Celeste E.; Goliath, Rene; Chaplin, George; Wilkinson, Robert J.; Jablonski, Nina G.

    2015-06-01

    Cape Town, South Africa, has a seasonal pattern of UVB radiation and a predominantly dark-skinned urban population who suffer high HIV-1 prevalence. This coexistent environmental and phenotypic scenario puts residents at risk for vitamin D deficiency, which may potentiate HIV-1 disease progression. We conducted a longitudinal study in two ethnically distinct groups of healthy young adults in Cape Town, supplemented with vitamin D3 in winter, to determine whether vitamin D status modifies the response to HIV-1 infection and to identify the major determinants of vitamin D status (UVB exposure, diet, pigmentation, and genetics). Vitamin D deficiency was observed in the majority of subjects in winter and in a proportion of individuals in summer, was highly correlated with UVB exposure, and was associated with greater HIV-1 replication in peripheral blood cells. High-dosage oral vitamin D3 supplementation attenuated HIV-1 replication, increased circulating leukocytes, and reversed winter-associated anemia. Vitamin D3 therefore presents as a low-cost supplementation to improve HIV-associated immunity.

  15. High-dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV-1 replication in urban Southern Africans

    PubMed Central

    Coussens, Anna K.; Naude, Celeste E.; Goliath, Rene; Chaplin, George; Wilkinson, Robert J.; Jablonski, Nina G.

    2015-01-01

    Cape Town, South Africa, has a seasonal pattern of UVB radiation and a predominantly dark-skinned urban population who suffer high HIV-1 prevalence. This coexistent environmental and phenotypic scenario puts residents at risk for vitamin D deficiency, which may potentiate HIV-1 disease progression. We conducted a longitudinal study in two ethnically distinct groups of healthy young adults in Cape Town, supplemented with vitamin D3 in winter, to determine whether vitamin D status modifies the response to HIV-1 infection and to identify the major determinants of vitamin D status (UVB exposure, diet, pigmentation, and genetics). Vitamin D deficiency was observed in the majority of subjects in winter and in a proportion of individuals in summer, was highly correlated with UVB exposure, and was associated with greater HIV-1 replication in peripheral blood cells. High-dosage oral vitamin D3 supplementation attenuated HIV-1 replication, increased circulating leukocytes, and reversed winter-associated anemia. Vitamin D3 therefore presents as a low-cost supplementation to improve HIV-associated immunity. PMID:26080414

  16. Deletion of Galgt2 (B4Galnt2) reduces muscle growth in response to acute injury and increases muscle inflammation and pathology in dystrophin-deficient mice.

    PubMed

    Xu, Rui; Singhal, Neha; Serinagaoglu, Yelda; Chandrasekharan, Kumaran; Joshi, Mandar; Bauer, John A; Janssen, Paulus M L; Martin, Paul T

    2015-10-01

    Transgenic overexpression of Galgt2 (official name B4Galnt2) in skeletal muscle stimulates the glycosylation of α dystroglycan (αDG) and the up-regulation of laminin α2 and dystrophin surrogates known to inhibit muscle pathology in mouse models of congenital muscular dystrophy 1A and Duchenne muscular dystrophy. Skeletal muscle Galgt2 gene expression is also normally increased in the mdx mouse model of Duchenne muscular dystrophy compared with the wild-type mice. To assess whether this increased endogenous Galgt2 expression could affect disease, we quantified muscular dystrophy measures in mdx mice deleted for Galgt2 (Galgt2(-/-)mdx). Galgt2(-/-) mdx mice had increased heart and skeletal muscle pathology and inflammation, and also worsened cardiac function, relative to age-matched mdx mice. Deletion of Galgt2 in wild-type mice also slowed skeletal muscle growth in response to acute muscle injury. In each instance where Galgt2 expression was elevated (developing muscle, regenerating muscle, and dystrophic muscle), Galgt2-dependent glycosylation of αDG was also increased. Overexpression of Galgt2 failed to inhibit skeletal muscle pathology in dystroglycan-deficient muscles, in contrast to previous studies in dystrophin-deficient mdx muscles. This study demonstrates that Galgt2 gene expression and glycosylation of αDG are dynamically regulated in muscle and that endogenous Galgt2 gene expression can ameliorate the extent of muscle pathology, inflammation, and dysfunction in mdx mice. PMID:26435413

  17. Maize porridge enriched with a micronutrient powder containing low-dose iron as NaFeEDTA but not amaranth grain flour reduces anemia and iron deficiency in Kenyan preschool children.

    PubMed

    Macharia-Mutie, Catherine W; Moretti, Diego; Van den Briel, Natalie; Omusundi, Agnes M; Mwangi, Alice M; Kok, Frans J; Zimmermann, Michael B; Brouwer, Inge D

    2012-09-01

    Few studies have evaluated the impact of fortification with iron-rich foods such as amaranth grain and multi-micronutrient powder (MNP) containing low doses of highly bioavailable iron to control iron deficiency anemia (IDA) in children. We assessed the efficacy of maize porridge enriched with amaranth grain or MNP to reduce IDA in Kenyan preschool children. In a 16-wk intervention trial, children (n = 279; 12-59 mo) were randomly assigned to: unrefined maize porridge (control; 4.1 mg of iron/meal; phytate:iron molar ratio 5:1); unrefined maize (30%) and amaranth grain (70%) porridge (amaranth group; 23 mg of iron/meal; phytate:iron molar ratio 3:1); or unrefined maize porridge with MNP (MNP group; 6.6 mg iron/meal; phytate:iron molar ratio 2.6:1; 2.5 mg iron as NaFeEDTA). Primary outcomes were anemia and iron status with treatment effects estimated relative to control. At baseline, 38% were anemic and 30% iron deficient. Consumption of MNP reduced the prevalence of anemia [-46% (95% CI: -67, -12)], iron deficiency [-70% (95% CI: -89, -16)], and IDA [-75% (95% CI: -92, -20)]. The soluble transferrin receptor [-10% (95% CI: -16, -4)] concentration was lower, whereas the hemoglobin (Hb) [2.7 g/L (95% CI: 0.4, 5.1)] and plasma ferritin [40% (95% CI: 10, 95)] concentrations increased in the MNP group. There was no significant change in Hb or iron status in the amaranth group. Consumption of maize porridge fortified with low-dose, highly bioavailable iron MNP can reduce the prevalence of IDA in preschool children. In contrast, fortification with amaranth grain did not improve iron status despite a large increase in iron intake, likely due to high ratio of phytic acid:iron in the meal. PMID:22810982

  18. Reduced Alzheimer's disease β-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin

    PubMed Central

    Meckler, Xavier; Roseman, Jelita; Das, Pritam; Cheng, Haipeng; Pei, Susan; Keat, Marcia; Kassarjian, Breanne; Golde, Todd E.; Parent, Angèle T.; Thinakaran, Gopal

    2010-01-01

    Sequential cleavage of amyloid precursor protein by β- and γ-secretases generates β-amyloid peptides (Aβ), which accumulate in the brains of patients with Alzheimer's disease. We recently identified S-palmitoylation of two γ-secretase subunits, APH1 and nicastrin. S-palmitoylation is an essential post-translational modification for the proper trafficking and function of many neuronal proteins. In cultured cell lines, lack of S-palmitoylation causes instability of nascent APH1 and nicastrin, but does not affect γ-secretase processing of amyloid precursor protein. To determine the importance of γ-secretase S-palmitoylation for Aβ deposition in the brain, we generated transgenic mice co-expressing human wild-type or S-palmitoylation-deficient APH1aL and nicastrin in neurons in the forebrain. We found that lack of S-palmitoylation did not impair the ability of APH1aL and nicastrin to form enzymatically active protein complexes with endogenous presenilin 1 and PEN2, or affect the localization of γ-secretase subunits in dendrites and axons of cortical neurons. When we crossed these mice with 85Dbo transgenic mice, which co-express familial Alzheimer's disease-causing amyloid precursor protein and presenilin 1 variants, we found that co-expression of wild-type or mutant APH1aL and nicastrin led to marked stabilization of transgenic presenilin 1 in the brains of double transgenic mice. Interestingly, we observed a moderate, but significant, reduction in amyloid deposits in the forebrain of mice expressing S-palmitoylation-deficient γ-secretase subunits as compared with mice overexpressing wild-type subunits, as well as a reduction in the levels of insoluble Aβ40-42. These results indicate that γ-secretase S-palmitoylation modulates Aβ deposition in the brain. PMID:21123562

  19. Reduced Alzheimer's disease ß-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin.

    PubMed

    Meckler, Xavier; Roseman, Jelita; Das, Pritam; Cheng, Haipeng; Pei, Susan; Keat, Marcia; Kassarjian, Breanne; Golde, Todd E; Parent, Angèle T; Thinakaran, Gopal

    2010-12-01

    Sequential cleavage of amyloid precursor protein by β- and γ-secretases generates β-amyloid peptides (Aβ), which accumulate in the brains of patients with Alzheimer's disease. We recently identified S-palmitoylation of two γ-secretase subunits, APH1 and nicastrin. S-Palmitoylation is an essential posttranslational modification for the proper trafficking and function of many neuronal proteins. In cultured cell lines, lack of S-palmitoylation causes instability of nascent APH1 and nicastrin but does not affect γ-secretase processing of amyloid precursor protein. To determine the importance of γ-secretase S-palmitoylation for Aβ deposition in the brain, we generated transgenic mice coexpressing human wild-type or S-palmitoylation-deficient APH1aL and nicastrin in neurons in the forebrain. We found that lack of S-palmitoylation did not impair the ability of APH1aL and nicastrin to form enzymatically active protein complexes with endogenous presenilin 1 and PEN2 or affect the localization of γ-secretase subunits in dendrites and axons of cortical neurons. When we crossed these mice with 85Dbo transgenic mice, which coexpress familial Alzheimer's disease-causing amyloid precursor protein and presenilin 1 variants, we found that coexpression of wild-type or mutant APH1aL and nicastrin led to marked stabilization of transgenic presenilin 1 in the brains of double-transgenic mice. Interestingly, we observed a moderate, but significant, reduction in amyloid deposits in the forebrain of mice expressing S-palmitoylation-deficient γ-secretase subunits compared with mice overexpressing wild-type subunits, as well as a reduction in the levels of insoluble Aβ(40-42). These results indicate that γ-secretase S-palmitoylation modulates Aβ deposition in the brain. PMID:21123562

  20. Alpha-1 Antitrypsin Deficiency

    MedlinePlus

    ... Liver Disease Information > Alpha-1 Antitrypsin Deficiency Alpha-1 Antitrypsin Deficiency Explore this section to learn more about alpha-1 antitrypsin deficiency, including a description of the disorder ...

  1. Multiple-Micronutrient Fortified Non-Dairy Beverage Interventions Reduce the Risk of Anemia and Iron Deficiency in School-Aged Children in Low-Middle Income Countries: A Systematic Review and Meta-Analysis (i–iv)

    PubMed Central

    Aaron, Grant J.; Dror, Daphna K.; Yang, Zhenyu

    2015-01-01

    Multiple-micronutrient (MMN) fortification of beverages may be an effective option to deliver micronutrients to vulnerable populations. The aim of the present systematic review and meta-analysis is to evaluate the nutritional impacts of MMN fortified beverages in the context of low-middle income countries. A systematic search of published literature yielded 1022 citations, of which 10 randomized controlled trials (nine in school-aged children and one in pregnant women) met inclusion criteria. Results of school-aged children were included in the meta-analysis. Compared to iso-caloric controls, children who received MMN fortified beverages for 8 weeks to 6 months showed significant improvements in hemoglobin (+2.76 g/L, 95% CI [1.19, 4.33], p = 0.004; 8 studies) and serum ferritin (+15.42 pmol/L, [5.73, 25.12], p = 0.007; 8 studies); and reduced risk of anemia (RR 0.58 [0.29, 0.88], p = 0.005; 6 studies), iron deficiency (RR 0.34 [0.21, 0.55], p = 0.002; 7 studies), and iron deficiency anemia (RR 0.17 [0.06, 0.53], p = 0.02; 3 studies). MMN fortified beverage interventions could have major programmatic implications for reducing the burden of anemia and iron deficiency in school-aged children in low-middle income countries. Additional research is needed to investigate effects on other biochemical outcomes and population subgroups. PMID:26007336

  2. Multiple-Micronutrient Fortified Non-Dairy Beverage Interventions Reduce the Risk of Anemia and Iron Deficiency in School-Aged Children in Low-Middle Income Countries: A Systematic Review and Meta-Analysis (i-iv).

    PubMed

    Aaron, Grant J; Dror, Daphna K; Yang, Zhenyu

    2015-05-01

    Multiple-micronutrient (MMN) fortification of beverages may be an effective option to deliver micronutrients to vulnerable populations. The aim of the present systematic review and meta-analysis is to evaluate the nutritional impacts of MMN fortified beverages in the context of low-middle income countries. A systematic search of published literature yielded 1022 citations, of which 10 randomized controlled trials (nine in school-aged children and one in pregnant women) met inclusion criteria. Results of school-aged children were included in the meta-analysis. Compared to iso-caloric controls, children who received MMN fortified beverages for 8 weeks to 6 months showed significant improvements in hemoglobin (+2.76 g/L, 95% CI [1.19, 4.33], p = 0.004; 8 studies) and serum ferritin (+15.42 pmol/L, [5.73, 25.12], p = 0.007; 8 studies); and reduced risk of anemia (RR 0.58 [0.29, 0.88], p = 0.005; 6 studies), iron deficiency (RR 0.34 [0.21, 0.55], p = 0.002; 7 studies), and iron deficiency anemia (RR 0.17 [0.06, 0.53], p = 0.02; 3 studies). MMN fortified beverage interventions could have major programmatic implications for reducing the burden of anemia and iron deficiency in school-aged children in low-middle income countries. Additional research is needed to investigate effects on other biochemical outcomes and population subgroups. PMID:26007336

  3. Reduced response of splenocytes after mitogen-stimulation in the prion protein (PrP) gene-deficient mouse: PrPLP/Doppel production and cerebral degeneration

    SciTech Connect

    Kim, Chi-Kyeong; Hirose, Yuko; Sakudo, Akikazu; Takeyama, Natsumi; Kang, Chung-Boo; Taniuchi, Yojiro; Matsumoto, Yoshitsugu; Itohara, Shigeyoshi; Sakaguchi, Suehiro; Onodera, Takashi . E-mail: aonoder@mail.ecc.u-tokyo.ac.jp

    2007-06-29

    Splenocytes of wild-type (Prnp {sup +/+}) and prion protein gene-deficient (Prnp {sup -/-}) mice were treated with various activation stimuli such as T cell mitogen concanavalin A (ConA), phorbol 12-myristate 13-acetate (PMA) + ionomycin (Io), or B cell mitogen lipopolysaccharide (LPS). Cellular prion protein (PrP{sup C}) expression was enhanced following ConA stimulation, but not PMA + Io or LPS in Prnp {sup +/+} splenocytes. Rikn Prnp {sup -/-} splenocytes elicited lower cell proliferations than Prnp {sup +/+} or Zrch I Prnp {sup -/-} splenocytes after LPS stimulation and showed sporadic nerve cells in the cerebral cortex and deeper structure. Around the degenerated nerve cells, mild vacuolation in the neuropil was observed. This neural alteration correlated well to the suppressed response of B cells in the spleen. The finding that discrete lesions within the central nervous systems induced marked modulation of immune function probably indicates the existence of a delicately balanced neural-endocrine network by PrP{sup C} and PrPLP/Doppel.

  4. Exendin-4 therapy still offered an additional benefit on reducing transverse aortic constriction-induced cardiac hypertrophy-caused myocardial damage in DPP-4 deficient rats.

    PubMed

    Lu, Hung-I; Chung, Sheng-Ying; Chen, Yi-Ling; Huang, Tein-Hung; Zhen, Yen-Yi; Liu, Chu-Feng; Chang, Meng-Wei; Chen, Yung-Lung; Sheu, Jiunn-Jye; Chua, Sarah; Yip, Hon-Kan; Lee, Fan-Yen

    2016-01-01

    Inhibition of dipeptidyl peptidase-IV (DPP-4) enzyme activity has been revealed to protect myocardium from ischemia-reperfusion through enhancing the endogenous glucagon-like peptide-1 (GLP-1) level. However, whether exogenous supply of exendin-4, an analogue of GLP-1, would still offer benefit for protecting myocardial damage from trans-aortic constriction (TAC)-induced hypertrophic cardiomyopathy in preexistence of DPP-4 deficiency (DPP-4(D)) remained unclear. Male-adult (DPP-4(D)) rats (n = 32) were randomized into group 1 [sham control (SC)], group 2 (DPP-4(D) + TAC), group 3 [DPP-4(D) + TAC + exendin-4 10 µg/day], and group 4 [DPP-4(D) + TAC + exendin-4 10 µg + exendin-9-39 10 µg/day]. The rats were sacrificed by day 60 after last echocardiographic examination. By day 60 after TAC, left ventricular ejection fraction (LVEF) (%) was highest in group 1 and lowest in group 2, and significantly lower in group 4 than that in group 3 (all p < 0.001). The protein expressions of oxidative stress (oxidized protein, NOX-1, NOX-2), inflammatory (MMP-9, TNF-α, NF-κB), apoptotic (Bax, cleaved caspase 3 and PARP), fibrotic (TGF-β, Smad3), heart failure (BNP, β-MHC), DNA damaged (γ-H2AX) and ischemic stress (p-P38, p-Akt, p53, ATM) biomarkers showed an opposite pattern of LVEF among the four groups (all p < 0.03). Fibrotic area (by Masson's trichrome, Sirius red), and cellular expressions of DNA-damaged markers (Ki-67+, γ-H2AX+, CD90+/53BP1+) displayed an identical pattern, whereas cellular expressions of angiogenesis (CD31+, α-SMA+) and sarcomere length exhibited an opposite pattern compared to that of oxidative stress among the four groups (all p < 0.001). Take altogether, Exendin-4 effectively suppressed TAC-induced pathological cardiac hypertrophy in DPP-4(D) rat. PMID:27158369

  5. Immunization with malondialdehyde-modified low-density lipoprotein (LDL) reduces atherosclerosis in LDL receptor-deficient mice challenged with Porphyromonas gingivalis.

    PubMed

    Turunen, S Pauliina; Kummu, Outi; Wang, Chunguang; Harila, Kirsi; Mattila, Riikka; Sahlman, Marjo; Pussinen, Pirkko J; Hörkkö, Sohvi

    2015-05-01

    Periodontal infections increase the risk of atherosclerotic vascular disease via partly unresolved mechanisms. Of the natural IgM Abs that recognize molecular mimicry on bacterial epitopes and modified lipid and protein structures, IgM directed against oxidized low-density lipoprotein (LDL) is associated with atheroprotective properties. Here, the effect of natural immune responses to malondialdehyde-modified LDL (MDA-LDL) in conferring protection against atherosclerosis, which was accelerated by the major periodontopathogen Porphyromonas gingivalis, was investigated. LDL receptor-deficient (LDLR(-/-)) mice were immunized with mouse MDA-LDL without adjuvant before topical application challenge with live P. gingivalis. Atherosclerosis was analyzed after a high-fat diet, and plasma IgG and IgM Ab levels were measured throughout the study, and the secretion of IL-5, IL-10 and IFN-γ in splenocytes stimulated with MDA-LDL was determined. LDLR(-/-) mice immunized with MDA-LDL had elevated IgM and IgG levels to MDA-LDL compared with saline-treated controls. MDA-LDL immunization diminished aortic lipid depositions after challenge with P. gingivalis compared with mice receiving only P. gingivalis challenge. Immunization of LDLR(-/-) mice with homologous MDA-LDL stimulated the production of IL-5, implicating general activation of B-1 cells. Immune responses to MDA-LDL protected from the P. gingivalis-accelerated atherosclerosis. Thus, the linkage between bacterial infectious burden and atherogenesis is suggested to be modulated via natural IgM directed against cross-reactive epitopes on bacteria and modified LDL. PMID:25134521

  6. Exendin-4 therapy still offered an additional benefit on reducing transverse aortic constriction-induced cardiac hypertrophy-caused myocardial damage in DPP-4 deficient rats

    PubMed Central

    Lu, Hung-I; Chung, Sheng-Ying; Chen, Yi-Ling; Huang, Tein-Hung; Zhen, Yen-Yi; Liu, Chu-Feng; Chang, Meng-Wei; Chen, Yung-Lung; Sheu, Jiunn-Jye; Chua, Sarah; Yip, Hon-Kan; Lee, Fan-Yen

    2016-01-01

    Inhibition of dipeptidyl peptidase-IV (DPP-4) enzyme activity has been revealed to protect myocardium from ischemia-reperfusion through enhancing the endogenous glucagon-like peptide-1 (GLP-1) level. However, whether exogenous supply of exendin-4, an analogue of GLP-1, would still offer benefit for protecting myocardial damage from trans-aortic constriction (TAC)-induced hypertrophic cardiomyopathy in preexistence of DPP-4 deficiency (DPP-4D) remained unclear. Male-adult (DPP-4D) rats (n = 32) were randomized into group 1 [sham control (SC)], group 2 (DPP-4D + TAC), group 3 [DPP-4D + TAC + exendin-4 10 µg/day], and group 4 [DPP-4D + TAC + exendin-4 10 µg + exendin-9-39 10 µg/day]. The rats were sacrificed by day 60 after last echocardiographic examination. By day 60 after TAC, left ventricular ejection fraction (LVEF) (%) was highest in group 1 and lowest in group 2, and significantly lower in group 4 than that in group 3 (all p < 0.001). The protein expressions of oxidative stress (oxidized protein, NOX-1, NOX-2), inflammatory (MMP-9, TNF-α, NF-κB), apoptotic (Bax, cleaved caspase 3 and PARP), fibrotic (TGF-β, Smad3), heart failure (BNP, β-MHC), DNA damaged (γ-H2AX) and ischemic stress (p-P38, p-Akt, p53, ATM) biomarkers showed an opposite pattern of LVEF among the four groups (all p < 0.03). Fibrotic area (by Masson’s trichrome, Sirius red), and cellular expressions of DNA-damaged markers (Ki-67+, γ-H2AX+, CD90+/53BP1+) displayed an identical pattern, whereas cellular expressions of angiogenesis (CD31+, α-SMA+) and sarcomere length exhibited an opposite pattern compared to that of oxidative stress among the four groups (all p < 0.001). Take altogether, Exendin-4 effectively suppressed TAC-induced pathological cardiac hypertrophy in DPP-4D rat. PMID:27158369

  7. PGK deficiency.

    PubMed

    Beutler, Ernest

    2007-01-01

    Phosphoglycerate kinase (PGK) deficiency is one of the relatively uncommon causes of hereditary non-spherocytic haemolytic anaemia (HNSHA). The gene encoding the erythrocyte enzyme PGK1, is X-linked. Mutations of this gene may cause chronic haemolysis with or without mental retardation and they may cause myopathies, often with episodes of myoglobinuria, or a combination of these clinical manifestations. Twenty-six families have been described and in 20 of these the mutations are known. The reason for different clinical manifestations of mutations of the same gene remains unknown. PMID:17222195

  8. Reduction of obesity-associated white adipose tissue inflammation by rosiglitazone is associated with reduced non-alcoholic fatty liver disease in LDLr-deficient mice.

    PubMed

    Mulder, Petra; Morrison, Martine C; Verschuren, Lars; Liang, Wen; van Bockel, J Hajo; Kooistra, Teake; Wielinga, Peter Y; Kleemann, Robert

    2016-01-01

    Obesity is associated with chronic low-grade inflammation that drives the development of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). We recently showed that white adipose tissue (WAT) constitutes an important source of inflammatory factors. Hence, interventions that attenuate WAT inflammation may reduce NAFLD development. Male LDLr-/- mice were fed a high-fat diet (HFD) for 9 weeks followed by 7 weeks of HFD with or without rosiglitazone. Effects on WAT inflammation and NAFLD development were analyzed using biochemical and (immuno)histochemical techniques, combined with gene expression analyses. Nine weeks of HFD feeding induced obesity and WAT inflammation, which progressed gradually until the end of the study. Rosiglitazone fully blocked progression of WAT inflammation and activated PPARγ significantly in WAT. Rosiglitazone intervention did not activate PPARγ in liver, but improved liver histology and counteracted the expression of genes associated with severe NAFLD in humans. Rosiglitazone reduced expression of pro-inflammatory factors in WAT (TNF-α, leptin) and increased expression of adiponectin, which was reflected in plasma. Furthermore, rosiglitazone lowered circulating levels of pro-inflammatory saturated fatty acids. Together, these observations provide a rationale for the observed indirect hepatoprotective effects and suggest that WAT represents a promising therapeutic target for the treatment of obesity-associated NAFLD. PMID:27545964

  9. Reduction of obesity-associated white adipose tissue inflammation by rosiglitazone is associated with reduced non-alcoholic fatty liver disease in LDLr-deficient mice

    PubMed Central

    Mulder, Petra; Morrison, Martine C.; Verschuren, Lars; Liang, Wen; van Bockel, J. Hajo; Kooistra, Teake; Wielinga, Peter Y.; Kleemann, Robert

    2016-01-01

    Obesity is associated with chronic low-grade inflammation that drives the development of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). We recently showed that white adipose tissue (WAT) constitutes an important source of inflammatory factors. Hence, interventions that attenuate WAT inflammation may reduce NAFLD development. Male LDLr−/− mice were fed a high-fat diet (HFD) for 9 weeks followed by 7 weeks of HFD with or without rosiglitazone. Effects on WAT inflammation and NAFLD development were analyzed using biochemical and (immuno)histochemical techniques, combined with gene expression analyses. Nine weeks of HFD feeding induced obesity and WAT inflammation, which progressed gradually until the end of the study. Rosiglitazone fully blocked progression of WAT inflammation and activated PPARγ significantly in WAT. Rosiglitazone intervention did not activate PPARγ in liver, but improved liver histology and counteracted the expression of genes associated with severe NAFLD in humans. Rosiglitazone reduced expression of pro-inflammatory factors in WAT (TNF-α, leptin) and increased expression of adiponectin, which was reflected in plasma. Furthermore, rosiglitazone lowered circulating levels of pro-inflammatory saturated fatty acids. Together, these observations provide a rationale for the observed indirect hepatoprotective effects and suggest that WAT represents a promising therapeutic target for the treatment of obesity-associated NAFLD. PMID:27545964

  10. Iron Deficiency in Cyanobacteria Causes Monomerization of Photosystem I Trimers and Reduces the Capacity for State Transitions and the Effective Absorption Cross Section of Photosystem I in Vivo1

    PubMed Central

    Ivanov, Alexander G.; Krol, Marianna; Sveshnikov, Dmitry; Selstam, Eva; Sandström, Stefan; Koochek, Maryam; Park, Youn-Il; Vasil'ev, Sergej; Bruce, Doug; Öquist, Gunnar; Huner, Norman P.A.

    2006-01-01

    The induction of the isiA (CP43′) protein in iron-stressed cyanobacteria is accompanied by the formation of a ring of 18 CP43′ proteins around the photosystem I (PSI) trimer and is thought to increase the absorption cross section of PSI within the CP43′-PSI supercomplex. In contrast to these in vitro studies, our in vivo measurements failed to demonstrate any increase of the PSI absorption cross section in two strains (Synechococcus sp. PCC 7942 and Synechocystis sp. PCC 6803) of iron-stressed cells. We report that iron-stressed cells exhibited a reduced capacity for state transitions and limited dark reduction of the plastoquinone pool, which accounts for the increase in PSII-related 685 nm chlorophyll fluorescence under iron deficiency. This was accompanied by lower abundance of the NADP-dehydrogenase complex and the PSI-associated subunit PsaL, as well as a reduced amount of phosphatidylglycerol. Nondenaturating polyacrylamide gel electrophoresis separation of the chlorophyll-protein complexes indicated that the monomeric form of PSI is favored over the trimeric form of PSI under iron stress. Thus, we demonstrate that the induction of CP43′ does not increase the PSI functional absorption cross section of whole cells in vivo, but rather, induces monomerization of PSI trimers and reduces the capacity for state transitions. We discuss the role of CP43′ as an effective energy quencher to photoprotect PSII and PSI under unfavorable environmental conditions in cyanobacteria in vivo. PMID:16798943

  11. Molybdenum cofactor deficiency.

    PubMed

    Atwal, Paldeep S; Scaglia, Fernando

    2016-01-01

    Molybdenum cofactor deficiency (MoCD) is a severe autosomal recessive inborn error of metabolism first described in 1978. It is characterized by a neonatal presentation of intractable seizures, feeding difficulties, severe developmental delay, microcephaly with brain atrophy and coarse facial features. MoCD results in deficiency of the molybdenum cofactor dependent enzymes sulfite oxidase, xanthine dehydrogenase, aldehyde oxidase and mitochondrial amidoxime reducing component. The resultant accumulation of sulfite, taurine, S-sulfocysteine and thiosulfate contributes to the severe neurological impairment. Recently, initial evidence has demonstrated early treatment with cyclic PMP can turn MoCD type A from a previously neonatal lethal condition with only palliative options, to near normal neurological outcomes in affected patients. We review MoCD and focus on describing the currently published evidence of this exciting new therapeutic option for MoCD type A caused by pathogenic variants in MOCD1. PMID:26653176

  12. Dietary Cocoa Powder Improves Hyperlipidemia and Reduces Atherosclerosis in apoE Deficient Mice through the Inhibition of Hepatic Endoplasmic Reticulum Stress

    PubMed Central

    Guan, Hua; Lin, Yan; Bai, Liang; An, Yingfeng; Shang, Jianan; Wang, Zhao; Zhao, Sihai; Fan, Jianglin

    2016-01-01

    Cocoa powder is rich in flavonoids, which have many beneficial effects on human health, including antioxidative and anti-inflammatory effects. The aim of our study was to investigate whether the intake of cocoa powder has any influence on hyperlipidemia and atherosclerosis and examine the underlying molecular mechanisms. We fed apoE knockout mice a Western diet supplemented with either 0.2% (low group) or 2% (high group) cocoa powder for 12 weeks. The groups fed dietary cocoa powder showed a significant reduction in both plasma cholesterol levels and aortic atherosclerosis compared to the control group. Analysis of mRNA profiling of aortic atherosclerotic lesions revealed that the expression of several genes related to apoptosis, lipid metabolism, and inflammation was significantly reduced, while the antiapoptotic gene Bcl2 was significantly increased in the cocoa powder group compared to the control. RT-PCR analysis along with Western blotting revealed that a diet containing cocoa powder inhibited the expression of hepatic endoplasmic reticulum stress. These data suggest that cocoa powder intake improves hyperlipidemia and atherosclerosis, and such beneficial effects are possibly mediated through the suppression of hepatic endoplasmic reticulum stress. PMID:26980943

  13. Dietary Cocoa Powder Improves Hyperlipidemia and Reduces Atherosclerosis in apoE Deficient Mice through the Inhibition of Hepatic Endoplasmic Reticulum Stress.

    PubMed

    Guan, Hua; Lin, Yan; Bai, Liang; An, Yingfeng; Shang, Jianan; Wang, Zhao; Zhao, Sihai; Fan, Jianglin; Liu, Enqi

    2016-01-01

    Cocoa powder is rich in flavonoids, which have many beneficial effects on human health, including antioxidative and anti-inflammatory effects. The aim of our study was to investigate whether the intake of cocoa powder has any influence on hyperlipidemia and atherosclerosis and examine the underlying molecular mechanisms. We fed apoE knockout mice a Western diet supplemented with either 0.2% (low group) or 2% (high group) cocoa powder for 12 weeks. The groups fed dietary cocoa powder showed a significant reduction in both plasma cholesterol levels and aortic atherosclerosis compared to the control group. Analysis of mRNA profiling of aortic atherosclerotic lesions revealed that the expression of several genes related to apoptosis, lipid metabolism, and inflammation was significantly reduced, while the antiapoptotic gene Bcl2 was significantly increased in the cocoa powder group compared to the control. RT-PCR analysis along with Western blotting revealed that a diet containing cocoa powder inhibited the expression of hepatic endoplasmic reticulum stress. These data suggest that cocoa powder intake improves hyperlipidemia and atherosclerosis, and such beneficial effects are possibly mediated through the suppression of hepatic endoplasmic reticulum stress. PMID:26980943

  14. Poor growth, thyroid dysfunction and vitamin D deficiency remain prevalent despite reduced intensity chemotherapy for hematopoietic stem cell transplantation in children and young adults.

    PubMed

    Myers, K C; Howell, J C; Wallace, G; Dandoy, C; El-Bietar, J; Lane, A; Davies, S M; Jodele, S; Rose, S R

    2016-07-01

    Myeloablative conditioning regimens for hematopoietic stem cell transplant (HSCT) are known to affect endocrine function, but little is known regarding reduced intensity conditioning (RIC) regimens. We retrospectively reviewed 114 children and young adults after single RIC HSCT. The analysis was grouped by age (<2 and ⩾2 years) and diagnosis (hemophagocytic lymphohistiocystosis/X-linked lymphoproliferative syndrome (HLH/XLP), other immune disorders, metabolic/genetic disorders). All groups displayed short stature by mean height-adjusted Z-score (HAZ) before (-1.29) and after HSCT (HAZ -1.38, P=0.47). After HSCT, younger children with HLH/XLP grew better (HAZ -3.41 vs -1.65, P=0.006), whereas older subjects had decline in growth (HAZ -0.8 vs -1.01, P=0.06). Those with steroid therapy beyond standard GVHD prophylaxis were shorter than those without (P 0.04). After HSCT, older subjects with HLH/XLP became thinner with a mean body mass index (BMI) Z-score of 1.20 vs 0.64, P=0.02, and similar to metabolic/genetic disorders (BMI-Z= 0.59 vs -0.99, P<0.001). BMI increased among younger children in these same groups. Thyroid function was abnormal in 24% (18/76). 25-OH vitamin D levels were insufficient in 73% (49/65), with low bone mineral density in 8 of 19 evaluable subjects. Despite RIC, children and young adults still have significant late endocrine effects. Further research is required to compare post-transplant endocrine effects after RIC to those after standard chemotherapy protocols. PMID:26974276

  15. Severity of DSS-induced colitis is reduced in Ido1-deficient mice with down-regulation of TLR-MyD88-NF-kB transcriptional networks.

    PubMed

    Shon, Woo-Jeong; Lee, Young-Kwan; Shin, Ji Hee; Choi, Eun Young; Shin, Dong-Mi

    2015-01-01

    Indoleamine 2,3 -dioxygenase 1 (IDO1) catalyzes L-tryptophan to kynurenine in the first and rate-limiting step of tryptophan metabolism. IDO1 is expressed widely throughout the body, with especially high expression in colonic intestinal tissues. To examine the role of IDO1 in the colon, transcriptome analysis was performed in both Ido1(-/-) and Ido1(+/+) mice. Gene set enrichment analysis identified the Inflammatory Response as the most significant category modulated by the absence of IDO1. This observation prompted us to further investigate the function of IDO1 in the development of tissue inflammation. By using DSS-induced experimental colitis mice models, we found that the disease in Ido1(-/-) mice was less severe than in Ido1(+/+) mice. Pharmacological inhibition of IDO1 by L-1MT attenuated the severity of DSS-colitis as well. Transcriptome analyses revealed that pathways involving TLR and NF-kB signaling were significantly down-regulated by the absence of IDO1. Furthermore, dramatic changes in TLR and NF-kB signaling resulted in substantial changes in the expression of many inflammatory cytokines and chemokines. Numbers of inflammatory cells in colon and peripheral blood were reduced in IDO1 deficiency. These findings suggest that IDO1 plays important roles in producing inflammatory responses and modulating transcriptional networks during the development of colitis. PMID:26610689

  16. MTHFR deficiency or reduced intake of folate or choline in pregnant mice results in impaired short-term memory and increased apoptosis in the hippocampus of wild-type offspring.

    PubMed

    Jadavji, N M; Deng, L; Malysheva, O; Caudill, M A; Rozen, R

    2015-08-01

    Genetic or nutritional disturbances in one-carbon metabolism, with associated hyperhomocysteinemia, can result in complex disorders including pregnancy complications and neuropsychiatric diseases. In earlier work, we showed that mice with a complete deficiency of methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate and homocysteine metabolism, had cognitive impairment with disturbances in choline metabolism. Maternal demands for folate and choline are increased during pregnancy and deficiencies of these nutrients result in several negative outcomes including increased resorption and delayed development. The goal of this study was to investigate the behavioral and neurobiological impact of a maternal genetic deficiency in MTHFR or maternal nutritional deficiency of folate or choline during pregnancy on 3-week-old Mthfr(+/+) offspring. Mthfr(+/+) and Mthfr(+/-) females were placed on control diets (CD); and Mthfr(+/+) females were placed on folate-deficient diets (FD) or choline-deficient diets (ChDD) throughout pregnancy and lactation until their offspring were 3weeks of age. Short-term memory was assessed in offspring, and hippocampal tissue was evaluated for morphological changes, apoptosis, proliferation and choline metabolism. Maternal MTHFR deficiency resulted in short-term memory impairment in offspring. These dams had elevated levels of plasma homocysteine when compared with wild-type dams. There were no differences in plasma homocysteine in offspring. Increased apoptosis and proliferation was observed in the hippocampus of offspring from Mthfr(+/-) mothers. In the maternal FD and ChDD study, offspring also showed short-term memory impairment with increased apoptosis in the hippocampus; increased neurogenesis was observed in ChDD offspring. Choline acetyltransferase protein was increased in the offspring hippocampus of both dietary groups and betaine was decreased in the hippocampus of FD offspring. Our results reveal short-term memory

  17. Zinc deficiency in elderly patients.

    PubMed

    Prasad, A S; Fitzgerald, J T; Hess, J W; Kaplan, J; Pelen, F; Dardenne, M

    1993-01-01

    Zinc is needed for growth and development, DNA synthesis, neurosensory functions, and cell-mediated immunity. Although zinc intake is reduced in elderly people, its deficiency and effects on cell-mediated immunity of the elderly have not been established. Subjects enrolled in "A Model Health Promotion and Intervention Program for Urban Middle Aged and Elderly Americans" were assessed for nutrition and zinc status. One hundred eighty healthy subjects were randomly selected for the study. Their mean dietary zinc intake was 9.06 mg/day, whereas the recommended dietary allowance is 15 mg/day. Plasma zinc was normal, but zinc in granulocytes and lymphocytes were decreased compared with younger control subjects. Of 118 elderly subjects in whom zinc levels in both granulocytes and lymphocytes were available, 36 had deficient levels. Plasma copper was increased, and interleukin 1 (IL-1) production was significantly decreased. Reduced response to the skin-test antigen panel and decreased taste acuity were observed. Thirteen elderly zinc-deficient subjects were supplemented with zinc, and various variables were assessed before and after zinc supplementation. Zinc supplementation corrected zinc deficiency and normalized plasma copper levels. Serum thymulin activity, IL-1 production, and lymphocyte ecto-5'-nucleotidase increased significantly after supplementation. Improvement in response to skin-test antigens and taste acuity was observed after zinc supplementation. A mild zinc deficiency appears to be a significant clinical problem in free-living elderly people. PMID:8353362

  18. Glucose-6-Phosphate Dehydrogenase Deficiency.

    PubMed

    Luzzatto, Lucio; Nannelli, Caterina; Notaro, Rosario

    2016-04-01

    G6PD is a housekeeping gene expressed in all cells. Glucose-6-phosphate dehydrogenase (G6PD) is part of the pentose phosphate pathway, and its main physiologic role is to provide NADPH. G6PD deficiency, one of the commonest inherited enzyme abnormalities in humans, arises through one of many possible mutations, most of which reduce the stability of the enzyme and its level as red cells age. G6PD-deficient persons are mostly asymptomatic, but they can develop severe jaundice during the neonatal period and acute hemolytic anemia when they ingest fava beans or when they are exposed to certain infections or drugs. G6PD deficiency is a global health issue. PMID:27040960

  19. Folate-deficiency anemia

    MedlinePlus

    ... medlineplus.gov/ency/article/000551.htm Folate-deficiency anemia To use the sharing features on this page, please enable JavaScript. Folate-deficiency anemia is a decrease in red blood cells (anemia) ...

  20. Alpha-1 Antitrypsin Deficiency

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Alpha-1 Antitrypsin Deficiency? Alpha-1 antitrypsin (an-tee-TRIP-sin) deficiency, or AAT ... as it relates to lung disease. Overview Alpha-1 antitrypsin, also called AAT, is a protein made ...

  1. Nutrition and hair: deficiencies and supplements.

    PubMed

    Finner, Andreas M

    2013-01-01

    Hair follicle cells have a high turnover. A caloric deprivation or deficiency of several components, such as proteins, minerals, essential fatty acids, and vitamins, caused by inborn errors or reduced uptake, can lead to structural abnormalities, pigmentation changes, or hair loss, although exact data are often lacking. The diagnosis is established through a careful history, clinical examination of hair loss activity, and hair quality and confirmed through targeted laboratory tests. Examples of genetic hair disorders caused by reduced nutritional components are zinc deficiency in acrodermatitis enteropathica and copper deficiency in Menkes kinky hair syndrome. PMID:23159185

  2. DOCK8 Deficiency

    MedlinePlus

    ... on ClinicalTrials.gov . Related Links Primary Immune Deficiency Diseases (PIDDs) Immune System ​​​​​​​ Javascript Error Your browser JavaScript is turned ... Scientists Identify Genetic Cause of Previously Undefined Primary Immune Deficiency Disease Signs and Symptoms DOCK8 deficiency causes persistent skin ...

  3. Iron deficiency in the tropics.

    PubMed

    Fleming, A F

    1982-06-01

    Iron in food is classified as belonging to the haem pool, the nonhaem pool, and extraneous sources. Haem iron is derived from vegetable and animal sources with varying bioavailability. Hookworm infestation of the intestinal tract affects 450 million people in the tropics. Schistosoma mansoni caused blood loss in 7 Egyptian patients of 7.5- 25.9 ml/day which is equivalent to a daily loss of iron of .6-7.3 mg daily urinary loss of iron in 9 Egyptian patients. Trichuris trichiura infestation by whipworm is widespread in children with blood loss of 5 ml/day/worm. The etiology of anemia in children besides iron deficiency includes malaria, bacterial or viral infections, folate deficiency and sickle-cell disease. Severe infections cause profound iron-deficiency anemia in children in central American and Malaysia. Plasmodium falciparum malaria-induced anaemia in tropical Africa lowers the mean haemoglobin concentration in the population by 2 g/dI, causing profound anaemia in some. The increased risk of premature delivery, low birthweight, fetal abnormalities, and fetal death is directly related to the degree of maternal anemia. Perinatal mortality was reduced from 38 to 4% in treated anemic mothers. Mental performance was significantly lower in anemic school children and improved after they received iron. Supplements of iron, soy-protein, calcium, and vitamins given to villagers with widespread malnutrition, iron deficiency, and hookworm infestation in Colombia reduced enteric infections in children. Severe iron-deficiency anemia was treated in adults in northern Nigeria by daily in Ferastral 10 ml, which is equivalent to 500 mg of iron per day. Choloroquine, folic acid, rephenium hydroxynaphthoate, and tetrachlorethylene treat adults with severe iron deficiency from hookworm infestation in rural tropical Africa. Blood transfusion is indicated if the patient is dying of anaemia or is pregnant with a haemoglobin concentration 6 gm/dl. In South East Asia, mg per day

  4. Carnitine Deficiency and Pregnancy

    PubMed Central

    de Bruyn, Anouk; Jacquemyn, Yves; Kinget, Kristof; Eyskens, François

    2015-01-01

    We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, supplementation with carnitine is advised. This supplementation should be continued throughout pregnancy according to plasma concentrations. PMID:26113999

  5. Carnitine Deficiency and Pregnancy.

    PubMed

    de Bruyn, Anouk; Jacquemyn, Yves; Kinget, Kristof; Eyskens, François

    2015-01-01

    We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, supplementation with carnitine is advised. This supplementation should be continued throughout pregnancy according to plasma concentrations. PMID:26113999

  6. Creatine deficiency syndromes.

    PubMed

    Schulze, Andreas

    2003-02-01

    Since the first description of a creatine deficiency syndrome, the guanidinoacetate methyltransferase (GAMT) deficiency, in 1994, the two further suspected creatine deficiency syndromes--the creatine transporter (CrT1) defect and the arginine:glycine amidinotransferase (AGAT) deficiency were disclosed. GAMT and AGAT deficiency have autosomal-recessive traits, whereas the CrT1 defect is a X-linked disorder. All patients reveal developmental delay/regression, mental retardation, and severe disturbance of their expressive and cognitive speech. The common feature of all creatine deficiency syndromes is the severe depletion of creatine/phosphocreatine in the brain. Only the GAMT deficiency is in addition characterized by accumulation of guanidinoacetic acid in brain and body fluids. Guanidinoacetic acid seems to be responsible for intractable seizures and the movement disorder, both exclusively found in GAMT deficiency. Treatment with oral creatine supplementation is in part successful in GAMT and AGAT deficiency, whereas in CrT1 defect it is not able to replenish creatine in the brain. Treatment of combined arginine restriction and ornithine substitution in GAMT deficiency is capable to decrease guanidinoacetic acid permanently and improves the clinical outcome. The lack of the creatine/phosphocreatine signal in the patient's brain by means of in vivo proton magnetic resonance spectroscopy is the common finding and the diagnostic clue in all three diseases. In AGAT deficiency guanidinoacetic acid is decreased, whereas creatine in blood was found to be normal. On the other hand the CrT1 defect is characterized by an increased concentration of creatine in blood and urine whereas guanidinoacetic acid concentration is normal. The increasing number of patients detected very recently suffering from a creatine deficiency syndrome and the unfavorable outcome highlights the need of further attempts in early recognition of affected individuals and in optimizing its treatment

  7. Management of Iron Deficiency Anemia

    PubMed Central

    Jimenez, Kristine; Kulnigg-Dabsch, Stefanie

    2015-01-01

    Anemia affects one-fourth of the world’s population, and iron deficiency is the predominant cause. Anemia is associated with chronic fatigue, impaired cognitive function, and diminished well-being. Patients with iron deficiency anemia of unknown etiology are frequently referred to a gastroenterologist because in the majority of cases the condition has a gastrointestinal origin. Proper management improves quality of life, alleviates the symptoms of iron deficiency, and reduces the need for blood transfusions. Treatment options include oral and intravenous iron therapy; however, the efficacy of oral iron is limited in certain gastrointestinal conditions, such as inflammatory bowel disease, celiac disease, and autoimmune gastritis. This article provides a critical summary of the diagnosis and treatment of iron deficiency anemia. In addition, it includes a management algorithm that can help the clinician determine which patients are in need of further gastrointestinal evaluation. This facilitates the identification and treatment of the underlying condition and avoids the unnecessary use of invasive methods and their associated risks. PMID:27099596

  8. Dopamine beta-hydroxylase deficiency

    PubMed Central

    Senard, Jean-Michel; Rouet, Philippe

    2006-01-01

    Dopamine beta-hydroxylase (DβH) deficiency is a very rare form of primary autonomic failure characterized by a complete absence of noradrenaline and adrenaline in plasma together with increased dopamine plasma levels. The prevalence of DβH deficiency is unknown. Only a limited number of cases with this disease have been reported. DβH deficiency is mainly characterized by cardiovascular disorders and severe orthostatic hypotension. First symptoms often start during a complicated perinatal period with hypotension, muscle hypotonia, hypothermia and hypoglycemia. Children with DβH deficiency exhibit reduced ability to exercise because of blood pressure inadaptation with exertion and syncope. Symptoms usually worsen progressively during late adolescence and early adulthood with severe orthostatic hypotension, eyelid ptosis, nasal stuffiness and sexual disorders. Limitation in standing tolerance, limited ability to exercise and traumatic morbidity related to falls and syncope may represent later evolution. The syndrome is caused by heterogeneous molecular alterations of the DBH gene and is inherited in an autosomal recessive manner. Restoration of plasma noradrenaline to the normal range can be achieved by therapy with the synthetic precursor of noradrenaline, L-threo-dihydroxyphenylserine (DOPS). Oral administration of 100 to 500 mg DOPS, twice or three times daily, increases blood pressure and reverses the orthostatic intolerance. PMID:16722595

  9. α1-Antitrypsin Deficiency.

    PubMed

    Hatipoğlu, Umur; Stoller, James K

    2016-09-01

    α1-Antitrypsin deficiency is an autosomal codominant condition that predisposes to emphysema and cirrhosis. The condition is common but grossly under-recognized. Identifying patients' α1-antitrypsin deficiency has important management implications (ie, smoking cessation, genetic and occupational counseling, and specific treatment with the infusion of pooled human plasma α1-antitrypsin). The weight of evidence suggests that augmentation therapy slows the progression of emphysema in individuals with severe α1-antitrypsin deficiency. PMID:27514595

  10. Micronutrient deficiency in urban Indonesia.

    PubMed

    Gross, R; Schultink, W

    1997-06-01

    The economic situation of Indonesia is characterized by a large increase in the gross national product which has been on average 7% annually during the last ten years. This was accompanied by rapid urbanization. With the economic improvement, "First World" and "Third World" health and nutrition problems are coexisting in Indonesia. In 1992, the most common of death cause was cardiovascular disease whereas tuberculosis was the second ranking. About 40% of the preschool children are stunted. The main stable food and energy source is rice, although the urban population has a more diverse food pattern than the rural population. In Jakarta, many children receive too late colostrum feeding and mothers are not aware about the importance of correct breastfeeding practices after delivery. Three studies had shown that about one fifth of preschool children and one fourth of elderly take micronutrient supplements. Nevertheless, micronutrient deficiencies are prevalent in Jakarta. About one third of women suffer from moderate vitamin A deficiency (plasma retinol < 0.70 mmol/L) and 50% of pregnant women are anemic. More information is necessary on other micronutrient deficiencies. For example, a small study revealed that nearly two thirds of non-institutionalized elderly living in Jakarta experience thiamine deficiency. Appropriate interventions to reduce micronutrient deficiencies should sensitize the urban population to the fact that the government should restrict itself to use its resources to assist only the poorest individuals and groups, whereas it must be expected from the middle class to spend more time and money to solve their own problems. PMID:9659420

  11. In vivo high-resolution magic angle spinning magnetic resonance spectroscopy of Drosophila melanogaster at 14.1 T shows trauma in aging and in innate immune-deficiency is linked to reduced insulin signaling

    PubMed Central

    RIGHI, VALERIA; APIDIANAKIS, YIORGOS; MINTZOPOULOS, DIONYSSIOS; ASTRAKAS, LOUKAS; RAHME, LAURENCE G.; TZIKA, A. ARIA

    2010-01-01

    In vivo magnetic resonance spectroscopy (MRS), a non-destructive biochemical tool for investigating live organisms, has yet to be used in the fruit fly Drosophila melanogaster, a useful model organism for investigating genetics and physiology. We developed and implemented a high-resolution magic-angle-spinning (HRMAS) MRS method to investigate live Drosophila at 14.1 T. We demonstrated, for the first time, the feasibility of using HRMAS MRS for molecular characterization of Drosophila with a conventional MR spectrometer equipped with an HRMAS probe. We showed that the metabolic HRMAS MRS profiles of injured, aged wild-type (wt) flies and of immune deficient (imd) flies were more similar to chico flies mutated at the chico gene in the insulin signaling pathway, which is analogous to insulin receptor substrate 1–4 (IRS1–4) in mammals and less to those of adipokinetic hormone receptor (akhr) mutant flies, which have an obese phenotype. We thus provide evidence for the hypothesis that trauma in aging and in innate immune-deficiency is linked to insulin signaling. This link may explain the mitochondrial dysfunction that accompanies insulin resistance and muscle wasting that occurs in trauma, aging and immune system deficiencies, leading to higher susceptibility to infection. Our approach advances the development of novel in vivo non-destructive research approaches in Drosophila, suggests biomarkers for investigation of biomedical paradigms, and thus may contribute to novel therapeutic development. PMID:20596596

  12. Iodine-deficiency disorders.

    PubMed

    Zimmermann, Michael B; Jooste, Pieter L; Pandav, Chandrakant S

    2008-10-01

    2 billion individuals worldwide have insufficient iodine intake, with those in south Asia and sub-Saharan Africa particularly affected. Iodine deficiency has many adverse effects on growth and development. These effects are due to inadequate production of thyroid hormone and are termed iodine-deficiency disorders. Iodine deficiency is the most common cause of preventable mental impairment worldwide. Assessment methods include urinary iodine concentration, goitre, newborn thyroid-stimulating hormone, and blood thyroglobulin. In nearly all countries, the best strategy to control iodine deficiency is iodisation of salt, which is one of the most cost-effective ways to contribute to economic and social development. When iodisation of salt is not possible, iodine supplements can be given to susceptible groups. Introduction of iodised salt to regions of chronic iodine-deficiency disorders might transiently increase the proportion of thyroid disorders, but overall the small risks of iodine excess are far outweighed by the substantial risks of iodine deficiency. International efforts to control iodine-deficiency disorders are slowing, and reaching the third of the worldwide population that remains deficient poses major challenges. PMID:18676011

  13. Vitamin deficiencies and excesses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vitamins are essential nutrients that must be supplied exogenously either as part of a well balanced diet or as supplements. Deficiency states are uncommon in developed countries except, perhaps, among some food insecure families. In contrast, deficiency states are quite common in many developing ...

  14. Testosterone deficiency myopathy.

    PubMed Central

    Orrell, R W; Woodrow, D F; Barrett, M C; Press, M; Dick, D J; Rowe, R C; Lane, R J

    1995-01-01

    Testosterone is recognized to have a positive effect on nitrogen balance and muscle development in hypogonadal men, but significantly myopathy secondary to testosterone deficiency has been reported only rarely. We describe a patient who presented with a myopathy associated with testosterone deficiency, and who demonstrated a significant functional and myometric response to treatment. PMID:7562829

  15. MENTAL DEFICIENCY. SECOND EDITION.

    ERIC Educational Resources Information Center

    HILLIARD, L.T.; KIRMAN, BRIAN H.

    REVISED TO INCLUDE LEGISLATIVE AND ADMINISTRATIVE PROCEDURES NEW IN BRITAIN SINCE THE 1957 EDITION, THE TEXT INCLUDES RECENT ADVANCES IN ETIOLOGY, PATHOLOGY, AND TREATMENT OF MENTAL DEFICIENCY. CONSIDERATION OF THE BACKGROUND OF MENTAL DEFICIENCY INCLUDES HISTORICAL AND LEGAL ASPECTS, THE SOCIAL BACKGROUND OF MENTAL DEFECT, PRENATAL CAUSES OF…

  16. Cerebral Folate Deficiency

    ERIC Educational Resources Information Center

    Gordon, Neil

    2009-01-01

    Cerebral folate deficiency (CFD) is associated with low levels of 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) with normal folate levels in the plasma and red blood cells. The onset of symptoms caused by the deficiency of folates in the brain is at around 4 to 6 months of age. This is followed by delayed development, with deceleration…

  17. Iron deficiency anemia

    MedlinePlus

    Anemia - iron deficiency ... iron from old red blood cells. Iron deficiency anemia develops when your body's iron stores run low. ... You may have no symptoms if the anemia is mild. Most of the time, ... slowly. Symptoms may include: Feeling weak or tired more often ...

  18. Factor X deficiency

    MedlinePlus

    Factor X (ten) deficiency is a disorder caused by a lack of a protein called factor X in the blood. It leads to problems with ... or are not functioning like they should. Factor X is one such coagulation factor. Factor X deficiency ...

  19. 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...

  20. G6PD Deficiency

    MedlinePlus

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder that is most common in males. About 1 in 10 African American males in the United States has it. G6PD deficiency mainly affects red blood cells, which carry oxygen ...

  1. Zinc: physiology, deficiency, and parenteral nutrition.

    PubMed

    Livingstone, Callum

    2015-06-01

    The essential trace element zinc (Zn) has a large number of physiologic roles, in particular being required for growth and functioning of the immune system. Adaptive mechanisms enable the body to maintain normal total body Zn status over a wide range of intakes, but deficiency can occur because of reduced absorption or increased gastrointestinal losses. Deficiency impairs physiologic processes, leading to clinical consequences that include failure to thrive, skin rash, and impaired wound healing. Mild deficiency that is not clinically overt may still cause nonspecific consequences, such as susceptibility to infection and poor growth. The plasma Zn concentration has poor sensitivity and specificity as a test of deficiency. Consequently, diagnosis of deficiency requires a combination of clinical assessment and biochemical tests. Patients receiving parenteral nutrition (PN) are susceptible to Zn deficiency and its consequences. Nutrition support teams should have a strategy for assessing Zn status and optimizing this by appropriate supplementation. Nutrition guidelines recommend generous Zn provision from the start of PN. This review covers the physiology of Zn, the consequences of its deficiency, and the assessment of its status, before discussing its role in PN. PMID:25681484

  2. Glucose-6-phosphate dehydrogenase deficiency

    MedlinePlus

    G-6-PD deficiency; Hemolytic anemia due to G6PD deficiency; Anemia - hemolytic due to G6PD deficiency ... Churchill Livingston; 2008:chap 45. Golan DER. Hemolytic anemias: red cell membrane and metabolic defects. In: Goldman ...

  3. Office ergonomics: deficiencies in computer workstation design.

    PubMed

    Shikdar, Ashraf A; Al-Kindi, Mahmoud A

    2007-01-01

    The objective of this research was to study and identify ergonomic deficiencies in computer workstation design in typical offices. Physical measurements and a questionnaire were used to study 40 workstations. Major ergonomic deficiencies were found in physical design and layout of the workstations, employee postures, work practices, and training. The consequences in terms of user health and other problems were significant. Forty-five percent of the employees used nonadjustable chairs, 48% of computers faced windows, 90% of the employees used computers more than 4 hrs/day, 45% of the employees adopted bent and unsupported back postures, and 20% used office tables for computers. Major problems reported were eyestrain (58%), shoulder pain (45%), back pain (43%), arm pain (35%), wrist pain (30%), and neck pain (30%). These results indicated serious ergonomic deficiencies in office computer workstation design, layout, and usage. Strategies to reduce or eliminate ergonomic deficiencies in computer workstation design were suggested. PMID:17599795

  4. Betaine deficiency in maize

    SciTech Connect

    Lerma, C. ); Rich, P.J.; Ju, G.C.; Yang, Wenju; Rhodes, D. ); Hanson, A.D. )

    1991-04-01

    Maize (Zea mays L.) is a betaine-accumulating species, but certain maize genotypes lack betaine almost completely; a single recessive gene has been implicated as the cause of this deficiency. This study was undertaken to determine whether betaine deficiency in diverse maize germplasm is conditioned by the same genetic locus, and to define the biochemical lesion(s) involved. Complementation tests indicated that all 13 deficient genotypes tested shared a common locus. One maize population (P77) was found to be segregating for betaine deficiency, and true breeding individuals were used to produce related lines with and without betaine. Leaf tissue of both betaine-positive and betaine-deficient lines readily converted supplied betaine aldehyde to betaine, but only the betaine-containing line was able to oxidize supplied choline to betaine. This locates the lesion in betaine-deficient plants at the choline {r arrow} betaine aldehyde step of betaine synthesis. Consistent with this location, betaine-deficient plants were shown to have no detectable endogenous pool of betaine aldehyde.

  5. Structural insights into human 5-lipoxygenase inhibition: combined ligand-based and target-based approach.

    PubMed

    Charlier, Caroline; Hénichart, Jean-Pierre; Durant, François; Wouters, Johan

    2006-01-12

    The human 5-LOX enzyme and its interaction with competitive inhibitors were investigated by means of a combined ligand-based and target-based approach. First, a pharmacophore model was generated for 16 non redox 5-LOX inhibitors with Catalyst (HipHop module). It includes two hydrophobic groups, an aromatic ring, and two hydrogen bond acceptors. The 3D structure of human 5-LOX was then modeled based on the crystal structure of rabbit 15-LOX, and the binding modes of representative ligands were studied by molecular docking. Confrontation of the docking results with the pharmacophore model allowed the weighting of the pharmacophoric features and the integration of structural information. This led to the proposal of an interaction model inside the 5-LOX active site, consisting of four major and two secondary interaction points: on one hand, two hydrophobic groups, an aromatic ring, and a hydrogen bond acceptor, and, on the other hand, an acidic moiety and an additional hydrogen bond acceptor. PMID:16392803

  6. Rapid Stimulation of 5-Lipoxygenase Activity in Potato by the Fungal Elicitor Arachidonic Acid 1

    PubMed Central

    Bostock, Richard M.; Yamamoto, Hiroyuki; Choi, Doil; Ricker, Karin E.; Ward, Bernard L.

    1992-01-01

    The activity of lipoxygenase (LOX) in aged potato tuber discs increased by almost 2-fold following treatment of the discs with the fungal elicitor arachidonic acid (AA). Enzyme activity increased above that in untreated discs within 30 min after AA treatment, peaked at 1 to 3 h, and returned to near control levels by 6 h. The majority of the activity was detected in a soluble fraction (105,000g supernatant), but a minor portion was also associated with a particulate fraction enriched in microsomal membranes (105,000g pellet); both activities were similarly induced. 5-Hydroperoxyeicosatetraenoic acid was the principal product following incubation of these extracts with AA. Antibodies to soybean LOX strongly reacted with a protein with a molecular mass of approximately 95-kD present in both soluble and particulate fractions whose abundance generally corresponded with LOX activity in extracts. LOX activity was not enhanced by treatment of the discs with nonelicitor fatty acids or by branched β-glucans from the mycelium of Phytophthora infestans. Prior treatment of the discs with abscisic acid, salicylhydroxamic acid, or n-propyl gallate, all of which have been shown to suppress AA induction of the hypersensitive response, inhibited the AA-induced increment in LOX activity. Cycloheximide pretreatment, which abolishes AA elicitor activity for other responses such as phytoalexin induction, did not inhibit LOX activity in water- or elicitor-treated discs but enhanced activity similar to that observed by AA treatment. The elicitor-induced increase in 5-LOX activity preceded or temporally paralleled the induction of other studied responses to AA, including the accumulation of mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A reductase and phenylalanine ammonia lyase reported here. The results are discussed in relation to the proposed role of the 5-LOX in signal-response coupling of arachidonate elicitation of the hypersensitive response. Images Figure 4 Figure 7 PMID:16653144

  7. Congenital limb deficiency disorders.

    PubMed

    Wilcox, William R; Coulter, Colleen P; Schmitz, Michael L

    2015-06-01

    Congenital limb deficiency disorders (LDDs) are birth defects characterized by the aplasia or hypoplasia of bones of the limbs. Limb deficiencies are classified as transverse, those due to intrauterine disruptions of previously normal limbs, or longitudinal, those that are isolated or associated with certain syndromes as well as chromosomal anomalies. Consultation with a medical geneticist is advisable. Long-term care should occur in a specialized limb deficiency center with expertise in orthopedics, prosthetics, and occupational and physical therapy and provide emotional support and contact with other families. With appropriate care, most children with LDDs can lead productive lives. PMID:26042905

  8. Iron deficiency anemia

    PubMed Central

    Naigamwalla, Dinaz Z.; Webb, Jinelle A.; Giger, Urs

    2012-01-01

    Iron is essential to virtually all living organisms and is integral to multiple metabolic functions. The most important function is oxygen transport in hemoglobin. Iron deficiency anemia in dogs and cats is usually caused by chronic blood loss and can be discovered incidentally as animals may have adapted to the anemia. Severe iron deficiency is characterized by a microcytic, hypochromic, potentially severe anemia with a variable regenerative response. Iron metabolism and homeostasis will be reviewed, followed by a discussion of diagnostic testing and therapeutic recommendations for dogs and cats with iron deficiency anemia. PMID:22942439

  9. Thiamine deficiency and delirium.

    PubMed

    Osiezagha, Kenneth; Ali, Shahid; Freeman, C; Barker, Narviar C; Jabeen, Shagufta; Maitra, Sarbani; Olagbemiro, Yetunde; Richie, William; Bailey, Rahn K

    2013-04-01

    Thiamine is an essential vitamin that plays an important role in cellular production of energy from ingested food and enhances normal neuronal actives. Deficiency of this vitamin leads to a very serious clinical condition known as delirium. Studies performed in the United States and other parts of the world have established the link between thiamine deficiency and delirium. This literature review examines the physiology, pathophysiology, predisposing factors, clinical manifestations (e.g., Wernicke's encephalopathy, Wernicke-Korsakoff syndrome, structural and functional brain injuries) and diagnosis of thiamine deficiency and delirium. Current treatment practices are also discussed that may improve patient outcome, which ultimately may result in a reduction in healthcare costs. PMID:23696956

  10. Multiple Peroxisomal Enzymatic Deficiency Disorders

    PubMed Central

    Vamecq, Joseph; Draye, Jean-Pierre; Van Hoof, François; Misson, Jean-Paul; Evrard, Philippe; Verellen, Gaston; Eyssen, Hendrik J.; Van Eldere, Johan; Schutgens, Ruud B. H.; Wanders, Ronald J. A.; Roels, Frank; Goldfischer, Sidney L.

    1986-01-01

    Biologic, morphologic, and biochemical investigations performed in 2 patients demonstrate multiple peroxisomal deficiencies in the cerebrohepatorenal syndrome of Zellweger (CHRS) and neonatal adrenoleukodystrophy (NALD). Very long chain fatty acids, abnormal bile acids, including bile acid precursors (di- and trihydroxycoprostanoic acids), and C29-dicarboxylic acid accumulated in plasma in both patients. Generalized hyperaminoaciduria was also present. Peroxisomes could not be detected in CHRS liver and kidney; however, in the NALD patient, small and sparse cytoplasmic bodies resembling altered peroxisomes were found in hepatocytes. Hepatocellular and Kupffer cell lysosomes were engorged with ferritin and contained clefts and trilaminar structures believed to represent very long chain fatty acids. Enzymatic deficiencies reflected the peroxisomal defects. Hepatic glycolate oxidase and palmitoyl-CoA oxidase activities were deficient. No particle-bound catalase was found in cultured fibroblasts, and ether glycerolipid (plasmalogen) biosynthesis was markedly reduced. Administration of phenobarbital and clofibrate, an agent that induces peroxisomal proliferation and enzymatic activities, to the NALD patient did not bring about any changes in plasma metabolites, liver peroxisome population, or oxidizing activities. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5 PMID:2879480

  11. Familial lipoprotein lipase deficiency

    MedlinePlus

    ... and white-colored blood vessels in the retinas Pancreatitis that keeps returning Yellowing of the eyes and ... discuss your diet needs with a registered dietitian. Pancreatitis that is related to lipoprotein lipase deficiency responds ...

  12. Growth hormone deficiency - children

    MedlinePlus

    ... the same age. The child will have normal intelligence in most cases. In older children, puberty may ... hormones cause the body to make. Tests can measure these growth factors. Accurate growth hormone deficiency testing ...

  13. Vitamin D Deficiency

    MedlinePlus

    ... deficiency can lead to a loss of bone density (size and strength), broken bones (fractures), muscle weakness, ... get too much calcium in their blood or urine. Careful monitoring of blood vitamin D levels will ...

  14. Factor V deficiency

    MedlinePlus

    ... as many as 20 different proteins in blood plasma. These proteins are called blood coagulation factors. Factor ... You will be given fresh blood plasma or fresh frozen plasma infusions ... These treatments will correct the deficiency temporarily.

  15. Folate-deficiency anemia

    MedlinePlus

    Folate-deficiency anemia is a decrease in red blood cells (anemia) due to a lack of folate. Folate is a type ... B vitamin. It is also called folic acid. Anemia is a condition in which the body does ...

  16. Clinical significance of complement deficiencies.

    PubMed

    Pettigrew, H David; Teuber, Suzanne S; Gershwin, M Eric

    2009-09-01

    The complement system is composed of more than 30 serum and membrane-bound proteins, all of which are needed for normal function of complement in innate and adaptive immunity. Historically, deficiencies within the complement system have been suspected when young children have had recurrent and difficult-to-control infections. As our understanding of the complement system has increased, many other diseases have been attributed to deficiencies within the complement system. Generally, complement deficiencies within the classical pathway lead to increased susceptibility to encapsulated bacterial infections as well as a syndrome resembling systemic lupus erythematosus. Complement deficiencies within the mannose-binding lectin pathway generally lead to increased bacterial infections, and deficiencies within the alternative pathway usually lead to an increased frequency of Neisseria infections. However, factor H deficiency can lead to membranoproliferative glomerulonephritis and hemolytic uremic syndrome. Finally, deficiencies within the terminal complement pathway lead to an increased incidence of Neisseria infections. Two other notable complement-associated deficiencies are complement receptor 3 and 4 deficiency, which result from a deficiency of CD18, a disease known as leukocyte adhesion deficiency type 1, and CD59 deficiency, which causes paroxysmal nocturnal hemoglobinuria. Most inherited deficiencies of the complement system are autosomal recessive, but properidin deficiency is X-linked recessive, deficiency of C1 inhibitor is autosomal dominant, and mannose-binding lectin and factor I deficiencies are autosomal co-dominant. The diversity of clinical manifestations of complement deficiencies reflects the complexity of the complement system. PMID:19758139

  17. A micronutrient powder with low doses of highly absorbable iron and zinc reduces iron and zinc deficiency and improves weight-for-age Z-scores in South African children.

    PubMed

    Troesch, Barbara; van Stuijvenberg, Martha E; van Stujivenberg, Martha E; Smuts, Cornelius M; Kruger, H Salomè; Biebinger, Ralf; Hurrell, Richard F; Baumgartner, Jeannine; Zimmermann, Michael B

    2011-02-01

    Micronutrient powders (MNP) are often added to complementary foods high in inhibitors of iron and zinc absorption. Most MNP therefore include high amounts of iron and zinc, but it is no longer recommended in malarial areas to use untargeted MNP that contain the Reference Nutrient Intake for iron in a single serving. The aim was to test the efficacy of a low-iron and -zinc (each 2.5 mg) MNP containing iron as NaFeEDTA, ascorbic acid (AA), and an exogenous phytase active at gut pH. In a double-blind controlled trial, South African school children with low iron status (n = 200) were randomized to receive either the MNP or the unfortified carrier added just before consumption to a high-phytate maize porridge 5 d/wk for 23 wk; primary outcomes were iron and zinc status and a secondary outcome was somatic growth. Compared with the control, the MNP increased serum ferritin (P < 0.05), body iron stores (P < 0.01) and weight-for-age Z-scores (P < 0.05) and decreased transferrin receptor (P < 0.05). The prevalence of iron deficiency fell by 30.6% (P < 0.01) and the prevalence of zinc deficiency decreased by 11.8% (P < 0.05). Absorption of iron from the MNP was estimated to be 7-8%. Inclusion of an exogenous phytase combined with NaFeEDTA and AA may allow a substantial reduction in the iron dose from existing MNP while still delivering adequate iron and zinc. In addition, the MNP is likely to enhance absorption of the high native iron content of complementary foods based on cereals and/or legumes. PMID:21178093

  18. Treatment of Iron Deficiency in Women

    PubMed Central

    Breymann, C.; Römer, T.; Dudenhausen, J. W.

    2013-01-01

    Iron deficiency with and without anaemia is a common cause of morbidity, particularly in women. Iron deficiency is generally the result of an imbalance between iron loss and iron absorption. In women with symptoms suspicious for iron deficiency, it is important to confirm or exclude the suspicion using proper tests. The use of serum ferritin levels is considered the gold standard for diagnosis. Although the ideal ferritin levels are not unknown the current consent is that levels < 40 ng/ml indicate iron deficiency, which needs to be treated in symptomatic patients. However, symptoms can already occur at ferritin levels of < 100 ng/ml and treatment must be adapted to the individual patient. Iron supplementation is only indicated in symptomatic patients diagnosed with iron deficiency whose quality of life is affected. It is important to treat iron deficiency together with its causes or risk factors. For example, blood loss from hypermenorrhea should be reduced. Women also need to receive information about the benefits of an iron-rich diet. If oral treatment with iron supplements is ineffective, parenteral iron administration is recommended. PMID:26633902

  19. VERMILION-DEFICIENCY.

    PubMed

    Bridges, C B

    1919-07-20

    In May, 1916, a culture of Drosophila melanogaster showed that a new sex-linked lethal had arisen. The linkage relations indicated that the position of the lethal was in the neighborhood of the sex-linked recessive "vermilion," whose locus in the X chromosome is at 33.0. When females heterozygous for the lethal were outcrossed to vermilion males, all the daughters that received the lethal-bearing chromosome showed vermilion eye-color, though, from the pedigree, vermilion was known to be absent from the ancestry of the mother. The lethal action and the unexpected appearance of vermilion both suggested that this was another instance of the phenomenon called "deficiency;" that is, the loss or "inactivation" of the genes of a section of the X chromosome. The lethal action would then be due to the deficient region including one or more genes necessary for the life of the individual. The appearance of vermilion in females carrying only one vermilion gene would be explainable on the ground that the deficient-bearing females are virtually haploid for the region including the vermilion locus. Linkage tests showed that the amount of crossing over in the neighborhood of the deficiency was cut down by about five units. Part of this may be attributed to the actual length of the "deficient" region, within which it is probable that no crossing over occurs, and part (probably most) to an alteration in the synaptic relations in the regions immediately adjacent. In more remote regions there was no disturbance or perhaps a slight rise in the frequency of crossing over. Both the local fall and the possible rise in more distant regions would seem to argue that a "pucker" at synapsis had been caused by an actual shortening of the deficient chromosome. That the deficient region extends to the left of the locus of vermilion was indicated by a test in which it was observed that the presence of an extra piece of chromosome including the loci for vermilion and sable ("vermilion

  20. Nature and nurture in vitamin B12 deficiency.

    PubMed

    Zschocke, J; Schindler, S; Hoffmann, G F; Albani, M

    2002-07-01

    We report on a child in whom severe nutritional vitamin B12 deficiency was exacerbated by a genetic impairment of the folate cycle, causing reduced CSF concentrations of the methyl group donor 5-methyltetrahydrofolate. Some patients with vitamin B12 deficiency may benefit from high dose folic acid supplementation, even if plasma concentrations are high. PMID:12089131

  1. Iron deficiency anaemia.

    PubMed

    Lopez, Anthony; Cacoub, Patrice; Macdougall, Iain C; Peyrin-Biroulet, Laurent

    2016-02-27

    Anaemia affects roughly a third of the world's population; half the cases are due to iron deficiency. It is a major and global public health problem that affects maternal and child mortality, physical performance, and referral to health-care professionals. Children aged 0-5 years, women of childbearing age, and pregnant women are particularly at risk. Several chronic diseases are frequently associated with iron deficiency anaemia--notably chronic kidney disease, chronic heart failure, cancer, and inflammatory bowel disease. Measurement of serum ferritin, transferrin saturation, serum soluble transferrin receptors, and the serum soluble transferrin receptors-ferritin index are more accurate than classic red cell indices in the diagnosis of iron deficiency anaemia. In addition to the search for and treatment of the cause of iron deficiency, treatment strategies encompass prevention, including food fortification and iron supplementation. Oral iron is usually recommended as first-line therapy, but the most recent intravenous iron formulations, which have been available for nearly a decade, seem to replenish iron stores safely and effectively. Hepcidin has a key role in iron homoeostasis and could be a future diagnostic and therapeutic target. In this Seminar, we discuss the clinical presentation, epidemiology, pathophysiology, diagnosis, and acute management of iron deficiency anaemia, and outstanding research questions for treatment. PMID:26314490

  2. Antepartum ornithine transcarbamylase deficiency.

    PubMed

    Nakajima, Hitoshi; Sasaki, Yosuke; Maeda, Tadashi; Takeda, Masako; Hara, Noriko; Nakanishi, Kazushige; Urita, Yoshihisa; Hattori, Risa; Miura, Ken; Taniguchi, Tomoko

    2014-01-01

    Ornithine transcarbamylase deficiency (OTCD) is the most common type urea cycle enzyme deficiencies. This syndrome results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase, which catalyzes the conversion of ornithine and carbamoyl phosphate to citrullin. Our case was a 28-year-old female diagnosed with OTCD following neurocognitive deficit during her first pregnancy. Although hyperammonemia was suspected as the cause of the patient's mental changes, there was no evidence of chronic liver disease. Plasma amino acid and urine organic acid analysis revealed OTCD. After combined modality treatment with arginine, sodium benzoate and hemodialysis, the patient's plasma ammonia level stabilized and her mental status returned to normal. At last she recovered without any damage left. PMID:25759629

  3. Transient neonatal zinc deficiency.

    PubMed

    Krieger, I; Alpern, B E; Cunnane, S C

    1986-06-01

    We report an infant who developed clinical manifestations of zinc deficiency during the first month of life although the diet was adequate for zinc and no other causes could be ascertained. The diagnosis was confirmed by low plasma-zinc concentrations and a positive response to zinc treatment. The fatty acid profile of plasma phospholipids was typical of zinc deficiency (ie, arachidonic acid was markedly decreased). The transient nature of this disorder was evident when no relapse occurred after cessation of zinc therapy and plasma-zinc and arachidonic acid concentrations remained normal. Several explanations for the development of transient neonatal zinc deficiency are offered. The observation demonstrates that occasional infants may have requirements for zinc that are beyond the intakes of the conventional RDA. PMID:3717070

  4. Natural killer cell deficiency

    PubMed Central

    Orange, Jordan S.

    2013-01-01

    Natural killer (NK) cells are part of the innate immune defense against infection and cancer, and are especially useful in combating certain viral pathogens. The utility of NK cells in human health has been underscored by a growing number of individuals who are deficient in NK cells and/or their functions. This can be in the context of a broader genetically-defined congenital immunodeficiency of which there are over forty presently known to impair NK cells. The abnormality of NK cells, however, in certain cases represents the majority immunological defect. In aggregate, these conditions are termed NK cell deficiency. Recent advances have added clarity to this diagnosis and identified defects in three different genes that can cause NK cell deficiency as well as some of the underlying biology. Appropriate consideration of these diagnoses and patients raises the potential for rational therapeutic options and further innovation. PMID:23993353

  5. Thiamine Deficiency and Delirium

    PubMed Central

    Ali, Shahid; Freeman, C.; Barker, Narviar C.; Jabeen, Shagufta; Maitra, Sarbani; Olagbemiro, Yetunde; Richie, William; Bailey, Rahn K.

    2013-01-01

    Thiamine is an essential vitamin that plays an important role in cellular production of energy from ingested food and enhances normal neuronal actives. Deficiency of this vitamin leads to a very serious clinical condition known as delirium. Studies performed in the United States and other parts of the world have established the link between thiamine deficiency and delirium. This literature review examines the physiology, pathophysiology, predisposing factors, clinical manifestations (e.g., Wernicke’s encephalopathy, Wernicke-Korsakoff syndrome, structural and functional brain injuries) and diagnosis of thiamine deficiency and delirium. Current treatment practices are also discussed that may improve patient outcome, which ultimately may result in a reduction in healthcare costs. PMID:23696956

  6. Deletion of sterol O-acyltransferase 2 (SOAT2) function in mice deficient in lysosomal acid lipase (LAL) dramatically reduces esterified cholesterol sequestration in the small intestine and liver

    PubMed Central

    Lopez, Adam M.; Posey, Kenneth S.; Turley, Stephen D.

    2014-01-01

    Sterol O-acyltransferase 2 (SOAT2), also known as ACAT2, is the major cholesterol esterifying enzyme in the liver and small intestine (SI). Esterified cholesterol (EC) carried in certain classes of plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease (WD) or cholesteryl ester storage disease (CESD). Hepatomegaly and a massive increase in tissue EC levels are hallmark features of both disorders. While these conditions can be corrected with enzyme replacement therapy, the question arose as to what effect the loss of SOAT2 function might have on tissue EC sequestration in LAL-deficient mice. When weaned at 21 days, Lal−/−:Soat2+/+ mice had a whole liver cholesterol content (mg/organ) of 24.7 mg vs. 1.9 mg in Lal+/+:Soat2+/+ littermates, with almost all the excess sterol being esterified. Over the next 31 days, liver cholesterol content in the Lal−/−:Soat2+/+ mice increased to 145 ± 2 mg but to only 29 ± 2 mg in their Lal−/−:Soat2−/− littermates. The level of EC accumulation in the SI of the Lal−/−:Soat2−/− mice was also much less than in their Lal−/−:Soat2+/+ littermates. In addition, there was a >70% reduction in plasma transaminase activities in the Lal−/−:Soat2−/− mice. These studies illustrate how the severity of disease in a mouse model for CESD can be substantially ameliorated by elimination of SOAT2 function. PMID:25450374

  7. The epidemiology of global micronutrient deficiencies.

    PubMed

    Bailey, Regan L; West, Keith P; Black, Robert E

    2015-01-01

    Micronutrients are essential to sustain life and for optimal physiological function. Widespread global micronutrient deficiencies (MNDs) exist, with pregnant women and their children under 5 years at the highest risk. Iron, iodine, folate, vitamin A, and zinc deficiencies are the most widespread MNDs, and all these MNDs are common contributors to poor growth, intellectual impairments, perinatal complications, and increased risk of morbidity and mortality. Iron deficiency is the most common MND worldwide and leads to microcytic anemia, decreased capacity for work, as well as impaired immune and endocrine function. Iodine deficiency disorder is also widespread and results in goiter, mental retardation, or reduced cognitive function. Adequate zinc is necessary for optimal immune function, and deficiency is associated with an increased incidence of diarrhea and acute respiratory infections, major causes of death in those <5 years of age. Folic acid taken in early pregnancy can prevent neural tube defects. Folate is essential for DNA synthesis and repair, and deficiency results in macrocytic anemia. Vitamin A deficiency is the leading cause of blindness worldwide and also impairs immune function and cell differentiation. Single MNDs rarely occur alone; often, multiple MNDs coexist. The long-term consequences of MNDs are not only seen at the individual level but also have deleterious impacts on the economic development and human capital at the country level. Perhaps of greatest concern is the cycle of MNDs that persists over generations and the intergenerational consequences of MNDs that we are only beginning to understand. Prevention of MNDs is critical and traditionally has been accomplished through supplementation, fortification, and food-based approaches including diversification. It is widely accepted that intervention in the first 1,000 days is critical to break the cycle of malnutrition; however, a coordinated, sustainable commitment to scaling up nutrition at the

  8. The neurology of folic acid deficiency.

    PubMed

    Reynolds, E H

    2014-01-01

    The metabolism of folic acid and the metabolism of vitamin B12 are intimately linked such that deficiency of either vitamin leads to an identical megaloblastic anemia. The neurologic manifestations of folate deficiency overlap with those of vitamin B12 deficiency and include cognitive impairment, dementia, depression, and, less commonly, peripheral neuropathy and subacute combined degeneration of the spinal cord. In both deficiency states there is often dissociation between the neuropsychiatric and the hematologic complications. There is a similar overlap and dissociation between neurologic and hematologic manifestations of inborn errors of folate and vitamin B12 metabolism. Low folate and raised homocysteine levels are risk factors for dementia, including Alzheimer's disease, and depression. Even when folate deficiency is secondary to psychiatric illness due to apathy or poor diet it may eventually aggravate the underlying disorder in a vicious circle effect. Clinical responses to treatment with folates are usually slow over weeks and months, probably due to the efficient blood-brain barrier mechanism for the vitamin, perhaps in turn related to the experimentally demonstrated excitatory properties of folate derivatives. The inappropriate administration of folic acid in the presence of vitamin B12 deficiency may lead to both neurologic and, later, hematologic relapse. Impaired maternal folate intake and status increases the risk of neural tube defects. Periconceptual prophylactic administration of the vitamin reduces, but does not eliminate the risk of neural tube defects even in the absence of folate deficiency. Folates and vitamin B12 have fundamental roles in central nervous system function at all ages, especially in purine, thymidine, neucleotide, and DNA synthesis, genomic and nongenomic methylation and, therefore, in tissue growth, differentiation and repair. There is interest in the potential role of both vitamins in the prevention of disorders of central

  9. Update on vitamin B12 deficiency.

    PubMed

    Langan, Robert C; Zawistoski, Kimberly J

    2011-06-15

    Vitamin B(12) (cobalamin) deficiency is a common cause of megaloblastic anemia, a variety of neuropsychiatric symptoms, and elevated serum homocysteine levels, especially in older persons. There are a number of risk factors for vitamin B(12) deficiency, including prolonged use of metformin and proton pump inhibitors. No major medical organizations, including the U.S. Preventive Services Task Force, have published guidelines on screening asymptomatic or low-risk adults for vitamin B(12) deficiency, but high-risk patients, such as those with malabsorptive disorders, may warrant screening. The initial laboratory assessment of a patient with suspected vitamin B(12) deficiency should include a complete blood count and a serum vitamin B(12) level. Measurements of serum vitamin B(12) may not reliably detect deficiency, and measurement of serum homocysteine and/or methylmalonic acid should be used to confirm deficiency in asymptomatic high-risk patients with low normal levels of vitamin B(12). Oral administration of high-dose vitamin B(12) (1 to 2 mg daily) is as effective as intramuscular administration in correcting the deficiency, regardless of etiology. Because crystalline formulations are better absorbed than naturally occurring vitamin B(12), patients older than 50 years and strict vegetarians should consume foods fortified with vitamin B(12) and vitamin B(12) supplements, rather than attempting to get vitamin B(12) strictly from dietary sources. Administration of vitamin B(12) to patients with elevated serum homocysteine levels has not been shown to reduce cardiovascular outcomes in high-risk patients or alter the cognitive decline of patients with mild to moderate Alzheimer disease. PMID:21671542

  10. Methemoglobinemia and eccentrocytosis in equine erythrocyte flavin adenine dinucleotide deficiency.

    PubMed

    Harvey, J W; Stockham, S L; Scott, M A; Johnson, P J; Donald, J J; Chandler, C J

    2003-11-01

    This report describes erythrocyte biochemical findings in an adult Spanish mustang mare that exhibited persistent methemoglobinemia, eccentrocytosis, and pyknocytosis that were not related to the consumption or administration of an exogenous oxidant. The methemoglobinemia was attributed to a deficiency in cytochrome-b5 reductase (Cb5R) activity, and the eccentrocytes and pyknocytes were attributed to a marked deficiency in reduced nicotinamide adenine dinucleotide phosphate-dependent glutathione reductase (GR) activity that resulted in decreased reduced glutathione concentration within erythrocytes. The GR activity increased to a near-normal value after addition of flavin adenine dinucleotide (FAD) to the enzyme assay, indicating a deficiency of FAD in erythrocytes. The methemoglobinemia, eccentrocytosis, and pyknocytosis were attributed to deficiency of FAD in erythrocytes because the GR and Cb5R enzymes use FAD as a cofactor. This deficiency in FAD results from a defect in erythrocyte riboflavin metabolism, which has not been documented previously in animals. PMID:14608016

  11. Color vision deficiencies

    NASA Astrophysics Data System (ADS)

    Vannorren, D.

    1982-04-01

    Congenital and acquired color vision defects are described in the context of physiological data. Light sources, photometry, color systems and test methods are described. A list of medicines is also presented. The practical social consequences of color vision deficiencies are discussed.

  12. Arginase-1 deficiency.

    PubMed

    Sin, Yuan Yan; Baron, Garrett; Schulze, Andreas; Funk, Colin D

    2015-12-01

    Arginase-1 (ARG1) deficiency is a rare autosomal recessive disorder that affects the liver-based urea cycle, leading to impaired ureagenesis. This genetic disorder is caused by 40+ mutations found fairly uniformly spread throughout the ARG1 gene, resulting in partial or complete loss of enzyme function, which catalyzes the hydrolysis of arginine to ornithine and urea. ARG1-deficient patients exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, persistent growth retardation, and infrequent episodes of hyperammonemia, a clinical pattern that differs strikingly from other urea cycle disorders. This review briefly highlights the current understanding of the etiology and pathophysiology of ARG1 deficiency derived from clinical case reports and therapeutic strategies stretching over several decades and reports on several exciting new developments regarding the pathophysiology of the disorder using ARG1 global and inducible knockout mouse models. Gene transfer studies in these mice are revealing potential therapeutic options that can be exploited in the future. However, caution is advised in extrapolating results since the lethal disease phenotype in mice is much more severe than in humans indicating that the mouse models may not precisely recapitulate human disease etiology. Finally, some of the functions and implications of ARG1 in non-urea cycle activities are considered. Lingering questions and future areas to be addressed relating to the clinical manifestations of ARG1 deficiency in liver and brain are also presented. Hopefully, this review will spark invigorated research efforts that lead to treatments with better clinical outcomes. PMID:26467175

  13. ODH, oxygen deficiency hazard cryogenic analysis

    SciTech Connect

    Augustynowicz, S.D.

    1993-07-01

    An oxygen deficiency exists when the concentration of oxygen, by volume, drops to a level at which atmosphere supplying respiratory protection must be provided. Since liquid cryogens can expand by factors of 700 (LN{sub 2}) to 850 (LH{sub e}), the uncontrolled release into an enclosed space can easily cause an oxygen-deficient condition. An oxygen deficiency hazard (ODH) fatality rate per hour ({O}) is defined as: {O} = {Sigma} N{sub i}P{sub i}F{sub i}, where N{sub i} = number of components, P{sub i} =probability of failure or operator error, and F{sub i} - fatality factor. ODHs range from ``unclassified`` ({O}<10{sup {minus}9} 1/h) to class 4, which is the most hazardous ({O}>10{sup {minus}1} 1/h). For Superconducting Super Collider Laboratory (SSCL) buildings where cryogenic systems exist, failure rate, fatality factor, reduced oxygen ratio, and fresh air circulation are examined.

  14. Omega-3 deficiency impairs honey bee learning

    PubMed Central

    Arien, Yael; Dag, Arnon; Zarchin, Shlomi; Masci, Tania

    2015-01-01

    Deficiency in essential omega-3 polyunsaturated fatty acids (PUFAs), particularly the long-chain form of docosahexaenoic acid (DHA), has been linked to health problems in mammals, including many mental disorders and reduced cognitive performance. Insects have very low long-chain PUFA concentrations, and the effect of omega-3 deficiency on cognition in insects has not been studied. We show a low omega-6:3 ratio of pollen collected by honey bee colonies in heterogenous landscapes and in many hand-collected pollens that we analyzed. We identified Eucalyptus as an important bee-forage plant particularly poor in omega-3 and high in the omega-6:3 ratio. We tested the effect of dietary omega-3 deficiency on olfactory and tactile associative learning of the economically highly valued honey bee. Bees fed either of two omega-3–poor diets, or Eucalyptus pollen, showed greatly reduced learning abilities in conditioned proboscis-extension assays compared with those fed omega-3–rich diets, or omega-3–rich pollen mixture. The effect on performance was not due to reduced sucrose sensitivity. Omega-3 deficiency also led to smaller hypopharyngeal glands. Bee brains contained high omega-3 concentrations, which were only slightly affected by diet, suggesting additional peripheral effects on learning. The shift from a low to high omega-6:3 ratio in the Western human diet is deemed a primary cause of many diseases and reduced mental health. A similar shift seems to be occurring in bee forage, possibly an important factor in colony declines. Our study shows the detrimental effect on cognitive performance of omega-3 deficiency in a nonmammal. PMID:26644556

  15. Immunoglobulin treatment in primary antibody deficiency.

    PubMed

    Maarschalk-Ellerbroek, L J; Hoepelman, I M; Ellerbroek, P M

    2011-05-01

    The primary antibody deficiency syndromes are characterised by recurrent respiratory tract infections and the inability to produce effective immunoglobulin (Ig) responses. The best-known primary antibody deficiencies are common variable immunodeficiency (CVID), X-linked agammaglobulinaemia (XLA), immunoglobulin G (IgG) subclass deficiency, and selective antibody deficiency with normal immunoglobulins (SADNI). Therapy in these patients consists of prophylactic antibiotics and/or Ig replacement therapy. Diagnostic delay remains common owing to limited awareness of the presenting features and may result in increased morbidity and mortality. Replacement therapy with immunoglobulins increases life expectancy and reduces the frequency and severity of infections, but the effect on end-organ damage is still unknown. Both intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) treatment appear to be safe, with comparable efficacy. A starting dose of 300-400 mg/kg/month in IVIg and 100 mg/week for SCIg is recommended. IgG trough levels should be >5 g/L for patients with agammaglobulinaemia and 3 g/L greater than the initial IgG level for patients with CVID; however, the clinical response should be foremost in choosing the dose and trough level. Infusion-related adverse reactions are generally mild owing to improved manufacturing processes. In this paper, aspects of Ig replacement therapy in primary antibody-deficient patients will be addressed. PMID:21276714

  16. Genetics Home Reference: biotinidase deficiency

    MedlinePlus

    ... Aydin HI, Sennaroğlu L, Belgin E, Jensen K, Wolf B. Hearing loss in biotinidase deficiency: genotype-phenotype ... corrected to Aydin, Halil Ibrahim]. Citation on PubMed Wolf B. Biotinidase deficiency: "if you have to have ...

  17. Factor XII (Hageman factor) deficiency

    MedlinePlus

    ... takes longer than normal to clot in a test tube. Factor XII deficiency is a rare inherited disorder. Symptoms There are usually no symptoms. Exams and Tests Factor XII deficiency is most often found when ...

  18. Genetics Home Reference: pseudocholinesterase deficiency

    MedlinePlus

    ... deficiency is a condition that results in increased sensitivity to certain muscle relaxant drugs used during general ... People with pseudocholinesterase deficiency may also have increased sensitivity to certain other drugs, including the local anesthetic ...

  19. Nickel deficiency affects nitrogenous forms and urease activity in spring xylem sap of pecan

    Technology Transfer Automated Retrieval System (TEKTRAN)

    While nickel (Ni) deficiency occurs in certain agricultural crops, little is known regarding the influence of deficiency on metabolic or physiological processes. We studied the influence of Ni deficiency on the reduced-nitrogen (N) composition of early spring xylem sap of pecan [Carya illinoinensis...

  20. Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology.

    PubMed

    Stockler, Sylvia; Schutz, Peter W; Salomons, Gajja S

    2007-01-01

    Cerebral creatine deficiency syndromes (CCDSs) are a group of inborn errors of creatine metabolism comprising two autosomal recessive disorders that affect the biosynthesis of creatine--i.e. arginine:glycine amidinotransferase deficiency (AGAT; MIM 602360) and guanidinoacetate methyltransferase deficiency (GAMT; MIM 601240)--and an X-linked defect that affects the creatine transporter, SLC6A8 deficiency (SLC6A8; MIM 300036). The biochemical hallmarks of these disorders include cerebral creatine deficiency as detected in vivo by 1H magnetic resonance spectroscopy (MRS) of the brain, and specific disturbances in metabolites of creatine metabolism in body fluids. In urine and plasma, abnormal guanidinoacetic acid (GAA) levels are found in AGAT deficiency (reduced GAA) and in GAMT deficiency (increased GAA). In urine of males with SLC6A8 deficiency, an increased creatine/creatinine ratio is detected. The common clinical presentation in CCDS includes mental retardation, expressive speech and language delay, autistic like behaviour and epilepsy. Treatment of the creatine biosynthesis defects has yielded clinical improvement, while for creatine transporter deficiency, successful treatment strategies still need to be discovered. CCDSs may be responsible for a considerable fraction of children and adults affected with mental retardation of unknown etiology. Thus, screening for this group of disorders should be included in the differential diagnosis of this population. In this review, also the importance of CCDSs for the unravelling of the (patho)physiology of cerebral creatine metabolism is discussed. PMID:18652076

  1. Transient partial growth hormone deficiency due to zinc deficiency.

    PubMed

    Nishi, Y; Hatano, S; Aihara, K; Fujie, A; Kihara, M

    1989-04-01

    We present here a 13-year-old boy with partial growth hormone deficiency due to chronic mild zinc deficiency. When zinc administration was started, his growth rate, growth hormone levels, and plasma zinc concentrations increased significantly. His poor dietary intake resulted in chronic mild zinc deficiency, which in turn could be the cause of a further loss of appetite and growth retardation. There was also a possibility of renal zinc wasting which may have contributed to zinc deficiency. Zinc deficiency should be carefully ruled out in patients with growth retardation. PMID:2708733

  2. Glucose-6-phosphate dehydrogenase deficiency

    MedlinePlus

    G6PD deficiency; Hemolytic anemia due to G6PD deficiency; Anemia - hemolytic due to G6PD deficiency ... Gallagher PG. Hemolytic anemias. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 161. Janz ...

  3. Adenylosuccinate lyase deficiency.

    PubMed

    Spiegel, Erin K; Colman, Roberta F; Patterson, David

    2006-01-01

    Adenylosuccinate lyase deficiency is a disease of purine metabolism which affects patients both biochemically and behaviorally. The symptoms are variable and include psychomotor retardation, autistic features, hypotonia, and seizures. Patients also accumulate the substrates of ADSL in body fluids. Both the presence of normal levels of ADSL enzyme activities in some patient tissues and the absence of a clear correlation between mutations, biochemistry, and behavior show that the system has unexplored biochemical and/or genetic complexity. It is unclear whether the pathological mechanisms of this disease result from a deficiency of purines, a toxicity of intermediates, or perturbation of another pathway or system. A patient with autistic features and mild psychomotor delay carries two novel mutations in this gene, E80D and D87E. The creation of a mouse model of this disease will be an important step in elucidating the in vivo mechanisms of the disease. Mice carrying mutations that cause ADSL deficiency in humans will be informative as to the effects of these mutations both during embryogenesis and on the brain, possibly leading to therapies for this disease in the future. PMID:16839792

  4. Primary antibody deficiency syndromes.

    PubMed

    Wood, P

    2009-03-01

    The primary antibody deficiency syndromes are a group of rare disorders characterized by an inability to produce clinically effective immunoglobulin responses. Some of these disorders result from genetic mutations in genes involved in B cell development, whereas others appear to be complex polygenic disorders. They most commonly present with recurrent infections due to encapsulated bacteria, although in the most common antibody deficiency, Common Variable Immunodeficiency, systemic and organ-specific autoimmunity can be a presenting feature. Diagnostic delay in this group of disorders remains a problem, and the laboratory has a vital role in the detection of abnormalities in immunoglobulin concentration and function. It is critical to distinguish this group of disorders from secondary causes of hypogammaglobulinaemia, in particular lymphoid malignancy, and appropriate laboratory investigations are of critical importance. Treatment of primary antibody deficiencies involves immunoglobulin replacement therapy, either via the intravenous or subcutaneous route. Patients remain at risk of a wide variety of complications, not all linked to diagnostic delay and inadequate therapy. In common variable immunodeficiency (CVID) in particular, patients remain at significantly increased risk of lymphoid malignancy, and regular clinical and laboratory monitoring is required. This review aims to give an overview of these conditions for the general reader, covering pathogenesis, clinical presentation, laboratory investigation, therapy and clinical management. PMID:19151170

  5. Iron-Deficiency Anemia (For Parents)

    MedlinePlus

    ... Things to Know About Zika & Pregnancy Iron-Deficiency Anemia KidsHealth > For Parents > Iron-Deficiency Anemia Print A ... common nutritional deficiency in children. About Iron-Deficiency Anemia Every red blood cell in the body contains ...

  6. Testosterone deficiency and cardiovascular mortality

    PubMed Central

    Morgentaler, Abraham

    2015-01-01

    New concerns have been raised regarding cardiovascular (CV) risks with testosterone (T) therapy (TTh). These concerns are based primarily on two widely reported retrospective studies. However, methodological flaws and data errors invalidate both studies as credible evidence of risk. One showed reduced adverse events by half in T-treated men but reversed this result using an unproven statistical approach. The authors subsequently acknowledged serious data errors including nearly 10% contamination of the dataset by women. The second study mistakenly used the rate of T prescriptions written by healthcare providers to men with recent myocardial infarction (MI) as a proxy for the naturally occurring rate of MI. Numerous studies suggest T is beneficial, including decreased mortality in association with TTh, reduced MI rate with TTh in men with the greatest MI risk prognosis, and reduced CV and overall mortality with higher serum levels of endogenous T. Randomized controlled trials have demonstrated benefits of TTh in men with coronary artery disease and congestive heart failure. Improvement in CV risk factors such as fat mass and glycemic control have been repeatedly demonstrated in T-deficient men treated with T. The current evidence does not support the belief that TTh is associated with increased CV risk or CV mortality. On the contrary, a wealth of evidence accumulated over several decades suggests that low serum T levels are associated with increased risk and that higher endogenous T, as well as TTh itself, appear to be beneficial for CV mortality and risk. PMID:25432501

  7. Strategic Selenium Management: Natural Biofortification of Grazing Livestock with Selenium to Avert Selenium Deficiency and Enhance the Nutritional Value of Food Products.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    : Efficient and effective management of Se deficiency is required to sustain profitability of grazing-based livestock operations. Selenium deficiency increases morbidity and mortality rates, reduces reproduction rates, and reduces yield and quality of marketable products. Therefore, producers must p...

  8. Managing vitamin D deficiency in children

    PubMed Central

    2010-01-01

    Vitamin D deficiency has been identified in many British children. This condition has many deleterious effects on their health. Taking vitamin D status into account needs to become a daily element of primary care practice, both in antenatal and postnatal situations. It is probable that a significant improvement in reducing chronic diseases in adulthood will result from a more proactive approach in children. PMID:25949615

  9. PRD125, a potent and selective inhibitor of sterol O-acyltransferase 2 markedly reduces hepatic cholesteryl ester accumulation and improves liver function in lysosomal acid lipase-deficient mice.

    PubMed

    Lopez, Adam M; Chuang, Jen-Chieh; Posey, Kenneth S; Ohshiro, Taichi; Tomoda, Hiroshi; Rudel, Lawrence L; Turley, Stephen D

    2015-11-01

    In most organs, the bulk of cholesterol is unesterified, although nearly all possess a varying capability of esterifying cholesterol through the action of either sterol O-acyltransferase (SOAT) 1 or, in the case of hepatocytes and enterocytes, SOAT2. Esterified cholesterol (EC) carried in plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease or cholesteryl ester storage disease (CESD). Hepatomegaly and a massive increase in tissue EC levels are hallmark features of both disorders. While these conditions can be corrected with enzyme replacement therapy, the question arose as to whether pharmacological inhibition of SOAT2 might reduce tissue EC accretion in CESD. When weaned at 21 days, Lal(-/-) mice, of either gender, had a whole liver cholesterol content that was 12- to 13-fold more than that of matching Lal(+/+) littermates (23 versus 1.8 mg, respectively). In Lal(-/-) males given the selective SOAT2 inhibitor PRD125 1,11-O-o-methylbenzylidene-7-O-p-cyanobenzoyl-1,7,11-trideacetylpyripyropene A in their diet (∼10 mg/day per kg body weight) from 21 to 53 days, whole liver cholesterol content was 48.6 versus 153.7 mg in untreated 53-day-old Lal(-/-) mice. This difference reflected a 59% reduction in hepatic EC concentration (mg/g), combined with a 28% fall in liver mass. The treated mice also showed a 63% reduction in plasma alanine aminotransferase activity, in parallel with decisive falls in hepatic mRNA expression levels for multiple proteins that reflect macrophage presence and inflammation. These data implicate SOAT2 as a potential target in CESD management. PMID:26283692

  10. The heparan sulphate deficient Hspg2 exon 3 null mouse displays reduced deposition of TGF-β1 in skin compared to C57BL/6 wild type mice.

    PubMed

    Shu, Cindy; Smith, Susan M; Melrose, James

    2016-06-01

    This was an observational study where we examined the role of perlecan HS on the deposition of TGF-β1 in C57BL/6 and Hspg2(∆3-/∆3-) perlecan exon 3 null mouse skin. Despite its obvious importance in skin repair and tissue homeostasis no definitive studies have immunolocalised TGF-β1 in skin in WT or Hspg2(∆3-/∆3-) perlecan exon 3 null mice. Vertical parasagittal murine dorsal skin from 3, 6 and 12 week old C57BL/6 and Hspg2(∆3-/∆3-) mice were fixed in neutral buffered formalin, paraffin embedded and 4 μm sections stained with Mayers haematoxylin and eosin (H & E). TGF-β1 was immunolocalised using a rabbit polyclonal antibody, heat retrieval and the Envision NovaRED detection system. Immunolocalisation of TGF-β1 differed markedly in C57BL/6 and Hspg2(∆3-/∆3-) mouse skin, ablation of exon 3 of Hspg2 resulted in a very severe reduction in the deposition of TGF-β1 in skin 3-12 weeks postnatally. The reduced deposition of TGF-β1 observed in the present study would be expected to impact detrimentally on the remodelling and healing capacity of skin in mutant mice compounding on the poor wound-healing properties already reported for perlecan exon 3 null mice due to an inability to signal with FGF-2 and promote angiogenic repair processes. TGF-β1 also has cell mediated effects in tissue homeostasis and matrix stabilisation a reduction in TGF-β1 deposition would therefore be expected to detrimentally impact on skin homeostasis in the perlecan mutant mice. PMID:27098652

  11. Carnitine palmitoyltransferase II deficiency

    PubMed Central

    Roe, C R.; Yang, B-Z; Brunengraber, H; Roe, D S.; Wallace, M; Garritson, B K.

    2008-01-01

    Background: Carnitine palmitoyltransferase II (CPT II) deficiency is an important cause of recurrent rhabdomyolysis in children and adults. Current treatment includes dietary fat restriction, with increased carbohydrate intake and exercise restriction to avoid muscle pain and rhabdomyolysis. Methods: CPT II enzyme assay, DNA mutation analysis, quantitative analysis of acylcarnitines in blood and cultured fibroblasts, urinary organic acids, the standardized 36-item Short-Form Health Status survey (SF-36) version 2, and bioelectric impedance for body fat composition. Diet treatment with triheptanoin at 30% to 35% of total daily caloric intake was used for all patients. Results: Seven patients with CPT II deficiency were studied from 7 to 61 months on the triheptanoin (anaplerotic) diet. Five had previous episodes of rhabdomyolysis requiring hospitalizations and muscle pain on exertion prior to the diet (two younger patients had not had rhabdomyolysis). While on the diet, only two patients experienced mild muscle pain with exercise. During short periods of noncompliance, two patients experienced rhabdomyolysis with exercise. None experienced rhabdomyolysis or hospitalizations while on the diet. All patients returned to normal physical activities including strenuous sports. Exercise restriction was eliminated. Previously abnormal SF-36 physical composite scores returned to normal levels that persisted for the duration of the therapy in all five symptomatic patients. Conclusions: The triheptanoin diet seems to be an effective therapy for adult-onset carnitine palmitoyltransferase II deficiency. GLOSSARY ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATP = adenosine triphosphate; BHP = β-hydroxypentanoate; BKP = β-ketopentanoate; BKP-CoA = β-ketopentanoyl–coenzyme A; BUN = blood urea nitrogen; CAC = citric acid cycle; CoA = coenzyme A; CPK = creatine phosphokinase; CPT II = carnitine palmitoyltransferase II; LDL = low-density lipoprotein; MCT

  12. Iatrogenic nutritional deficiencies.

    PubMed

    Young, R C; Blass, J P

    1982-01-01

    This article catalogs the nutritional deficiencies inadvertently introduced by certain treatment regimens. Specifically, the iatrogenic effects on nutrition of surgery, hemodialysis, irradiation, and drugs are reviewed. Nutritional problems are particularly frequent consequences of surgery on the gastrointestinal tract. Gastric surgery can lead to deficiencies of vitamin B12, folate, iron, and thiamine, as well as to metabolic bone disease. The benefits of small bowel bypass are limited by the potentially severe nutritional consequences of this procedure. Following bypass surgery, patients should be monitored for signs of possible nutritional probems such as weight loss, neuropathy, cardiac arrhythmias, loss of stamina, or changes in mental status. Minimal laboratory tests should include hematologic evaluation, B12, folate, iron, albumin, calcium, phosphorus, alkaline phosphatase, transaminases, sodium, potassium, chloride, and carbon dioxide levels. Roentgenologic examination of the bone should also be obtained. Loss of bone substance is a major consequence of many forms of treatment, and dietary supplementation with calcium is warranted. Patients undergoing hemodialysis have shown carnitine and choline deficiencies, potassium depletion, and hypovitaminosis, as well as osteomalacia. Chronic drug use may alter intake, synthesis, absorption, transport, storage, metabolism, or excretion of nutrients. Patients vary markedly in the metabolic effects of drugs, and recommendations for nutrition must be related to age, sex, reproductive status, and genetic endowment. Moreover, the illness being treated can itself alter nutritional requirements and the effect of the treatment on nutrient status. The changes in nutritional levels induced by use of estrogen-containing oral contraceptives (OCs) are obscure; however, the effects on folate matabolism appear to be of less clinical import than previously suggested. Reduction in pyridoxine and serum vitamin B12 levels has been

  13. Treatment of carnitine deficiency.

    PubMed

    Winter, S C

    2003-01-01

    Carnitine deficiency is a secondary complication of many inborn errors of metabolism. Pharmacological treatment with carnitine not only corrects the deficiency, it facilitates removal of accumulating toxic acyl intermediates and the generation of mitochondrial free coenzyme A (CoA). The United States Food and Drug Administration (US FDA) approved the use of carnitine for the treatment of inborn errors of metabolism in 1992. This approval was based on retrospective chart analysis of 90 patients, with 18 in the untreated cohort and 72 in the treated cohort. Efficacy was evaluated on the basis of clinical and biochemical findings. Compelling data included increased excretion of disease-specific acylcarnitine derivatives in a dose-response relationship, decreased levels of metabolites in the blood, and improved clinical status with decreased hospitalization frequency, improved growth and significantly lower mortality rates as compared to historical controls. Complications of carnitine treatment were few, with gastrointestinal disturbances and odour being the most frequent. No laboratory or clinical safety issues were identified. Intravenous carnitine preparations were also approved for treatment of secondary carnitine deficiency. Since only 25% of enteral carnitine is absorbed and gastrointestinal tolerance of high doses is poor, parenteral carnitine treatment is an appealing alternative therapeutic approach. In 7 patients treated long term with high-dose weekly to daily venous boluses of parenteral carnitine through a subcutaneous venous port, benefits included decreased frequency of decompensations, improved growth, improved muscle strength and decreased reliance on medical foods with liberalization of protein intake. Port infections were the most troubling complication. Theoretical concerns continue to be voiced that carnitine might result in fatal arrhythmias in patients with long-chain fat metabolism defects. No published clinical studies substantiate these

  14. Antithrombin deficiency in pregnancy.

    PubMed

    Durai, Shivani; Tan, Lay Kok; Lim, Serene

    2016-01-01

    We present a case of a 39-year-old, gravida 3 para 2, Chinese female with a history of inherited type 1 Antithrombin deficiency and multiple prior episodes of venous thromboembolism. She presented at 29+4 weeks' gestation with severe pre-eclampsia complicated by haemolysis, elevated liver enzymes and low platelet (HELLP) syndrome. She subsequently underwent an emergency caesarean section for non-reassuring fetal status, which was complicated by postpartum haemorrhage secondary to uterine atony, requiring a B-Lynch suture intraoperatively. PMID:27207982

  15. Nasal Tip Deficiency.

    PubMed

    Cerkes, Nazim

    2016-01-01

    Nasal tip deficiency can be congenital or secondary to previous nasal surgeries. Underdeveloped medial crura usually present with underprojected tip and lack of tip definition. Weakness or malposition of lateral crura causes alar rim retraction and lateral nasal wall weakness. Structural grafting of alar cartilages strengthens the tip framework, reinforces the disrupted support mechanisms, and controls the position of the nasal tip. In secondary cases, anatomic reconstruction of the weakened or interrupted alar cartilages and reconstitution of a stable nasal tip tripod must be the goal for a predictable outcome. PMID:26616702

  16. Disialotransferrin developmental deficiency syndrome.

    PubMed Central

    Kristiansson, B; Andersson, M; Tonnby, B; Hagberg, B

    1989-01-01

    Seven mentally deficient children and adolescents (three pairs of siblings and one singleton) were studied. A peculiar external appearance, a characteristic neurohepatosubcutaneous tissue impairment syndrome and, as a biological marker, an abnormal sialic acid transferrin pattern were characteristic features. All seven seemed odd from birth and prone to acute cerebral dysfunction during catabolic states. Abnormal lower neurone, cerebellar, and retinal functions dominated from later childhood. The disialotransferrin pattern found in serum and cerebrospinal fluid is thought to be the biological marker of a newly discovered inborn error of glycoprotein metabolism with autosomal recessive inheritance. Images Fig 1 Fig 2 p74-b PMID:2466439

  17. Loss of LRPPRC causes ATP synthase deficiency.

    PubMed

    Mourier, Arnaud; Ruzzenente, Benedetta; Brandt, Tobias; Kühlbrandt, Werner; Larsson, Nils-Göran

    2014-05-15

    Defects of the oxidative phosphorylation system, in particular of cytochrome-c oxidase (COX, respiratory chain complex IV), are common causes of Leigh syndrome (LS), which is a rare neurodegenerative disorder with severe progressive neurological symptoms that usually present during infancy or early childhood. The COX-deficient form of LS is commonly caused by mutations in genes encoding COX assembly factors, e.g. SURF1, SCO1, SCO2 or COX10. However, other mutations affecting genes that encode proteins not directly involved in COX assembly can also cause LS. The leucine-rich pentatricopeptide repeat containing protein (LRPPRC) regulates mRNA stability, polyadenylation and coordinates mitochondrial translation. In humans, mutations in Lrpprc cause the French Canadian type of LS. Despite the finding that LRPPRC deficiency affects the stability of most mitochondrial mRNAs, its pathophysiological effect has mainly been attributed to COX deficiency. Surprisingly, we show here that the impaired mitochondrial respiration and reduced ATP production observed in Lrpprc conditional knockout mouse hearts is caused by an ATP synthase deficiency. Furthermore, the appearance of inactive subassembled ATP synthase complexes causes hyperpolarization and increases mitochondrial reactive oxygen species production. Our findings shed important new light on the bioenergetic consequences of the loss of LRPPRC in cardiac mitochondria. PMID:24399447

  18. [Pyruvate dehydrogenase deficiency and cerebral malformations].

    PubMed

    Eirís, J; Alvarez-Moreno, A; Briones, P; Alonso-Alonso, C; Castro-Gago, M

    1996-10-01

    Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and severe global developmental delay. A deficiency of PDH E1 alpha, a subunit of the PDH complex is a prominent cause of congenital lactic acidosis. The E1 alpha cDNA and corresponding genomic DNA have been located in the short arm of the X-chromosome (Xp22-1). A isolated 'cerebral' lactic acidosis with cerebral dysgenesis is a recognized pattern of presentation of PDH deficiency. Here, we report clinical features, magnetic resonance, and biochemical studies of two females aged 6 months (case 1) and 26 months (case 2). Both had severe development delay, minor dysmorphic features, microcephaly, severe hypoplasia of the corpus callosum, cerebral atrophy, ventricular dilatation and increase in serum lactate levels without systemic acidosis. Urinary organic acid profile was compatible with PDH deficiency. Increased CSF lactate and pyruvate levels and reduced total PDH and PDH E1 activities in muscle and fibroblasts were observed in case 1. Otherwise, decreased total PDH activity in muscle but not in fibroblasts was seen in case 2. The PDH E1á gene was sequenced in the case 1 and a deletion in exon 7 was demonstrated. Dysmorphism with severe cerebral malformations in female patients merits a metabolic evaluation, including determination of lactate and pyruvate levels in CSF. PMID:8983728

  19. Selenium deficiency mitigates hypothyroxinemia in iodine-deficient subjects.

    PubMed

    Vanderpas, J B; Contempré, B; Duale, N L; Deckx, H; Bebe, N; Longombé, A O; Thilly, C H; Diplock, A T; Dumont, J E

    1993-02-01

    Studies were performed to assess the role of combined selenium and iodine deficiency in the etiology of endemic myxedematous cretinism in a population in Zaire. One effect of selenium deficiency may be to lower glutathione peroxidase activity in the thyroid gland, thus allowing hydrogen peroxide produced during thyroid hormone synthesis to be cytotoxic. In selenium-and-iodine-deficient humans, selenium supplementation may aggravate hypothyroidism by stimulating thyroxin metabolism by the selenoenzyme type I iodothyronine 5'-deiodinase. Selenium supplementation is thus not indicated without iodine or thyroid hormone supplementation in cases of combined selenium and iodine deficiencies. PMID:8427203

  20. [Iron deficiency in chronic heart failure: from diagnosis to therapy].

    PubMed

    von Haehling, S; Anker, S D

    2014-04-01

    Anaemia and iron deficiency are frequent co-morbidities in patients with chronic heart failure. Both are bound to worsen an already reduced exercise capacity in these patients. Recent data have demonstrated that iron deficiency alone, i.e. without concomitant anaemia, reduces quality of life, exercise capacity and likely also survival. Two clinical entities should be differentiated in this context: absolute and functional iron deficiency, the first being an absolute deficiency of iron, the second representing a disturbed mobilisation capacity. The FAIR-HF study has shown that intravenous iron administration can improve quality of life and exercise capacity in affected patients. A correct diagnosis can easily be arrived at using parameters such as serum ferritin and transferrin saturation. Replenishing iron stores is most useful using the intravenous route, and administered doses need to be adjusted to individual needs. PMID:24722935

  1. Iron deficiency in pregnancy

    PubMed Central

    McMahon, Lawrence P

    2010-01-01

    Iron deficiency (ID) and related anaemia (IDA) during pregnancy are highly prevalent worldwide in both developed and developing nations although the causes are often different. At conception, many women lack sufficient iron stores to meet the increased requirements of pregnancy, which are calculated at approximately 1200 mg. Appraisal of iron status in pregnant women is problematic, however the most reliable available diagnostic test is a serum ferritin < 20 µg/L. ID is often associated with other nutritional disorders, and there is frequently a secondary cause or association. A greater oral intake is usually insufficient to meet the increased demands of pregnancy, however regular oral supplements (given either daily or intermittently) can often meet maternal needs and avoid associated neonatal complications of IDA. Over-treatment with iron should be avoided, but intravenous administration is useful when deficiency is discovered late, is severe, or if the woman is intolerant of oral formulations. This paper reviews the current literature, and addresses differences in the prevalence and causes of ID betwen developed and developing nations. It examines gestational iron requirements, distinguishes between ID and IDA, and highlights difficulties in diagnostic testing. Finally, it appraises the evidence for and against different treatment regimens, ranging from food fortification to intravenous iron infusions, according to availability and to need.

  2. Vitamin D Deficiency

    PubMed Central

    Alshishtawy, Moeness Moustafa

    2012-01-01

    Recently, scientists have generated a strong body of evidence providing new information about the preventive effect of vitamin D on a broad range of disorders. This evidence suggests that vitamin D is much more than a nutrient needed for bone health; it is an essential hormone required for regulation of a large number of physiological functions. Sufficient concentration of serum 25-hydroxyvitamin D is essential for optimising human health. This article reviews the present state-of-the-art knowledge about vitamin D’s status worldwide and refers to recent articles discussing some of the general background of vitamin D, including sources, benefits, deficiencies, and dietary requirements, especially in pregnancy. They offer evidence that vitamin D deficiency could be a major public health burden in many parts of the world, mostly because of sun deprivation. The article also discusses the debate about optimal concentration of circulating serum 25-hydroxyvitamin D, and explores different views on the amount of vitamin D supplementation required to achieve and maintain this concentration. PMID:22548132

  3. Acquired coagulation factor XIII deficiency: a case report.

    PubMed

    Jia, Yongqing; Hu, Huixian; Wei, Bin

    2016-06-01

    The main objective of the study is to summarize the clinical characteristics of acquired factor XIII (FXIII) deficiency caused by a spontaneous FXIII inhibitor. Here we report a new case of acquired FXIII deficiency caused by FXIII inhibitor and review the medical literature regarding the characteristics and treatment of this disorder. FXIII deficiency caused by FXIII inhibitors is rare and of uncertain pathogenesis. Experience with therapeutic measures is limited to data from case reports. Immunosuppressive drugs may reduce autoantibodies or inhibit the cell clone generating the antibodies and may have been of benefit in our patient. The impact of such therapy on patient prognosis is incompletely known. PMID:26588447

  4. Glucose-6-phosphatase deficiency

    PubMed Central

    2011-01-01

    Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed

  5. Zinc deficiency and eating disorders.

    PubMed

    Humphries, L; Vivian, B; Stuart, M; McClain, C J

    1989-12-01

    Decreased food intake, a cyclic pattern of eating, and weight loss are major manifestations of zinc deficiency. In this study, zinc status was evaluated in 62 patients with bulimia and 24 patients with anorexia nervosa. Forty percent of patients with bulimia and 54% of those with anorexia nervosa had biochemical evidence of zinc deficiency. The authors suggest that for a variety of reasons, such as lower dietary intake of zinc, impaired zinc absorption, vomiting, diarrhea, and binging on low-zinc foods, patients with eating disorders may develop zinc deficiency. This acquired zinc deficiency could then add to the chronicity of altered eating behavior in those patients. PMID:2600063

  6. Diagnosis and treatment of vitamin D deficiency.

    PubMed

    Cannell, J J; Hollis, B W; Zasloff, M; Heaney, R P

    2008-01-01

    The recent discovery--in a randomised, controlled trial--that daily ingestion of 1100 IU of colecalciferol (vitamin D) over a 4-year period dramatically reduced the incidence of non-skin cancers makes it difficult to overstate the potential medical, social and economic implications of treating vitamin D deficiency. Not only are such deficiencies common, probably the rule, vitamin D deficiency stands implicated in a host of diseases other than cancer. The metabolic product of vitamin D is a potent, pleiotropic, repair and maintenance, secosteroid hormone that targets > 200 human genes in a wide variety of tissues, meaning it has as many mechanisms of action as genes it targets. A common misconception is that government agencies designed present intake recommendations to prevent or treat vitamin D deficiency. They did not. Instead, they are guidelines to prevent particular metabolic bone diseases. Official recommendations were never designed and are not effective in preventing or treating vitamin D deficiency and in no way limit the freedom of the physician--or responsibility--to do so. At this time, assessing serum 25-hydroxy-vitamin D is the only way to make the diagnosis and to assure that treatment is adequate and safe. The authors believe that treatment should be sufficient to maintain levels found in humans living naturally in a sun-rich environment, that is, > 40 ng/ml, year around. Three treatment modalities exist: sunlight, artificial ultraviolet B radiation or supplementation. All treatment modalities have their potential risks and benefits. Benefits of all treatment modalities outweigh potential risks and greatly outweigh the risk of no treatment. As a prolonged 'vitamin D winter', centred on the winter solstice, occurs at many temperate latitudes, < or = 5000 IU (125 microg) of vitamin D/day may be required in obese, aged and/or dark-skinned patients to maintain adequate levels during the winter, a dose that makes many physicians uncomfortable. PMID

  7. Essential fatty acid deficiency in mice impairs lactose digestion.

    PubMed

    Lukovac, S; Los, E L; Stellaard, F; Rings, E H H M; Verkade, H J

    2008-09-01

    Essential fatty acid (EFA) deficiency in mice induces fat malabsorption. We previously reported indications that the underlying mechanism is located at the level of the intestinal mucosa. We have investigated the effects of EFA deficiency on small intestinal morphology and function. Mice were fed an EFA-deficient or control diet for 8 wk. A 72-h fat balance, the EFA status, and small intestinal histology were determined. Carbohydrate absorptive and digestive capacities were assessed by stable isotope methodology after administration of [U-(13)C]glucose and [1-(13)C]lactose. The mRNA expression and enzyme activity of lactase, and concentrations of the EFA linoleic acid (LA) were measured in small intestinal mucosa. Mice fed the EFA-deficient diet were markedly EFA-deficient with a profound fat malabsorption. EFA deficiency did not affect the histology or proliferative capacity of the small intestine. Blood [13C6]glucose appearance and disappearance were similar in both groups, indicating unaffected monosaccharide absorption. In contrast, blood appearance of [13C]glucose, originating from [1-(13)C]lactose, was delayed in EFA-deficient mice. EFA deficiency profoundly reduced lactase activity (-58%, P<0.01) and mRNA expression (-55%, P<0.01) in mid-small intestine. Both lactase activity and its mRNA expression strongly correlated with mucosal LA concentrations (r=0.77 and 0.79, respectively, P<0.01). EFA deficiency in mice inhibits the capacity to digest lactose but does not affect small intestinal histology. These data underscore the observation that EFA deficiency functionally impairs the small intestine, which in part may be mediated by low LA levels in the enterocytes. PMID:18653724

  8. Iron deficiency anemia in celiac disease

    PubMed Central

    Freeman, Hugh James

    2015-01-01

    Iron is an important micronutrient that may be depleted in celiac disease. Iron deficiency and anemia may complicate well-established celiac disease, but may also be the presenting clinical feature in the absence of diarrhea or weight loss. If iron deficiency anemia occurs, it should be thoroughly evaluated, even if celiac disease has been defined since other superimposed causes of iron deficiency anemia may be present. Most often, impaired duodenal mucosal uptake of iron is evident since surface absorptive area in the duodenum is reduced, in large part, because celiac disease is an immune-mediated disorder largely focused in the proximal small intestinal mucosa. Some studies have also suggested that blood loss may occur in celiac disease, sometimes from superimposed small intestinal disorders, including ulceration or neoplastic diseases, particularly lymphoma. In addition, other associated gastric or colonic disorders may be responsible for blood loss. Rarely, an immune-mediated hemolytic disorder with increased urine iron loss may occur that may respond to a gluten-free diet. Reduced expression of different regulatory proteins critical in iron uptake has also been defined in the presence and absence of anemia. Finally, other rare causes of microcytic anemia may occur in celiac disease, including a sideroblastic form of anemia reported to have responded to a gluten-free diet. PMID:26309349

  9. Symptomatic zinc deficiency in experimental zinc deprivation.

    PubMed Central

    Taylor, C M; Goode, H F; Aggett, P J; Bremner, I; Walker, B E; Kelleher, J

    1992-01-01

    An evaluation of indices of poor zinc status was undertaken in five male subjects in whom dietary zinc intake was reduced from 85 mumol d-1 in an initial phase of the study to 14 mumol d-1. One of the subjects developed features consistent with zinc deficiency after receiving the low zinc diet for 12 days. These features included retroauricular acneform macullo-papular lesions on the face, neck, and shoulders and reductions in plasma zinc, red blood cell zinc, neutrophil zinc and plasma alkaline phosphatase activity. Alcohol induced hepatitis, which was suspected in this subject, may have caused a predisposition to altered zinc metabolism and possible zinc deficiency which was exacerbated by subsequent zinc deprivation. The report supports the value of neutrophil zinc concentration as an indicator of poor zinc status. PMID:1740525

  10. Caspase 1 deficiency reduces inflammation-induced brain transcription

    PubMed Central

    Mastronardi, Claudio; Whelan, Fiona; Yildiz, Ozlem A.; Hannestad, Jonas; Elashoff, David; McCann, Samuel M.; Licinio, Julio; Wong, Ma-Li

    2007-01-01

    The systemic inflammatory response syndrome (SIRS) is a life-threatening medical condition characterized by a severe and generalized inflammatory state that can lead to multiple organ failure and shock. The CNS regulates many features of SIRS such as fever, cardiovascular, and neuroendocrine responses. Central and systemic manifestations of SIRS can be induced by LPS or IL-1β administration. The crucial role of IL-1β in inflammation has been further highlighted by studies of mice lacking caspase 1 (casp1, also known as IL-1β convertase), a protease that cleaves pro-IL-1β into mature IL-1β. Indeed, casp1 knockout (casp1−/−) mice survive lethal doses of LPS. The key role of IL-1β in sickness behavior and its de novo expression in the CNS during inflammation led us to test the hypothesis that IL-1β plays a major role modulating the brain transcriptome during SIRS. We show a gene–environment effect caused by LPS administration in casp1−/− mice. During SIRS, the expression of several genes, such as chemokines, GTPases, the metalloprotease ADAMTS1, IL-1RA, the inducible nitric oxide synthase, and cyclooxygenase-2, was differentially increased in casp1−/− mice. Our findings may contribute to the understanding of the molecular changes that take place within the CNS during sepsis and SIRS and the development of new therapies for these serious conditions. Our results indicate that those genes may also play a role in several neuropsychiatric conditions in which inflammation has been implicated and indicate that casp1 might be a potential therapeutic target for such disorders. PMID:17409187

  11. Basic Skills: Dealing with Deficiencies.

    ERIC Educational Resources Information Center

    New Mexico State Univ., Las Cruces.

    Research findings on college instruction and basic skills deficiencies are discussed in 12 papers from the first Regional Conference on University Teaching. Titles and authors are as follows: "Basic Skills: Dealing with Deficiencies" (Susanne D. Roueche, with responses by Gary B. Donart, Betty Harris, and James Nordyke); "Is Higher Education an…

  12. Iron deficiency anemia in children.

    PubMed

    Subramaniam, Girish; Girish, Meenakshi

    2015-06-01

    Iron deficiency is not just anemia; it can be responsible for a long list of other manifestations. This topic is of great importance, especially in infancy and early childhood, for a variety of reasons. Firstly, iron need is maximum in this period. Secondly, diet in infancy is usually deficient in iron. Thirdly and most importantly, iron deficiency at this age can result in neurodevelopmental and cognitive deficits, which may not be reversible. Hypochromia and microcytosis in a complete blood count (CBC) makes iron deficiency anemia (IDA) most likely diagnosis. Absence of response to iron should make us look for other differential diagnosis like β thalassemia trait and anemia of chronic disease. Celiac disease is the most important cause of true IDA not responding to oral iron therapy. While oral ferrous sulphate is the cheapest and most effective therapy for IDA, simple nonpharmacological and pharmacological measures can go a long way in prevention of iron deficiency. PMID:25636824

  13. Are brain and heart tissue prone to the development of thiamine deficiency?

    PubMed

    Klooster, Astrid; Larkin, James R; Wiersema-Buist, Janneke; Gans, Reinold O B; Thornalley, Paul J; Navis, Gerjan; van Goor, Harry; Leuvenink, Henri G D; Bakker, Stephan J L

    2013-05-01

    Thiamine deficiency is a continuing problem leading to beriberi and Wernicke's encephalopathy. The symptoms of thiamine deficiency develop in the heart, brain and neuronal tissue. Yet, it is unclear how rapid thiamine deficiency develops and which organs are prone to development of thiamine deficiency. We investigated these issues in a thiamine deficient animal model. Twenty-four male Lewis rats were fed a thiamine deficient diet, which contained 0.04% of normal thiamine intake. Six control rats were fed 200 μg of thiamine per day. Every week a group of six rats on the thiamine-deficient diet was sacrificed and blood, urine and tissue were stored. Blood and tissue transketolase activity, thiamine and thiamine metabolites were measured and PCR of thiamine transporter-1 (ThTr-1) was performed. Transketolase activity was significantly reduced in red blood cells, liver, lung, kidney and spleen tissue after two weeks of thiamine deficient diet. In brain tissue, transketolase activity was not reduced after up to four weeks of thiamine deficient diet. The amount of thiamine pyrophosphate was also significantly conserved in brain and heart tissue (decrease of 31% and 28% respectively), compared to other tissues (decrease of ~70%) after four weeks of thiamine deficient diet. There was no difference between tissues in ThTr-1 expression after four weeks of thiamine deficient diet. Despite the fact that the heart and the brain are predilection sites for complications from thiamine deficiency, these tissues are protected against thiamine deficiency. Other organs could be suffering from thiamine deficiency without resulting in clinical signs of classic thiamine deficiency in beriberi and Wernicke's encephalopathy. PMID:23357554

  14. Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice

    PubMed Central

    Li, Yanli; Gao, Rufei; Liu, Xueqing; Chen, Xuemei; Liao, Xinggui; Geng, Yanqing; Ding, Yubin; Wang, Yingxiong; He, Junlin

    2015-01-01

    The mechanism of birth defects induced by folate deficiency was focused on mainly in fetal development. Little is known about the effect of folate deficiency on the maternal uterus, especially on decidual angiogenesis after implantation which establishes vessel networks to support embryo development. The aim of this study was to investigate the effects of folate deficiency on decidual angiogenesis. Serum folate levels were measured by electrochemiluminescence. The status of decidual angiogenesis was examined by cluster designation 34 (CD34) immunohistochemistry and the expression of angiogenic factors, including vascular endothelial growth factor A (VEGFA), placental growth factor (PLGF), and VEGF receptor 2 (VEGFR2) were also tested. Serum levels of homocysteine (Hcy), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), and estradiol (E2) were detected by Enzyme-linked immunosorbent assay. The folate-deficient mice had a lower folate level and a higher Hcy level. Folate deficiency restrained decidual angiogenesis with significant abnormalities in vascular density and the enlargement and elongation of the vascular sinus. It also showed a reduction in the expressions of VEGFA, VEGFR2, and PLGF. In addition, the serum levels of P4, E2, LH, and PRL were reduced in folate-deficient mice, and the expression of progesterone receptor (PR) and estrogen receptor α (ERα) were abnormal. These results indicated that folate deficiency could impaire decidual angiogenesis and it may be related to the vasculotoxic properties of Hcy and the imbalance of the reproductive hormone. PMID:26247969

  15. Determining Functional Vitamin B12 Deficiency in the Elderly

    PubMed Central

    Khodabandehloo, Niloofar; Vakili, Masoud; Hashemian, Zahra; Zare Zardini, Hadi

    2015-01-01

    Background: Elevated concentration of serum total homocysteine usually occurs in vitamin B-12 deficiency. This metabolite can be measured and used for screening functional vitamin B-12 deficiency. Objectives: We assessed functional vitamin B12 deficiency in Tehranian elderly admitted to elderly research center, University of Social Welfare and Rehabilitation Sciences. Patients and Materials: A cross-sectional study was performed on 232 elderly admitted to elderly research center in Tehran, Iran in 2012. According to other studies, individuals were classified into two groups: high risk of vitamin B-12 deficiency (< 220 pmol/L) and borderline vitamin B-12 (220–258 pmol/L) accompanied by elevated homocysteine (> 15 micmol/L). Results: Cut-off of 15.0 pmol/L for homocysteine was identified for persons with normal or elevated concentrations. Among persons aged 65–74 and ≥ 75 years, respectively, 56% and 93% were at high risk of vitamin B-12 deficiency. Conclusions: The prevalence of B12 deficiency was higher in this study compared to other studies, so more attention and massive efficacious policy should be designed to reduce the deficiency of this vitamin. PMID:26430518

  16. Interactions between copper deficiency, selenium deficiency and adriamycin toxicity

    SciTech Connect

    Fischer, J.; Tackett, R.; Johnson, M.A. )

    1991-03-15

    The objective of this study was to test the hypothesis that there are interactions between copper (Cu) and selenium (Se) status, and adriamycin (ADR) toxicity. Male Sprague Dawley rats were fed Cu,Se adequate; Cu deficient, Se adequate ({minus}Cu); Cu adequate, Se deficient; or Cu,Se deficient diets for 38-41 days. ADR or saline (SAL) were administered weekly for the last 4 weeks of the study. Cu deficiency was confirmed by a 3-fold decrease in liver Cu,Zn-superoxide dismutase and liver Cu, and a 5-fold decrease in RBC Cu,Zn-SOD. Se deficiency was confirmed by a 10-fold decrease in liver glutathione peroxidase (GSH-Px). ADR, Cu deficiency and Se deficiency all caused EKG abnormalities. However, Cu and Se deficiencies did not enhance ADR's influence on EKGs. ADR increased lipid peroxidation in liver by 15% and in heart by 18% (NS). Cu deficiency decreased ADR-induced lipid peroxidation in heart tissue by 25%. ADR influenced Se status by significantly increasing heart GSH-Px, and Cu status by increasing liver Cu, plasma ceruloplasmin and liver Cu, Zn-SOD. These elevations in Cu,Zn-SOD and GSH-Px may be a consequence of the increased lipid peroxidation initiated by ADR. In {minus}Cu rats, ADR caused severe hemolytic anemia characterized by a 19% decrease in hematocrit and a 17-fold increase in splenic Fe. These data suggest that there are numerous interactions between ADR toxicity and Cu and Se status.

  17. Osteopontin deficiency reduces kidney damage from hypercholesterolemia in Apolipoprotein E-deficient mice

    PubMed Central

    Pei, Zouwei; Okura, Takafumi; Nagao, Tomoaki; Enomoto, Daijiro; Kukida, Masayoshi; Tanino, Akiko; Miyoshi, Ken-ichi; Kurata, Mie; Higaki, Jitsuo

    2016-01-01

    Hypercholesterolemia is a well-established risk factor for kidney injury, which can lead to chronic kidney disease (CKD). Osteopontin (OPN) has been implicated in the pathology of several renal conditions. This study was to evaluate the effects of OPN on hypercholesterolemia induced renal dysfunction. Eight-week-old male mice were divided into 4 groups: apolipoprotein E knockout (ApoE−/−) and ApoE/OPN knockout (ApoE−/−/OPN−/−) mice fed a normal diet (ND) or high cholesterol diet (HD). After 4 weeks, Periodic acid-Schiff (PAS) and oil red O staining revealed excessive lipid deposition in the glomeruli of ApoE−/−HD mice, however, significantly suppressed in ApoE−/−/OPN−/−HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression was lower in the glomeruli of ApoE−/−/OPN−/−HD mice than ApoE−/−HD mice. In vitro study, primary mesangial cells were incubated with recombinant mouse OPN (rmOPN). RmOPN induced LOX-1 mRNA and protein expression in primary mesangial cells. Pre-treatment with an ERK inhibitor suppressed the LOX-1 gene expression induced by rmOPN. These results indicate that OPN contributes to kidney damage in hypercholesterolemia and suggest that inhibition of OPN may provide a potential therapeutic target for the prevention of hypercholesterolemia. PMID:27353458

  18. Osteopontin deficiency reduces kidney damage from hypercholesterolemia in Apolipoprotein E-deficient mice.

    PubMed

    Pei, Zouwei; Okura, Takafumi; Nagao, Tomoaki; Enomoto, Daijiro; Kukida, Masayoshi; Tanino, Akiko; Miyoshi, Ken-Ichi; Kurata, Mie; Higaki, Jitsuo

    2016-01-01

    Hypercholesterolemia is a well-established risk factor for kidney injury, which can lead to chronic kidney disease (CKD). Osteopontin (OPN) has been implicated in the pathology of several renal conditions. This study was to evaluate the effects of OPN on hypercholesterolemia induced renal dysfunction. Eight-week-old male mice were divided into 4 groups: apolipoprotein E knockout (ApoE(-/-)) and ApoE/OPN knockout (ApoE(-/-)/OPN(-/-)) mice fed a normal diet (ND) or high cholesterol diet (HD). After 4 weeks, Periodic acid-Schiff (PAS) and oil red O staining revealed excessive lipid deposition in the glomeruli of ApoE(-/-)HD mice, however, significantly suppressed in ApoE(-/-)/OPN(-/-)HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression was lower in the glomeruli of ApoE(-/-)/OPN(-/-)HD mice than ApoE(-/-)HD mice. In vitro study, primary mesangial cells were incubated with recombinant mouse OPN (rmOPN). RmOPN induced LOX-1 mRNA and protein expression in primary mesangial cells. Pre-treatment with an ERK inhibitor suppressed the LOX-1 gene expression induced by rmOPN. These results indicate that OPN contributes to kidney damage in hypercholesterolemia and suggest that inhibition of OPN may provide a potential therapeutic target for the prevention of hypercholesterolemia. PMID:27353458

  19. Genetics Home Reference: glucose phosphate isomerase deficiency

    MedlinePlus

    ... Me Understand Genetics Home Health Conditions GPI deficiency glucose phosphate isomerase deficiency Enable Javascript to view the ... boxes. Download PDF Open All Close All Description Glucose phosphate isomerase (GPI) deficiency is an inherited disorder ...

  20. Genetics Home Reference: adenosine deaminase 2 deficiency

    MedlinePlus

    ... Health Conditions adenosine deaminase 2 deficiency adenosine deaminase 2 deficiency Enable Javascript to view the expand/collapse ... PDF Open All Close All Description Adenosine deaminase 2 (ADA2) deficiency is a disorder characterized by abnormal ...

  1. What Causes Alpha-1 Antitrypsin Deficiency?

    MedlinePlus

    ... from the NHLBI on Twitter. What Causes Alpha-1 Antitrypsin Deficiency? Alpha-1 antitrypsin (AAT) deficiency is an inherited disease. "Inherited" ... have AAT deficiency inherit two faulty AAT genes, one from each parent. These genes tell cells in ...

  2. Monocular Elevation Deficiency - Double Elevator Palsy

    MedlinePlus

    ... Español Condiciones Chinese Conditions Monocular Elevation Deficiency/ Double Elevator Palsy En Español Read in Chinese What is monocular elevation deficiency (Double Elevator Palsy)? Monocular Elevation Deficiency, also known by the ...

  3. Genetics Home Reference: protein C deficiency

    MedlinePlus

    ... Understand Genetics Home Health Conditions protein C deficiency protein C deficiency Enable Javascript to view the expand/ ... boxes. Download PDF Open All Close All Description Protein C deficiency is a disorder that increases the ...

  4. Genetics Home Reference: protein S deficiency

    MedlinePlus

    ... Me Understand Genetics Home Health Conditions protein S deficiency protein S deficiency Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Protein S deficiency is a disorder of blood clotting. People ...

  5. Genetics Home Reference: factor V deficiency

    MedlinePlus

    ... Genetics Home Health Conditions factor V deficiency factor V deficiency Enable Javascript to view the expand/collapse ... Download PDF Open All Close All Description Factor V deficiency is a rare bleeding disorder. The signs ...

  6. Genetics Home Reference: isolated growth hormone deficiency

    MedlinePlus

    ... Health Conditions isolated growth hormone deficiency isolated growth hormone deficiency Enable Javascript to view the expand/collapse ... PDF Open All Close All Description Isolated growth hormone deficiency is a condition caused by a severe ...

  7. Does Vitamin C Deficiency Affect Cognitive Development and Function?

    PubMed Central

    Hansen, Stine Normann; Tveden-Nyborg, Pernille; Lykkesfeldt, Jens

    2014-01-01

    Vitamin C is a pivotal antioxidant in the brain and has been reported to have numerous functions, including reactive oxygen species scavenging, neuromodulation, and involvement in angiogenesis. Absence of vitamin C in the brain has been shown to be detrimental to survival in newborn SVCT2(−/−) mice and perinatal deficiency have shown to reduce hippocampal volume and neuron number and cause decreased spatial cognition in guinea pigs, suggesting that maternal vitamin C deficiency could have severe consequences for the offspring. Furthermore, vitamin C deficiency has been proposed to play a role in age-related cognitive decline and in stroke risk and severity. The present review discusses the available literature on effects of vitamin C deficiency on the developing and aging brain with particular focus on in vivo experimentation and clinical studies. PMID:25244370

  8. Fatal cerebral edema associated with serine deficiency in CSF.

    PubMed

    Keularts, Irene M L W; Leroy, Piet L J M; Rubio-Gozalbo, Estela M; Spaapen, Leo J M; Weber, Biene; Dorland, Bert; de Koning, Tom J; Verhoeven-Duif, Nanda M

    2010-12-01

    Two young girls without a notable medical history except for asthma presented with an acute toxic encephalopathy with very low serine concentrations both in plasma and cerebrospinal fluid (CSF) comparable to patients with 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency. Clinical symptoms and enzyme measurement (in one patient) excluded 3-PGDH deficiency. Deficiencies in other serine biosynthesis enzymes were highly unlikely on clinical grounds. On basis of the fasting state, ketone bodies and lactate in plasma, urine and CSF, we speculate that reduced serine levels were due to its use as gluconeogenic substrate, conversion to pyruvate by brain serine racemase or decreased L-serine production because of a lack of glucose. These are the first strikingly similar cases of patients with a clear secondary serine deficiency associated with a toxic encephalopathy. PMID:20300853

  9. [Physiopathology of iodine deficiency].

    PubMed

    Pinchera, A; Rago, T; Vitti, P

    1998-01-01

    The process of goitrogenesis is likely to be the consequence of an increased TSH stimulation linked to an initial reduction of circulating thyroid hormone caused by iodine deficiency (ID). Other growth factors associated to TSH may have a role in the pathogenesis of goiter. Natural history of goiter is the evolution towards nodularity and functional autonomy. This phenomenon is due to the heterogeneity of thyroid follicular cells, some of which, with an intrinsic elevated growth rate, under the stimulation of ID progress to nodule formation and hyperfunction. In multinodular goiter TSH receptor mutations activating adenylate cyclase-cAMP pathway were found. In a recent epidemiological survey it was shown that nodular goiter increased with the age, being about 1% in schoolchildren and 23% in the adults (56-75 years). Also nodular autonomy and hyperthyroidism were more frequent in the 36-75 year age group. Severe ID is also cause of endemic cretinism. In Europe minor neuropsychological impairments and cognitive deficits were described in areas of moderate ID. The exposure to a mild ID during fetal life causes minor neuropsychological damage. In conclusion, ID is responsible of goiter and its evolution towards nodularity and functional autonomy. Severe ID is also cause of endemic cretinism, while cognitive deficits and minor neuropsychological impairments were found in mild to moderate ID. PMID:10052165

  10. Iodine deficiency disorders.

    PubMed

    Elliott, T C

    1987-01-01

    Iodine deficiency disorder (IDD) affects 800 million people in the world, yet iodine supplementation is one of the most cost-effective nutritional interventions known. Iodine is incorporated into thyroid hormones, necessary for regulating metabolic rate, growth, and development of the brain and nervous system. IDD may appear as goiter in adults, usually not a serious problem, or in cretinism in children, which is marked by severe mental and physical retardation, with irreversible hearing and speech defects and either deaf-mutism, squint and paralysis, or stunting and edema. Children supplemented by age 1 or 2 can sometimes be helped. Foods contain variable amounts of iodine dependent on the soil where they are grown, hence mountainous and some inland regions have high goiter and IDD incidence. There are also goitrogenic foods, typically those of the cabbage family. Diagnosis is clinical or by blood tests for thyroid hormone levels and ratios. Finger-stick methods are available. Prevention of IDD is simple with either iodized salt or flour, iodinated central water supplies, injectable or oral iodine-containing oil. All cost about $.04 per person per year, except injections, which cost about $1 per person, but have the advantage that they could be combined with immunizations. Local problems with supplements are loss of iodine in salt with storage in tropics, and local production of cheaper uniodinated salt. Emphasis should be given to pregnant women and young children. There is no harm in giving pregnant women iodine injections in 2nd or 3rd trimester. PMID:12343033

  11. α1-Antitrypsin deficiency.

    PubMed

    Greene, Catherine M; Marciniak, Stefan J; Teckman, Jeffrey; Ferrarotti, Ilaria; Brantly, Mark L; Lomas, David A; Stoller, James K; McElvaney, Noel G

    2016-01-01

    α1-Antitrypsin deficiency (A1ATD) is an inherited disorder caused by mutations in SERPINA1, leading to liver and lung disease. It is not a rare disorder but frequently goes underdiagnosed or misdiagnosed as asthma, chronic obstructive pulmonary disease (COPD) or cryptogenic liver disease. The most frequent disease-associated mutations include the S allele and the Z allele of SERPINA1, which lead to the accumulation of misfolded α1-antitrypsin in hepatocytes, endoplasmic reticulum stress, low circulating levels of α1-antitrypsin and liver disease. Currently, there is no cure for severe liver disease and the only management option is liver transplantation when liver failure is life-threatening. A1ATD-associated lung disease predominately occurs in adults and is caused principally by inadequate protease inhibition. Treatment of A1ATD-associated lung disease includes standard therapies that are also used for the treatment of COPD, in addition to the use of augmentation therapy (that is, infusions of human plasma-derived, purified α1-antitrypsin). New therapies that target the misfolded α1-antitrypsin or attempt to correct the underlying genetic mutation are currently under development. PMID:27465791

  12. Betaine Deficiency in Maize 1

    PubMed Central

    Lerma, Claudia; Rich, Patrick J.; Ju, Grace C.; Yang, Wen-Ju; Hanson, Andrew D.; Rhodes, David

    1991-01-01

    Maize (Zea mays L.) is a betaine-accumulating species, but certain maize genotypes lack betaine almost completely; a single recessive gene has been implicated as the cause of this deficiency (D Rhodes, PJ Rich [1988] Plant Physiol 88: 102-108). This study was undertaken to determine whether betaine deficiency in diverse maize germplasm is conditioned by the same genetic locus, and to define the biochemical lesion(s) involved. Complementation tests indicated that all 13 deficient genotypes tested shared a common locus. One maize population (P77) was found to be segregating for betaine deficiency, and true breeding individuals were used to produce related lines with and without betaine. Leaf tissue of both betaine-positive and betaine-deficient lines readily converted supplied betaine aldehyde to betaine, but only the betaine-containing line was able to oxidize supplied choline to betaine. This locates the lesion in betaine-deficient plants at the choline → betaine aldehyde step of betaine synthesis. Consistent with this location, betaine-deficient plants were shown to have no detectable endogenous pool of betaine aldehyde. PMID:16668098

  13. Iron may play a role in pancreatic atrophy in copper deficiency

    SciTech Connect

    Fields, M.; Lewis, C.G.; Lure, M.D. Dept. of Agriculture, Beltsville, MD Univ. of Maryland, College Park )

    1991-03-15

    The present study was undertaken to determine if pancreatic atrophy in copper deficient rats fed fructose is associated with excessive iron deposition. Weanling male and female rats were fed a copper deficient or copper adequate diet containing 62% carbohydrate as either fructose or starch. Another group of weanling rats consumed a copper deficient diet containing fructose that was low in iron. After consuming their respective diets for five weeks, the highest pancreatic iron concentration was seen in male rats consuming the copper deficient diet containing fructose. These animals also exhibited pancreatic atrophy. In contrast, neither copper deficient female rats fed fructose nor males fed starch exhibited pancreatic atrophy and their pancreata did not contain high levels of iron. In addition, reducing the availability of dietary iron in copper deficient rats fed fructose decreased pancreatic iron concentration and ameliorated the pathology. The data suggest that pancreatic atrophy in copper deficiency may be related to iron deposition in that tissue.

  14. Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden death. Physiopathological approach to carnitine palmitoyltransferase II deficiencies.

    PubMed Central

    Demaugre, F; Bonnefont, J P; Colonna, M; Cepanec, C; Leroux, J P; Saudubray, J M

    1991-01-01

    Reported cases of carnitine palmitoyltransferase II (CPT II) deficiency are characterized only by a muscular symptomatology in young adults although the defect is expressed in extra-muscular tissues as well as in skeletal muscle. We describe here a CPT II deficiency associating hypoketotic hypoglycemia, high plasma creatine kinase level, heart beat disorders, and sudden death in a 3-mo-old boy. CPT II defect (-90%) diagnosed in fibroblasts is qualitatively similar to that (-75%) of two "classical" CPT II-deficient patients previously studied: It resulted from a decreased amount of CPT II probably arising from its reduced biosynthesis. Consequences of CPT II deficiency studied in fibroblasts differed in both sets of patients. An impaired oxidation of long-chain fatty acids was found in the proband but not in patients with the "classical" form of the deficiency. The metabolic and clinical consequences of CPT II deficiency might depend, in part, on the magnitude of residual CPT II activity. With 25% residual activity CPT II would become rate limiting in skeletal muscle but not in liver, heart, and fibroblasts. As observed in the patient described herein, CPT II activity ought to be more reduced to induce an impaired oxidation of long-chain fatty acids in these tissues. Images PMID:1999498

  15. "Myelodysplasia," myeloneuropathy, and copper deficiency.

    PubMed

    Kumar, Neeraj; Elliott, Michelle A; Hoyer, James D; Harper, Charles M; Ahlskog, J Eric; Phyliky, Robert L

    2005-07-01

    We describe a patient with a suspected myelodysplastic syndrome that developed in association with a neurologic disorder resembling subacute combined degeneration but without vitamin B12 deficiency. Ultimately, the hematologic manifestations and the neurologic syndrome were linked to severe copper deficiency. Prompt and complete reversal of the hematologic abnormalities occurred with copper replacement. Serum copper determination should be included in the work-up of patients with anemia and leukopenia of unclear etiology who have associated myeloneuropathy. The hematologic picture can resemble sideroblastic anemia or myelodysplastic syndrome. Hyperzincemia can be an accompanying abnormality even without exogenous zinc ingestion. The reason for the copper deficiency may not be evident. PMID:16007901

  16. Clinical manifestations of zinc deficiency.

    PubMed

    Prasad, A S

    1985-01-01

    The essentiality of zinc for humans was recognized in the early 1960s. The causes of zinc deficiency include malnutrition, alcoholism, malabsorption, extensive burns, chronic debilitating disorders, chronic renal diseases, following uses of certain drugs such as penicillamine for Wilson's disease and diuretics in some cases, and genetic disorders such as acrodermatitis enteropathica and sickle cell disease. In pregnancy and during periods of growth the requirement of zinc is increased. The clinical manifestations in severe cases of zinc deficiency include bullous-pustular dermatitis, alopecia, diarrhea, emotional disorder, weight loss, intercurrent infections, hypogonadism in males; it is fatal if unrecognized and untreated. A moderate deficiency of zinc is characterized by growth retardation and delayed puberty in adolescents, hypogonadism in males, rough skin, poor appetite, mental lethargy, delayed wound healing, taste abnormalities, and abnormal dark adaptation. In mild cases of zinc deficiency in human subjects, we have observed oligospermia, slight weight loss, and hyperammonemia. Zinc is a growth factor. Its deficiency adversely affects growth in many animal species and humans. Inasmuch as zinc is needed for protein and DNA synthesis and for cell division, it is believed that the growth effect of zinc is related to its effect on protein synthesis. Whether or not zinc is required for the metabolism of somatomedin needs to be investigated in the future. Testicular functions are affected adversely as a result of zinc deficiency in both humans and experimental animals. This effect of zinc is at the end organ level; the hypothalamic-pituitary axis is intact in zinc-deficient subjects. Inasmuch as zinc is intimately involved in cell division, its deficiency may adversely affect testicular size and thus affect its functions. Zinc is required for the functions of several enzymes and whether or not it has an enzymatic role in steroidogenesis is not known at present

  17. Genetics of growth hormone deficiency.

    PubMed

    Mullis, Primus E

    2007-03-01

    When a child is not following the normal, predicted growth curve, an evaluation for underlying illness and central nervous system abnormalities is required and appropriate consideration should be given to genetic defects causing growth hormone (GH) deficiency. This article focuses on the GH gene, the various gene alterations, and their possible impact on the pituitary gland. Transcription factors regulating pituitary gland development may cause multiple pituitary hormone deficiency but may present initially as GH deficiency. The role of two most important transcription factors, POU1F1 (Pit-1) and PROP 1, is discussed. PMID:17336732

  18. [Immune deficiencies in nutritional anemias].

    PubMed

    Bonnet Gajdos, M; Navarro, J; Belas, F; Traineau, R

    1982-12-16

    A transient cellular immunologic defect caused by folic acid deficiency was seen in a goat-milk-fed infant with severe enterocolitis. Data on the immunologic consequences of folic acid, protein and iron deficiencies were reviewed in the medical literature. Investigations are difficult because of the patients' poor general condition. Results are difficult to interpret as many etiologic factors are often combined and mechanisms of immunologic responses are complex. Attention is drawn to the danger of iron therapy in patients with transferrin deficiency. PMID:6297076

  19. Ces3/TGH Deficiency Attenuates Steatohepatitis

    PubMed Central

    Lian, Jihong; Wei, Enhui; Groenendyk, Jody; Das, Subhash K.; Hermansson, Martin; Li, Lena; Watts, Russell; Thiesen, Aducio; Oudit, Gavin Y.; Michalak, Marek; Lehner, Richard

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in developed countries. NAFLD describes a wide range of liver pathologies from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is distinguished from simple steatosis by inflammation, cell death and fibrosis. In this study we found that mice lacking triacylglycerol hydrolase (TGH, also known as carboxylesterase 3 or carboxylesterase 1d) are protected from high-fat diet (HFD) - induced hepatic steatosis via decreased lipogenesis, increased fatty acid oxidation and improved hepatic insulin sensitivity. To examine the effect of the loss of TGH function on the more severe NAFLD form NASH, we ablated Tgh expression in two independent NASH mouse models, Pemt−/− mice fed HFD and Ldlr−/− mice fed high-fat, high-cholesterol Western-type diet (WTD). TGH deficiency reduced liver inflammation, oxidative stress and fibrosis in Pemt−/− mice. TGH deficiency also decreased NASH in Ldlr−/− mice. Collectively, these findings indicate that TGH deficiency attenuated both simple hepatic steatosis and irreversible NASH. PMID:27181051

  20. Correcting Systemic Deficiencies in Our Scientific Infrastructure

    PubMed Central

    Doss, Mohan

    2014-01-01

    Scientific method is inherently self-correcting. When different hypotheses are proposed, their study would result in the rejection of the invalid ones. If the study of a competing hypothesis is prevented because of the faith in an unverified one, scientific progress is stalled. This has happened in the study of low dose radiation. Though radiation hormesis was hypothesized to reduce cancers in 1980, it could not be studied in humans because of the faith in the unverified linear no-threshold model hypothesis, likely resulting in over 15 million preventable cancer deaths worldwide during the past two decades, since evidence has accumulated supporting the validity of the phenomenon of radiation hormesis. Since our society has been guided by scientific advisory committees that ostensibly follow the scientific method, the long duration of such large casualties is indicative of systemic deficiencies in the infrastructure that has evolved in our society for the application of science. Some of these deficiencies have been identified in a few elements of the scientific infrastructure, and remedial steps suggested. Identifying and correcting such deficiencies may prevent similar tolls in the future. PMID:24910580

  1. Ces3/TGH Deficiency Attenuates Steatohepatitis.

    PubMed

    Lian, Jihong; Wei, Enhui; Groenendyk, Jody; Das, Subhash K; Hermansson, Martin; Li, Lena; Watts, Russell; Thiesen, Aducio; Oudit, Gavin Y; Michalak, Marek; Lehner, Richard

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in developed countries. NAFLD describes a wide range of liver pathologies from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is distinguished from simple steatosis by inflammation, cell death and fibrosis. In this study we found that mice lacking triacylglycerol hydrolase (TGH, also known as carboxylesterase 3 or carboxylesterase 1d) are protected from high-fat diet (HFD) - induced hepatic steatosis via decreased lipogenesis, increased fatty acid oxidation and improved hepatic insulin sensitivity. To examine the effect of the loss of TGH function on the more severe NAFLD form NASH, we ablated Tgh expression in two independent NASH mouse models, Pemt(-/-) mice fed HFD and Ldlr(-/-) mice fed high-fat, high-cholesterol Western-type diet (WTD). TGH deficiency reduced liver inflammation, oxidative stress and fibrosis in Pemt(-/-) mice. TGH deficiency also decreased NASH in Ldlr(-/-) mice. Collectively, these findings indicate that TGH deficiency attenuated both simple hepatic steatosis and irreversible NASH. PMID:27181051

  2. Palmoplantar Keratoderma in Slurp2-Deficient Mice.

    PubMed

    Allan, Christopher M; Procaccia, Shiri; Tran, Deanna; Tu, Yiping; Barnes, Richard H; Larsson, Mikael; Allan, Bernard B; Young, Lorraine C; Hong, Cynthia; Tontonoz, Peter; Fong, Loren G; Young, Stephen G; Beigneux, Anne P

    2016-02-01

    SLURP1, a member of the lymphocyte antigen 6 protein family, is secreted by suprabasal keratinocytes. Mutations in SLURP1 cause a palmoplantar keratoderma (PPK) known as mal de Meleda. SLURP2, another secreted lymphocyte antigen 6 protein, is encoded by a gene located ?20 kb downstream from SLURP1. SLURP2 is produced by suprabasal keratinocytes. To investigate the importance of SLURP2, we first examined Slurp2 knockout mice in which exon 2-3 sequences had been replaced with lacZ and neo cassettes. Slurp2(-/-) mice exhibited hyperkeratosis on the volar surface of the paws (i.e., palmoplantar keratoderma), increased keratinocyte proliferation, and an accumulation of lipid droplets in the stratum corneum. They also exhibited reduced body weight and hind limb clasping. These phenotypes are similar to those of Slurp1(-/-) mice. To solidify a link between Slurp2 deficiency and palmoplantar keratoderma and to be confident that the disease phenotypes in Slurp2(-/-) mice were not secondary to the effects of the lacZ and neo cassettes on Slurp1 expression, we created a new line of Slurp2 knockout mice (Slurp2X(-/-)) in which Slurp2 was inactivated with a simple nonsense mutation. Slurp2X(-/-) mice exhibited the same disease phenotypes. Thus, Slurp2 deficiency and Slurp1 deficiencies cause the same disease phenotypes. PMID:26967477

  3. Palmoplantar keratoderma in Slurp2-deficient mice

    PubMed Central

    Allan, Christopher M.; Procaccia, Shiri; Tran, Deanna; Tu, Yiping; Barnes, Richard H.; Larsson, Mikael; Allan, Bernard B.; Young, Lorraine C.; Hong, Cynthia; Tontonoz, Peter; Fong, Loren G.; Young, Stephen G.; Beigneux, Anne P.

    2015-01-01

    SLURP1, a member of the Ly6 protein family, is secreted by suprabasal keratinocytes. Mutations in SLURP1 cause a palmoplantar keratoderma (PPK) known as mal de Meleda. Another secreted Ly6 protein, SLURP2, is encoded by a gene located ~20 kb downstream from SLURP1. SLURP2 is produced by suprabasal keratinocytes. To investigate the importance of SLURP2, we first examined Slurp2 knockout mice in which exon 2–3 sequences had been replaced with lacZ and neo cassettes. Slurp2−/− mice exhibited hyperkeratosis on the volar surface of the paws (i.e., PPK), increased keratinocyte proliferation, and an accumulation of lipid droplets in the stratum corneum. They also exhibited reduced body weight and hind limb clasping. These phenotypes are very similar to those of Slurp1−/− mice. To solidify a link between Slurp2 deficiency and PPK and to be confident that the disease phenotypes in Slurp2−/− mice were not secondary to the effects of the lacZ and neo cassettes on Slurp1 expression, we created a new line of Slurp2 knockout mice (Slurp2X−/−) in which Slurp2 was inactivated with a simple nonsense mutation. Slurp2X−/− mice exhibited the same disease phenotypes. Thus, Slurp2 deficiency and Slurp1 deficiencies cause the same disease phenotypes. PMID:26967477

  4. Zinc deficiency in molybdenum poisoned cattle

    SciTech Connect

    Parada, R.

    1981-02-01

    Clinical signs ascribable to zinc deficiency were noted in a group of Friesian cows industrially poisoned with molybdenum. Zinc, copper, and molybdenum were determined in blood serum and black hair, and in the contaminated alfalfa pasture the group grazed on. Hematological parameters, and serum calcium and alkaline phosphatase activity, were also determined. Pooled samples of alfalfa from 2 uncontaminated pastures, and of blood, serum and black hair of clinically normal Friesian cattle grazing on these were used as controls. A mixed contamination of the polluted pasture with molybdenum and copper was found, both metals being inversely correlated with he distance to the polluting chimney. Zinc concentrations were normal and not significantly correlated with the distance to the chimney very high molybdenum was found in serum and hair of the poisoned animals; copper was normal in serum and hair. Low calcium and Alkaline phosphatase activity were found in serum, both variables being significantly correlated with serum zinc. Reduced red blood cell number, packed cell volumes and hemoglobin concentrations were also found, but no significant correlation of these parameters with any of the trace metals in serum or hair was found. Signs ascribed to zinc deficiency were consistent with the reduction of zinc in serum and hair and decreased alkaline phosphatase activity in serum. A zinc deficiency conditioned by a simultaneous increased intake of molybdenum and copper is proposed.

  5. Genetics Home Reference: tetrahydrobiopterin deficiency

    MedlinePlus

    ... 3. Citation on PubMed Liu TT, Chiang SH, Wu SJ, Hsiao KJ. Tetrahydrobiopterin-deficient hyperphenylalaninemia in the ... Citation on PubMed Wang L, Yu WM, He C, Chang M, Shen M, Zhou Z, Zhang Z, ...

  6. Genetics Home Reference: arginase deficiency

    MedlinePlus

    ... deficiency is an inherited disorder that causes the amino acid arginine (a building block of proteins) and ammonia ... links) Encyclopedia: Hereditary urea cycle abnormality Health Topic: Amino Acid Metabolism Disorders Health Topic: Genetic Brain Disorders Health ...

  7. Genetics Home Reference: prekallikrein deficiency

    MedlinePlus

    ... a role in a process called the intrinsic coagulation pathway (also called the contact activation pathway). This ... functional plasma kallikrein, which likely impairs the intrinsic coagulation pathway. Researchers suggest that this lack (deficiency) of ...

  8. Genetics Home Reference: dihydropyrimidinase deficiency

    MedlinePlus

    ... An abnormally small head size ( microcephaly ) and autistic behaviors that affect communication and social interaction also occur ... deficiency MalaCards: dihydropyrimidinuria Merck Manual Professional Version: Pyrimidine ... Dihydropyrimidinuria Patient Support and Advocacy Resources ( ...

  9. Evolutionary Processes and Mental Deficiency

    ERIC Educational Resources Information Center

    Spitz, Herman H.

    1973-01-01

    The author hypothesizes that central nervous system damage of deficiency associated with mental retardation affects primarily those cortical processes which developed at a late stage in man's evolutionary history. (Author)

  10. [Niacin deficiency and cutaneous immunity].

    PubMed

    Ikenouchi-Sugita, Atsuko; Sugita, Kazunari

    2015-01-01

    Niacin, also known as vitamin B3, is required for the synthesis of coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin binds with G protein-coupled receptor (GPR) 109A on cutaneous Langerhans cells and causes vasodilation with flushing in head and neck area. Niacin deficiency due to excessive alcohol consumption, certain drugs or inadequate uptake in diet causes pellagra, a photosensitivity dermatitis. Recently several studies have revealed the mechanism of photosensitivity in niacin deficiency, which may pave a way for new therapeutic approaches. The expression level of prostaglandin E synthase (PTGES) is up-regulated in the skin of both pellagra patients and niacin deficient pellagra mouse models. In addition, pellagra is mediated through prostaglandin E₂-EP4 (PGE₂-EP4) signaling via reactive oxygen species (ROS) production in keratinocytes. In this article, we have reviewed the role of niacin in immunity and the mechanism of niacin deficiency-induced photosensitivity. PMID:25765687

  11. Detecting Alpha-1 Antitrypsin Deficiency.

    PubMed

    Stoller, James K

    2016-08-01

    Alpha-1 antitrypsin deficiency is a widely underrecognized condition, with evidence of persisting long diagnostic delays and patients' frequent need to see multiple physicians before initial diagnosis. Reasons for underrecognition include inadequate understanding of alpha-1 antitrypsin deficiency by physicians and allied health care providers; failure to implement available, guideline-based practice recommendations; and the belief that effective therapy is unavailable. Multiple studies have described both the results of screening and targeted detection of individuals with alpha-1 antitrypsin deficiency, with both varying strategies employed to identify at-risk individuals and varying results of testing. Also, various strategies to enhance detection of affected individuals have been examined, including use of the electronic medical record to prompt testing and empowerment of allied health providers, especially respiratory therapists, to promote testing for alpha-1 antitrypsin deficiency. Such efforts are likely to enhance detection with the expected result that the harmful effects of delayed diagnosis can be mitigated. PMID:27564667

  12. Genetics Home Reference: prothrombin deficiency

    MedlinePlus

    ... Patients and Caregivers: How Blood Clots Orphanet: Congenital factor II deficiency University of Iowa Health Care: Prothrombin Gene Mutation Patient Support and Advocacy Resources (2 links) Canadian Hemophilia Society National Hemophilia Foundation: Factor II ... Genetic Testing Registry (1 link) Prothrombin ...

  13. Cutaneous findings of nutritional deficiencies in children.

    PubMed

    Goskowicz, M; Eichenfield, L F

    1993-08-01

    Nutritional deficiencies may be associated with a variety of cutaneous findings in children. This review emphasizes new developments relating to cutaneous findings of nutritional deficiencies. Zinc deficiency, acrodermatitis enteropathica, and acrodermatitis enteropathica-like eruptions are seen with a variety of conditions including cystic fibrosis, anorexia nervosa, and breastfeeding. Similar cutaneous findings not related to zinc deficiency may also occur with such metabolic disorders as methylmalonic aciduria, multiple carboxylase deficiency, essential fatty acid deficiency and other amino acid deficiencies. Vitamin K deficiency is associated with hemorrhagic disease of the newborn and coagulopathy. Vitamin A deficiency presents with a variety of systemic findings and distinctive dermatologic findings. Acute vitamin A deficiency may be seen in children infected with measles and is associated with more severe disease. The systemic and cutaneous findings of vitamin C deficiency, scurvy, are discussed. PMID:8374671

  14. Zinc and its deficiency diseases.

    PubMed

    Evans, G W

    1986-01-01

    The pervasive role of zinc in the metabolic function of the body results from its function as a cofactor of a multitude of enzymes. Zinc is found in every tissue in the body, and because zinc metalloenzymes are found in every known class of enzymes, the metal has a function in every conceivable type of biochemical pathway. Symptoms resulting from zinc deficiency are as diverse as the enzymes with which the metal is associated. If chronic, severe, and untreated, zinc deficiency can be fatal. Less drastic symptoms include infections, hypogonadism, weight loss, emotional disturbance, dermatitis, alopecia, impaired taste acuity, night blindness, poor appetite, delayed wound healing, and elevated blood ammonia levels. Many symptoms of zinc deficiency result from poor diet consumption, but often the most severe symptoms result from other factors including excessive alcohol use, liver diseases, malabsorption syndromes, renal disease, enteral or parenteral alimentation, administration of sulfhydryl-containing drugs, and sickle cell disease. The most severe symptoms of zinc deficiency occur in young children affected with the autosomal-recessive trait, acrodermatitis enteropathica. This disease results in decreased synthesis of picolinic acid which causes an impaired ability to utilize zinc from common food. Because simple laboratory analyses are often not reliable in determining zinc nutriture of a patient, those symptoms caused by suspected zinc deficiency are best verified by the oral administration of zinc dipicolinate. This zinc compound is efficacious and safe and would provide an accurate means of identifying symptoms that do result from zinc deficiency. PMID:3514057

  15. [Effect of zinc deficiency on 3',5'-cyclic-AMP content and parameters of energy metabolism in the rat].

    PubMed

    Roth, H P; Kirchgessner, M

    1983-06-01

    Loss of appetite, strongly reduced feed intake, and stop in weight gain are characteristic signs of alimentary zinc deficiency. The present paper investigates some parameters of the energy metabolism of Zn-deficient rats in order to obtain information on possible disturbances. The blood of Zn-deficient rats showed an increased activity of adenosine triphosphatase (ATPase) in comparison to ad-libitum- and pair-fed control animals. Therefore the concentration of adenosine triphosphate (ATP) was reduced and the concentration of adenosine diphosphate (ADP) increased in deficient animals. As a consequence, the ratio ATP/ADP was strongly reduced in Zn-deficient rats compared with both control groups. The concentration of adenosine monophosphate (AMP) was reduced in the blood of Zn-deficient rats. The levels of c-AMP in serum and urine were markedly increased in Zn-deficient rats in comparison with both control groups. Key enzymes of energetic utilization of carbohydrates such as fructose-1.6-biphosphatase and glucose-6-phosphate dehydrogenase were reduced in their activities in livers and kidneys of Zn-deficient animals. The results show that alimentary Zn deficiency impairs some parameters of the energy metabolism. The problems of reduced feed intake in Zn deficiency still remain unsolved. PMID:6308919

  16. Nippostrongylus brasiliensis infection in the rat: effect of iron and protein deficiency on the anthelmintic efficacy of mebendazole, pyrantel, piperazine, and levamisole.

    PubMed Central

    Duncombe, V M; Bolin, T D; Davis, A E; Fagan, M R; Kelly, J D

    1979-01-01

    The benzimidazole anthelmintics mebendazole and fenbendazole have been shown to be much less effective against Nippostrongylus brasiliensis infections in the rat on a combined iron and protein deficient diet. In the present experiments it was shown that the anthelmintic efficacy of mebendazole was significantly impaired in the rat on either an iron deficient or a protein deficient diet. Furthermore, iron and protein deficiency reduced the efficacy of the anthelmintics pyrantel and piperazine but not levamisole. The finding that nutritional deficiencies reduce anthelmintic efficacy may well be relevant to worm eradication programmes in iron deficient and protein calorie malnourished populations. PMID:447110

  17. Response of protein C and protein C inhibitor to warfarin therapy in patient with combined deficiency of Factors V and VIII.

    PubMed

    Bern, M M; Suzuki, K; Mann, K; Tracy, P; Hoyer, L; Jensen, W; Gallivan, M; Arkin, C; Davis, G

    1984-12-15

    The role of Protein C in combined factor V/VIII deficiency was examined by reducing the Protein C concentration using warfarin therapy in a patient with the combined deficiency. The factor VIII deficiency was like Hemophilia-A, with deficiency of VIII:C and VIII:C(Ag), but normal VIIIR:Ag and VIIIR:cof. The factor V deficiency was due to loss of the V antigen. During warfarin therapy the Protein C level was reduced, but concentrations of factors V and VIII did not change. Protein C Inhibitor was normal throughout. Thus combined factor V/VIII deficiency is not related to Protein C levels. PMID:6098970

  18. A comparison of the effects of factor XII deficiency and prekallikrein deficiency on thrombus formation.

    PubMed

    Kokoye, Yasin; Ivanov, Ivan; Cheng, Qiufang; Matafonov, Anton; Dickeson, S Kent; Mason, Shauna; Sexton, Daniel J; Renné, Thomas; McCrae, Keith; Feener, Edward P; Gailani, David

    2016-04-01

    Studies with animal models implicate the plasma proteases factor XIIa (FXIIa) and α-kallikrein in arterial and venous thrombosis. As congenital deficiencies of factor XII (FXII) or prekallikrein (PK), the zymogens of FXIIa and α-kallikrein respectively, do not cause bleeding disorders, inhibition of these enzymes may have therapeutic benefit without compromising hemostasis. The relative contributions of FXIIa and α-kallikrein to thrombosis in animal models are not clear. We compared mice lacking FXII or PK to wild type mice in established models of arterial thrombosis. Wild type mice developed carotid artery occlusion when the vessel was exposed to a 3.5% solution of ferric chloride (FeCl3). FXII-deficient mice were resistant to occlusion at 5% FeCl3 and partially resistant at 10% FeCl3. PK-deficient mice were resistant at 3.5% FeCl3 and partially resistant at 5% FeCl3. Mice lacking high molecular weight kininogen, a cofactor for PK activation and activity, were also partially resistant to thrombosis at 5% FeCl3. Induction of carotid artery thrombosis with Rose Bengal was delayed in FXII-deficient mice compared to wild type or PK-deficient animals. In human plasma supplemented with silica, DNA or collagen to induce contact activation, an antibody to the FXIIa active site was more effective at preventing thrombin generation than an antibody to the α-kallikrein active site. Similarly, the FXIIa antibody was more effective at reducing fibrin formation in human blood flowing through collagen coated-tubes. The findings suggest that inhibitors of FXIIa will have more potent anti-thrombotic effects than inhibitors of α-kallikrein. PMID:26950760

  19. Spectra of normal and nutrient-deficient maize leaves

    NASA Technical Reports Server (NTRS)

    Al-Abbas, A. H.; Barr, R.; Hall, J. D.; Crane, F. L.; Baumgardner, M. F.

    1973-01-01

    Reflectance, transmittance and absorptance spectra of normal and six types of nutrient-deficient (N, P, K, S, Mg, and Ca) maize (Zea mays L.) leaves were analyzed at 30 selected wavelengths from 500 to 2600 nm. The analysis of variance showed significant differences in reflectance, transmittance and absorptance in the visible wavelengths among leaf numbers 3, 4, and 5, among the seven treatments, and among the interactions of leaf number and treatments. In the infrared wavelengths only treatments produced significant differences. The chlorophyll content of leaves was reduced in all nutrient-deficient treatments. Percent moisture was increased in S-, Mg-, and N-deficiencies. Polynomial regression analysis of leaf thickness and leaf moisture content showed that these two variables were significantly and directly related. Leaves from the P- and Ca-deficient plants absorbed less energy in the near infrared than the normal plants; S-, Mg-, K-, and N-deficient leaves absorbed more than the normal. Both S- and N-deficient leaves had higher temperatues than normal maize leaves.

  20. Mitochondrial respiration in hearts of copper-deficient rats

    SciTech Connect

    Bode, A.M.; Saari, J.T. USDA/ARS, Grand Forks, ND )

    1991-03-11

    Morphological observations indicate that dietary copper deficiency causes structural damage of cardiac mitochondria. The purpose of this study was to determine whether mitochondrial function is impaired as well. Male, weanling Sprague-Dawley rats were fed diets deficient or sufficient in copper for 4 wks. Copper deficiency was verified by measurement of plasma (ND (CuD) vs 0.46 {plus minus} 0.15 {mu}g/ml (CuS)) and kidney copper. Mitochondria were isolated and P/O ratio, state 3 and state 4 respiration rate and acceptor control index (ACI) were determined using succinate or pyruvate/malate as substrate. Determinations were made polarographically at 30C in a reaction medium consisting of 0.25 M sucrose, 0.1 mM EDTA, 200 mM MgCl and 200 mM sodium phosphate buffer. State 3 respiration rate in mitochondria from CuD hearts was 30% lower than in CuS mitochondria when succinate was used as substrate and 28% lower when pyruvate/malate was used. Copper deficiency reduced state 4 respiration rate by 31% when succinate was used and 16% when pyruvate/malate was used. P/O ratio and ACI were not significantly affected by copper deficiency. The observed decreases in respiration rates are consistent with decreased cytochrome c oxidase activity shown by others to occur in mitochondria isolated from hearts of copper-deficient rats.

  1. Intrinsic deficiencies of lectures as a teaching method.

    PubMed

    Pale, Predrag

    2013-06-01

    Lectures were, still are and seem to remain a dominant form of teaching, despite an increased research and use of other methods of teaching and leverage of technology aimed at improving teaching results and efficiency. Learning, as the result of a lecture, greatly depends on the subject, the competence and abilities of the lecturer as well as on other transient causes. However, lectures also have some intrinsic deficiencies as a teaching method pertinent to their very nature. In order to fully understand the teaching value of lectures and their role and proper use in educational systems, their deficiencies have been studied in a theoretical analysis from the perspective of cognitive learning theories. Fifteen deficiencies have been identified and clustered in three categories based on root causes of deficiencies: synchronicity problems, time constraint and individual student abilities, needs and knowledge. These findings can be used to adjust expected learning outcomes of lectures, to properly (re)design lecture content and process and to design other learning and teaching activities that would compensate and complement lectures. Recommendations are given on replacing and amending lectures with other instructional methods, amending lectures in the course of delivery with additional content and tools and complementing lectures after delivery with content, tools and activities. Suggestions on the use of information technology that could substitute, reduce or eliminate at least some of the deficiencies are made. Lecture captures seem to be valuable supplement for live lectures compensating in all three categories of deficiencies. Suggestions and directions for further research are given. PMID:23941004

  2. Proline synthesis in barley under iron deficiency and salinity.

    PubMed

    Arias-Baldrich, Cirenia; Bosch, Nadja; Begines, Digna; Feria, Ana B; Monreal, José A; García-Mauriño, Sofía

    2015-07-01

    This work investigates proline synthesis in six barley varieties subjected to iron deficiency, salinity or both stresses. The highest growth under Fe sufficiency corresponded to Belgrano and Shakira. A moderate augment of leaf phosphoenolpyruvate carboxylase (PEPC) activity was observed in all six varieties in response to Fe deficiency, consistently in leaves and sporadically in roots. All six varieties accumulated proline under Fe deficiency, to a higher extent in leaves than in roots. The decrease of Fe supply from 100 μM NaFe(III)-EDTA to 0.5 μM NaFe(III)-EDTA reduced growth and photosynthetic pigments similarly in the six barley varieties. On the contrary, differences between varieties could be observed with respect to increased or, conversely, decreased proline content as a function of the amount of NaFe(III)-EDTA supplied. These two opposite types were represented by Belgrano (higher proline under Fe deficiency) and Shakira (higher proline under Fe sufficiency). Time-course experiments suggested that leaf PEPC activity was not directly responsible for supplying C for proline synthesis under Fe deficiency. High proline levels in the leaves of Fe-deficient Belgrano plants in salinity were associated to a better performance of this variety under these combined stresses. PMID:26125122

  3. 33 CFR 154.1070 - Deficiencies.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... equipment or records maintained in connection with this subpart. (b) Deficiencies shall be corrected within... who disagrees with a deficiency issued by the COTP may appeal the deficiency to the cognizant COTP within 7 days or the time specified by the COTP to correct the deficiency, whichever is less. This...

  4. Genotyping the GGGCGG Tandem Repeat Promoter Polymorphism in the 5-Lipoxygenase Enzyme Gene (ALOX5) by Pyrosequencing Assay

    PubMed Central

    Schentrup, Anzeela M.; Allayee, Hooman; Lima, John J.; Johnson, Julie A.

    2009-01-01

    Aims: Efficient genotyping methods for many biologically significant repeat genetic polymorphisms, particularly in GC-rich regions of the genome, are limited. In particular, a short tandem repeat polymorphism [GGCGGG] in the promoter region of ALOX5 has been implicated as an important marker for inflammatory diseases. We developed a pyrosequencing assay to genotype the ALOX5 short tandem repeat polymorphism using pyrosequencing technology that will make assessing this important genetic marker in large, diverse populations more accessible than using current methods. Materials and Methods: We used a nested polymerase chain reaction approach to amplify DNA for pyrosequencing. Population allele frequencies were assessed in two cohorts of previously collected human DNA samples with 188 and 1032 samples, respectively. Sixteen genetic samples with known genotypes were used to confirm the accuracy of the method. Results and Discussion: Genotypes were 100% concordant with samples of known genotype. Genotype frequencies in European American, Hispanic, and African American agreed with previously published results (wild-type homozygotes 66%, 64%, and 19%, respectively). The method presented here will facilitate both genetic association and pharmacogenomic research on this polymorphism in large samples that are ethnically and/or racially admixed. PMID:19473080

  5. Dietary DHA reduces downstream endocannabinoid and inflammatory gene expression and epididymal fat mass while improving aspects of glucose use in muscle in C57BL/6J mice

    PubMed Central

    Kim, J; Carlson, M E; Kuchel, G A; Newman, J W; Watkins, B A

    2016-01-01

    Objectives: Endocannabinoid system (ECS) overactivation is associated with increased adiposity and likely contributes to type 2 diabetes risk. Elevated tissue cannabinoid receptor 1 (CB1) and circulating endocannabinoids (ECs) derived from the n-6 polyunsaturated acid (PUFA) arachidonic acid (AA) occur in obese and diabetic patients. Here we investigate whether the n-3 PUFA docosahexaenoic acid (DHA) in the diet can reduce ECS overactivation (that is, action of ligands, receptors and enzymes of EC synthesis and degradation) to influence glycemic control. This study targets the ECS tonal regulation of circulating glucose uptake by skeletal muscle as its primary end point. Design: Male C57BL/6J mice were fed a semipurified diet containing DHA or the control lipid. Serum, skeletal muscle, epididymal fat pads and liver were collected after 62 and 118 days of feeding. Metabolites, genes and gene products associated with the ECS, glucose uptake and metabolism and inflammatory status were measured. Results: Dietary DHA enrichment reduced epididymal fat pad mass and increased ECS-related genes, whereas it reduced downstream ECS activation markers, indicating that ECS activation was diminished. The mRNA of glucose-related genes and proteins elevated in mice fed the DHA diet with increases in DHA-derived and reductions in AA-derived EC and EC-like compounds. In addition, DHA feeding reduced plasma levels of various inflammatory cytokines, 5-lipoxygenase-dependent inflammatory mediators and the vasoconstrictive 20-HETE. Conclusions: This study provides evidence that DHA feeding altered ECS gene expression to reduce CB1 activation and reduce fat accretion. Furthermore, the DHA diet led to higher expression of genes associated with glucose use by muscle in mice, and reduced those associated with systemic inflammatory status. PMID:26219414

  6. Renalase deficiency aggravates ischemic myocardial damage.

    PubMed

    Wu, Yanling; Xu, Jianchao; Velazquez, Heino; Wang, Peili; Li, Guoyong; Liu, Dinggang; Sampaio-Maia, Benedita; Quelhas-Santos, Janete; Russell, Kerry; Russell, Raymond; Flavell, Richard A; Pestana, Manuel; Giordano, Frank; Desir, Gary V

    2011-04-01

    Chronic kidney disease (CKD) leads to an 18-fold increase in cardiovascular complications not fully explained by traditional risk factors. Levels of renalase, a recently discovered oxidase that metabolizes catecholamines, are decreased in CKD. Here we show that renalase deficiency in a mouse knockout model causes increased plasma catecholamine levels and hypertension. Plasma blood urea nitrogen, creatinine, and aldosterone were unaffected. However, knockout mice had normal systolic function and mild ventricular hypertrophy but tolerated cardiac ischemia poorly and developed myocardial necrosis threefold more severe than that found in wild-type mice. Treatment with recombinant renalase completely rescued the cardiac phenotype. To gain insight into the mechanisms mediating this cardioprotective effect, we tested if gene deletion affected nitrate and glutathione metabolism, but found no differences between hearts of knockout and wild-type mice. The ratio of oxidized (NAD) to reduced (NADH) nicotinamide adenine dinucleotide in cardiac tissue, however, was significantly decreased in the hearts of renalase knockout mice, as was plasma NADH oxidase activity. In vitro studies confirmed that renalase metabolizes NADH and catecholamines. Thus, renalase plays an important role in cardiovascular pathology and its replacement may reduce cardiac complications in renalase-deficient states such as CKD. PMID:21178975

  7. Interactions between zinc deficiency and environmental enteropathy in developing countries.

    PubMed

    Lindenmayer, Greta W; Stoltzfus, Rebecca J; Prendergast, Andrew J

    2014-01-01

    Zinc deficiency affects one-fifth of the world's population and leads to substantial morbidity and mortality. Environmental enteropathy (EE), a subclinical pathology of altered intestinal morphology and function, is almost universal among people living in developing countries and affects long-term growth and health. This review explores the overlapping nature of these 2 conditions and presents evidence for their interaction. EE leads to impaired zinc homeostasis, predominantly due to reduced absorptive capacity arising from disturbed intestinal architecture, and zinc deficiency exacerbates several of the proposed pathways that underlie EE, including intestinal permeability, enteric infection, and chronic inflammation. Ongoing zinc deficiency likely perpetuates the adverse outcomes of EE by worsening malabsorption, reducing intestinal mucosal immune responses, and exacerbating systemic inflammation. Although the etiology of EE is predominantly environmental, zinc deficiency may also have a role in its pathogenesis. Given the impact of both EE and zinc deficiency on morbidity and mortality in developing countries, better understanding the relation between these 2 conditions may be critical for developing combined interventions to improve child health. PMID:24425714

  8. Metabolic Adaptations of White Lupin Roots and Shoots under Phosphorus Deficiency

    PubMed Central

    Müller, Julia; Gödde, Victoria; Niehaus, Karsten; Zörb, Christian

    2015-01-01

    White lupin (Lupinus albus L.) is highly adapted to phosphorus-diminished soils. P-deficient white lupin plants modify their root architecture and physiology to acquire sparingly available soil phosphorus. We employed gas chromatography–mass spectrometry (GC-MS) for metabolic profiling of P-deficient white lupins, to investigate biochemical pathways involved in the P-acquiring strategy. After 14 days of P-deficiency, plants showed reduced levels of fructose, glucose, and sucrose in shoots. Phosphorylated metabolites such as glucose-6-phosphate, fructose-6-phosphate, myo-inositol-phosphate and glycerol-3-phosphate were reduced in both shoots and roots. After 22 days of P-deficiency, no effect on shoot or root sugar metabolite levels was found, but the levels of phosphorylated metabolites were further reduced. Organic acids, amino acids and several shikimate pathway products showed enhanced levels in 22-day-old P-deficient roots and shoots. These results indicate that P-deficient white lupins adapt their carbohydrate partitioning between shoot and root in order to supply their growing root system as an early response to P-deficiency. Organic acids are released into the rhizosphere to mobilize phosphorus from soil particles. A longer period of P-deficiency leads to scavenging of Pi from P-containing metabolites and reduced protein anabolism, but enhanced formation of secondary metabolites. The latter can serve as stress protection molecules or actively acquire phosphorus from the soil. PMID:26635840

  9. Developmental Vitamin D3 deficiency alters the adult rat brain.

    PubMed

    Féron, F; Burne, T H J; Brown, J; Smith, E; McGrath, J J; Mackay-Sim, A; Eyles, D W

    2005-03-15

    There is growing evidence that Vitamin D(3) (1,25-dihydroxyvitamin D(3)) is involved in brain development. We have recently shown that the brains of newborn rats from Vitamin D(3) deficient dams were larger than controls, had increased cell proliferation, larger lateral ventricles, and reduced cortical thickness. Brains from these animals also had reduced expression of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor. The aim of the current study was to examine if there were any permanent outcomes into adulthood when the offspring of Vitamin D(3) deficient dams were restored to a normal diet. The brains of adult rats were examined at 10 weeks of age after Vitamin D(3) deficiency until birth or weaning. Compared to controls animals that were exposed to transient early Vitamin D(3) deficiency had larger lateral ventricles, reduced NGF protein content, and reduced expression of a number genes involved in neuronal structure, i.e. neurofilament or MAP-2 or neurotransmission, i.e. GABA-A(alpha4). We conclude that transient early life hypovitaminosis D(3) not only disrupts brain development but leads to persistent changes in the adult brain. In light of the high incidence of hypovitaminosis D(3) in women of child-bearing age, the public health implications of these findings warrant attention. PMID:15763180

  10. Health consequences of iodine deficiency.

    PubMed

    Kapil, Umesh

    2007-12-01

    Iodine Deficiency Disorders (IDD) are one of the biggest worldwide public health problem of today. Their effect is hidden and profoundly affects the quality of human life. Iodine deficiency occurs when the soil is poor in iodine, causing a low concentration in food products and insufficient iodine intake in the population. When iodine requirements are not met, the thyroid may no longer be able to synthesize sufficient amounts of thyroid hormone. The resulting low-level of thyroid hormones in the blood is the principal factor responsible for the series of functional and developmental abnormalities, collectively referred to as IDD. Iodine deficiency is a significant cause of mental developmental problems in children, including implications on reproductive functions and lowering of IQ levels in school-aged children. The consequence of iodine deficiency during pregnancy is impaired synthesis of thyroid hormones by the mother and the foetus. An insufficient supply of thyroid hormones to the developing brain may result in mental retardation. Brain damage and irreversible mental retardation are the most important disorders induced by iodine deficiency. Daily consumption of salt fortified with iodine is a proven effective strategy for prevention of IDD. PMID:21748117

  11. Leaf Senescence by Magnesium Deficiency

    PubMed Central

    Tanoi, Keitaro; Kobayashi, Natsuko I.

    2015-01-01

    Magnesium ions (Mg2+) are the second most abundant cations in living plant cells, and they are involved in various functions, including photosynthesis, enzyme catalysis, and nucleic acid synthesis. Low availability of Mg2+ in an agricultural field leads to a decrease in yield, which follows the appearance of Mg-deficient symptoms such as chlorosis, necrotic spots on the leaves, and droop. During the last decade, a variety of physiological and molecular responses to Mg2+ deficiency that potentially link to leaf senescence have been recognized, allowing us to reconsider the mechanisms of Mg2+ deficiency. This review focuses on the current knowledge about the physiological responses to Mg2+ deficiency including a decline in transpiration, accumulation of sugars and starch in source leaves, change in redox states, increased oxidative stress, metabolite alterations, and a decline in photosynthetic activity. In addition, we refer to the molecular responses that are thought to be related to leaf senescence. With these current data, we give an overview of leaf senescence induced by Mg deficiency. PMID:27135350

  12. Pagophagia in iron deficiency anemia.

    PubMed

    Uchida, Tatsumi; Kawati, Yasunori

    2014-04-01

    The relationship between pagophagia (ice pica) and iron deficiency anemia was studied. All 81 patients with iron deficiency anemia defined as hemoglobin <12.0 g/dl and ferritin level <12 ng/ml were interviewed about their habits of eating ice or other non-food substances. Pagophagia was defined as compulsive and repeated ingestion of at least one tray of ice or ice eating which was relieved after iron administration. Pagophagia was present in 13 patients (16.0%). All patients who received oral iron were periodically assessed employing a questionnaire on pagophagia and laboratory data. Iron therapy can cure the pagophagia earlier than hemoglobin recovery and repair of tissue iron deficiency. Although the pathogenesis of pagophagia is unclear, a biochemical approach involving the central nervous system might elucidate the mechanism underlying these abnormal behaviors. PMID:24850454

  13. Cathepsin K Deficiency Suppresses Disuse-Induced Bone Loss.

    PubMed

    Moriya, Shuichi; Izu, Yayoi; Arayal, Smriti; Kawasaki, Makiri; Hata, Koki; Pawaputanon Na Mahasarakhahm, Chantida; Izumi, Yuichi; Saftig, Paul; Kaneko, Kazuo; Noda, Masaki; Ezura, Yoichi

    2016-05-01

    Unloading induces bone loss and causes disuse osteoporosis. However, the mechanism underlying disuse osteoporosis is still incompletely understood. Here, we examined the effects of cathepsin K (CatK) deficiency on disuse osteoporosis induced by using sciatic neurectomy (Nx) model. After 4 weeks of surgery, CatK KO and WT mice were sacrificed and subjected to analyses. For cancellous bone rich region, Nx reduced the bone mineral density (BMD) compared to the BMD in the sham operated side in wild type mice. In contrast, CatK deficiency suppressed such Nx-induced reduction of BMD in cancellous bone. Nx also reduced BMD in the mid shaft cortical bone compared to the BMD in the corresponding region on the sham operated side in wild type mice. In contrast, CatK deficiency suppressed such Nx-induced reduction of BMD in the mid shaft cortical bone. Bone volume (BV/TV) was reduced by Nx in WT mice. In contrast, Cat-K deficiency suppressed such reduction in bone volume. Interestingly, CatK deficiency suppressed osteoclast number and osteoclast surface in the Nx side compared to sham side. When bone marrow cells obtained from Nx side femur of CatK-KO mice were cultured, the levels of the calcified area in culture were increased. Further examination of gene expression indicated that Nx suppressed the expression of genes encoding osteoblast-phenotype-related molecules such as Runx2 and alkaline phosphatase in WT mice. In contrast, CatK deficiency suppressed such reduction. These data indicate that CatK is involved in the disuse-induced bone mass reduction. PMID:26460818

  14. Prevention of vitamin D deficiency in mothers and infants worldwide — a paradigm shift

    PubMed Central

    Dawodu, A.; Wagner, C. L.

    2015-01-01

    Vitamin D deficiency in mothers and infants is a global health disorder despite recognition that it is preventable. Recent data support the theory that vitamin D deficiency in adults and children may increase the risk of infections and auto-immune diseases. In most cases, vitamin D deficiency is caused by sunlight deprivation and inadequate corrective vitamin D intake. There is a strong mother/infant vitamin D relationship that affects vitamin D status both in utero and in infancy. Recognition that vitamin D deficiency is a worldwide mother/infant health problem is a basis on which to modify public health strategies to reduce the burden of disease and improve maternal and child vitamin D nutrition. This review provides an update on vitamin D function and the global scope and implications of vitamin D deficiency as it relates to pregnancy and infancy. It also addresses a combined strategy to prevent vitamin D deficiency during pregnancy, lactation and infancy. PMID:22525442

  15. Betaine deficiency in maize: Metabolic basis and relation to osmotic adjustment

    SciTech Connect

    Rhodes, D. ); Hanson, A.D. ); Lerma, C.; Bolanos, J.

    1990-05-01

    A single recessive gene causes betaine deficiency in certain maize inbred lines. As betaine may act as a cytosolic osmolyte, deficiency might be expected to reduce osmotic adjustment. Two near-isogenic maize lines differing for betaine, as well as groups of diverse betaine-containing and deficient inbreds, were tested under field water-stress conditions. The betaine-deficient isogenic line, and the group of deficient inbreds as a whole, showed significantly (P<0.05) less osmotic adjustment than their respective betaine-containing counterparts. When leaves from field-grown plants of the isogenic lines were supplied with ({sup 14}C)choline, the betaine-containing line produced ({sup 14}C)betaine whereas the deficient line did not.

  16. [Phosphate metabolism and iron deficiency].

    PubMed

    Yokoyama, Keitaro

    2016-02-01

    Autosomal dominant hypophosphatemic rickets(ADHR)is caused by gain-of-function mutations in FGF23 that prevent its proteolytic cleavage. Fibroblast growth factor 23(FGF23)is a hormone that inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D biosynthesis. Low iron status plays a role in the pathophysiology of ADHR. Iron deficiency is an environmental trigger that stimulates FGF23 expression and hypophosphatemia in ADHR. It was reported that FGF23 elevation in patients with CKD, who are often iron deficient. In patients with nondialysis-dependent CKD, treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and FGF23. PMID:26813504

  17. Responses of Sugar Beet Roots to Iron Deficiency. Changes in Carbon Assimilation and Oxygen Use1

    PubMed Central

    López-Millán, Ana Flor; Morales, Fermín; Andaluz, Sofía; Gogorcena, Yolanda; Abadía, Anunciación; Rivas, Javier De Las; Abadía, Javier

    2000-01-01

    Different root parts with or without increased iron-reducing activities have been studied in iron-deficient and iron-sufficient control sugar beet (Beta vulgaris L. Monohil hybrid). The distal root parts of iron-deficient plants, 0 to 5 mm from the root apex, were capable to reduce Fe(III)-chelates and contained concentrations of flavins near 700 μm, two characteristics absent in the 5 to 10 mm sections of iron-deficient plants and the whole root of iron-sufficient plants. Flavin-containing root tips had large pools of carboxylic acids and high activities of enzymes involved in organic acid metabolism. In iron-deficient yellow root tips there was a large increase in carbon fixation associated to an increase in phosphoenolpyruvate carboxylase activity. Part of this carbon was used, through an increase in mitochondrial activity, to increase the capacity to produce reducing power, whereas another part was exported via xylem. Root respiration was increased by iron deficiency. In sugar beet iron-deficient roots flavins would provide a suitable link between the increased capacity to produce reduced nucleotides and the plasma membrane associated ferric chelate reductase enzyme(s). Iron-deficient roots had a large oxygen consumption rate in the presence of cyanide and hydroxisalycilic acid, suggesting that the ferric chelate reductase enzyme is able to reduce oxygen in the absence of Fe(III)-chelates. PMID:11027736

  18. Prevention and control of iron deficiency: policy and strategy issues.

    PubMed

    Yip, Ray

    2002-04-01

    Substantial efforts have been made in the past several decades to implement programs to reduce iron deficiency. Yet, compared with other micronutrients such as vitamin A and iodine, overall progress in reducing iron deficiency has been limited. Such limited progress is not attributed to a lack of scientific knowledge about the prevalence, causes or consequences of iron deficiency, but to limited implementation of effective interventions and ineffective communication tools. The challenge is to coordinate and balance research efforts more constructively with the implementation of practical and effective intervention programs. More attention must be paid to evaluating the operational feasibility of various intervention strategies to demonstrate their effectiveness under normal field conditions. Moreover, intervention efforts must be supported by substantially increased attention to communications to achieve effective advocacy for policy support and resource mobilization, foster partnerships and alliances, clarify priority target groups, including infants and young children, and support behavioral change. Through collaboration, researchers, program implementers and communicators can achieve substantial progress in reducing iron deficiency. PMID:11925485

  19. Biochemical and Immunologic Analysis of Hereditary Myeloperoxidase Deficiency

    PubMed Central

    Nauseef, William M.; Root, Richard K.; Malech, Harry L.

    1983-01-01

    Myeloperoxidase (MPO), a heme enzyme present in the azurophilic granules of human polymorphonuclear neutrophils (PMN), is important in the oxygen-dependent microbicidal activity of PMN. MPO deficiency, defined as the lack of PMN peroxidative activity, is a common genetic defect of human PMN. The purpose of our study was to characterize the structural basis for this loss of enzymatic activity, using protein biochemical and immunochemical techniques to examine PMN from three subjects with partial MPO deficiency and from five subjects with complete MPO deficiency. We purified MPO from normal PMN and defined its electrophoretic mobility after two-dimensional electrophoretic separation, using nondenaturing acidic polyacrylamide gel electrophoresis (PAGE) followed by sodium dodecyl sulfate (SDS) denaturation and SDS-PAGE separation of MPO subunit peptides. In agreement with previous studies, we found that normal MPO had subunits of 59,000 and 13,500 mol wt when subjected to SDS-PAGE under reducing conditions. Granule protein extracts of normal PMN, partially MPO-deficient PMN, and completely MPO-deficient PMN were analyzed with two-dimensional PAGE. Partially MPO-deficient PMN granules contained electrophoretically normal MPO in less than normal amounts, whereas completely MPO-deficient PMN granules contain no protein with the electrophoretic mobility of normal MPO. Using rabbit antiserum against purified MPO, we used immunoautoradiographic analysis to examine whole PMN for peptides immunochemically related to MPO. PMN from normal, partially MPO-deficient, and completely MPO-deficient subjects were solubilized in SDS and component peptides separated by SDS-PAGE. The peptides were electroblotted onto nitrocellulose paper that was exposed sequentially to rabbit anti-MPO and 125I-protein A before autoradiography. Radiolabeled bands were identical when partially purified MPO or normal PMN were compared except that whole PMN contained a small amount of an immunologically

  20. Iodine deficiency disorders in Bangladesh.

    PubMed

    Yusuf, H K; Quazi, S; Kahn, M R; Mohiduzzaman, M; Nahar, B; Rahman, M M; Islam, M N; Khan, M A; Shahidullah, M; Hoque, T; Baquer, M; Pandav, C S

    1996-01-01

    An extensive iodine deficiency disorders survey was conducted in Bangladesh in 1993 to assess the latest iodine nutriture status of the country. The clinical variables of the survey were goitre and cretinism, and the biochemical variable was urinary iodine. The "EPI-30 cluster" sampling methodology was followed for selecting the survey sites. In each survey site, the study population consisted of boys and girls, aged 5-11 years, and men and women, aged 15-44 years, in about equal populations. The total number of survey sites was 78 and the total number of respondents was 30,072. The total number of urine samples was 4512 (15% sub-sample). The current total goitre rate (grade 1 + grade 2) in Bangladesh is 47.1% (hilly, 44.4%; flood-prone, 50.7%; and plains, 45.6%). The prevalence of cretinism in the country is 0.5% (hilly, 0.8%; flood-prone, 0.5%; and plains, 0.3%). Nearly 69% of Bangladeshi population have biochemical iodine deficiency (urinary iodine excretion [UIE] < 10 mg/dl) (hilly, 84.4; flood-prone, 67.1%; and plains 60.4%). Women and children are more affected that men, in terms of both goitre prevalence and UIE. The widespread severe iodine deficiency in all ecological zones indicates that the country as a whole is an iodine-deficient region. Important recommendations of global interest are made from the experience of the survey. PMID:10829973

  1. Growth hormone deficiency: an update.

    PubMed

    Audí, L; Fernández-Cancio, M; Camats, N; Carrascosa, A

    2013-03-01

    Growth hormone (GH) deficiency (GHD) in humans manifests differently according to the individual developmental stage (early after birth, during childhood, at puberty or in adulthood), the cause or mechanism (genetic, acquired or idiopathic), deficiency intensity and whether it is the only pituitary-affected hormone or is combined with that of other pituitary hormones or forms part of a complex syndrome. Growing knowledge of the genetic basis of GH deficiency continues to provide us with useful information to further characterise mutation types and mechanisms for previously described and new candidate genes. Despite these advances, a high proportion of GH deficiencies with no recognisable acquired basis continue to be labelled as idiopathic, although less frequently when they are congenital and/or familial. The clinical and biochemical diagnoses continue to be a conundrum despite efforts to harmonise biochemical assays for GH and IGF-1 analysis, probably because the diagnosis based on the so-called GH secretion stimulation tests will prove to be of limited usefulness for predicting therapy indications. PMID:23435439

  2. VISUAL DEFICIENCIES AND READING DISABILITY.

    ERIC Educational Resources Information Center

    ROSEN, CARL L.

    THE ROLE OF VISUAL SENSORY DEFICIENCIES IN THE CAUSATION READING DISABILITY IS DISCUSSED. PREVIOUS AND CURRENT RESEARCH STUDIES DEALING WITH SPECIFIC VISUAL PROBLEMS WHICH HAVE BEEN FOUND TO BE NEGATIVELY RELATED TO SUCCESSFUL READING ACHIEVEMENT ARE LISTED--(1) FARSIGHTEDNESS, (2) ASTIGMATISM, (3) BINOCULAR INCOORDINATIONS, AND (4) FUSIONAL…

  3. Psychological Problems in Mental Deficiency.

    ERIC Educational Resources Information Center

    Sarason, Seymour B.; Doris, John

    A statement of goals and the rationale for organization precede a historical discussion of mental deficiency and society. The problem of labels like IQ and brain injured and the consequences of the diagnostic process are illustrated by case histories; case studies are also used to examine the criteria used to decide who is retarded and to discuss…

  4. Thiamine Deficiency Induced Neurochemical, Neuroanatomical, and Neuropsychological Alterations: A Reappraisal

    PubMed Central

    Höller, Yvonne; Storti, Monica; Christova, Monica; Tezzon, Frediano; Golaszewski, Stefan; Trinka, Eugen

    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. PMID:24235882

  5. Chromospheric, transition layer and coronal emission of metal deficient stars

    NASA Technical Reports Server (NTRS)

    Boehm-Vitense, E.

    1982-01-01

    It is shown that while MgII k line emission decreases for metal deficient stars, the Ly alpha emission increases. The sum of chromospheric hydrogen and metallic emission appears to be independent of metal abundances. The total chromospheric energy loss is estimated to be 0.0004 F sub bol. The chromospheric energy input does not seem to decrease for increasing age. The transition layer emission is reduced for metal deficient stars, but it is not known whether the reduction is larger than can be explained by curve of growth effects only. Coronal X-ray emission was measured for 4 metal deficient stars. Within a 12 limit it could still be consistent with the emission of solar abundance stars.

  6. Dissipation in noisy chemical networks: The role of deficiency.

    PubMed

    Polettini, M; Wachtel, A; Esposito, M

    2015-11-14

    We study the effect of intrinsic noise on the thermodynamic balance of complex chemical networks subtending cellular metabolism and gene regulation. A topological network property called deficiency, known to determine the possibility of complex behavior such as multistability and oscillations, is shown to also characterize the entropic balance. In particular, when deficiency is zero the average stochastic dissipation rate equals that of the corresponding deterministic model, where correlations are disregarded. In fact, dissipation can be reduced by the effect of noise, as occurs in a toy model of metabolism that we employ to illustrate our findings. This phenomenon highlights that there is a close interplay between deficiency and the activation of new dissipative pathways at low molecule numbers. PMID:26567642

  7. Maternal bile acid transporter deficiency promotes neonatal demise

    PubMed Central

    Zhang, Yuanyuan; Li, Fei; Wang, Yao; Pitre, Aaron; Fang, Zhong-ze; Frank, Matthew W.; Calabrese, Christopher; Krausz, Kristopher W.; Neale, Geoffrey; Frase, Sharon; Vogel, Peter; Rock, Charles O.; Gonzalez, Frank J.; Schuetz, John D.

    2015-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse neonatal survival and is estimated to impact between 0.4 and 5% of pregnancies worldwide. Here we show that maternal cholestasis (due to Abcb11 deficiency) produces neonatal death among all offspring within 24 h of birth due to atelectasis-producing pulmonary hypoxia, which recapitulates the neonatal respiratory distress of human ICP. Neonates of Abcb11-deficient mothers have elevated pulmonary bile acids and altered pulmonary surfactant structure. Maternal absence of Nr1i2 superimposed on Abcb11 deficiency strongly reduces maternal serum bile acid concentrations and increases neonatal survival. We identify pulmonary bile acids as a key factor in the disruption of the structure of pulmonary surfactant in neonates of ICP. These findings have important implications for neonatal respiratory failure, especially when maternal bile acids are elevated during pregnancy, and highlight potential pathways and targets amenable to therapeutic intervention to ameliorate this condition. PMID:26416771

  8. Recurrent Encephalopathy: NAGS (N-acetylglutamate synthase) Deficiency in Adults

    PubMed Central

    Cartagena, A; Prasad, AN; Rupar, CA; Strong, M; Tuchman, M; Ah Mew, N; Prasad, C.

    2014-01-01

    Urea cycle disorders (UCDs) are a group of uncommon heterogeneous conditions that are often detected in childhood and only rarely in adults where the presentations are subtle or non specific with symptoms of confusion and encephalopathy. N-acetyl-glutamate synthase (NAGS) deficiency is a rare urea cycle disorder that uncommonly presents in adulthood. To date there has been no detailed neurological description of an adult onset presentation of NAGS deficiency. In this review we examine the clinical presentation and management of UCDs with an emphasis on NAGS deficiency. An illustrative case is provided. Plasma ammonia levels should be measured in all patients with unexplained encephalopathy as treatment can be life-saving. Management of this rare disorder includes protein restriction and adjunct pharmacologic treatment to reduce plasma ammonia levels. Genetic counselling remains an essential component of management of UCDs. PMID:23250120

  9. Dissipation in noisy chemical networks: The role of deficiency

    SciTech Connect

    Polettini, M. Wachtel, A. Esposito, M.

    2015-11-14

    We study the effect of intrinsic noise on the thermodynamic balance of complex chemical networks subtending cellular metabolism and gene regulation. A topological network property called deficiency, known to determine the possibility of complex behavior such as multistability and oscillations, is shown to also characterize the entropic balance. In particular, when deficiency is zero the average stochastic dissipation rate equals that of the corresponding deterministic model, where correlations are disregarded. In fact, dissipation can be reduced by the effect of noise, as occurs in a toy model of metabolism that we employ to illustrate our findings. This phenomenon highlights that there is a close interplay between deficiency and the activation of new dissipative pathways at low molecule numbers.

  10. Altered microglial phagocytosis in GPR34-deficient mice.

    PubMed

    Preissler, Julia; Grosche, Antje; Lede, Vera; Le Duc, Diana; Krügel, Katja; Matyash, Vitali; Szulzewsky, Frank; Kallendrusch, Sonja; Immig, Kerstin; Kettenmann, Helmut; Bechmann, Ingo; Schöneberg, Torsten; Schulz, Angela

    2015-02-01

    GPR34 is a Gi/o protein-coupled receptor (GPCR) of the nucleotide receptor P2Y12 -like group. This receptor is highly expressed in microglia, however, the functional relevance of GPR34 in these glial cells is unknown. Previous results suggested an impaired immune response in GPR34-deficient mice infected with Cryptococcus neoformans. Here we show that GPR34 deficiency results in morphological changes in retinal and cortical microglia. RNA sequencing analysis of microglia revealed a number of differentially expressed transcripts involved in cell motility and phagocytosis. We found no differences in microglial motility after entorhinal cortex lesion and in response to laser lesion. However, GPR34-deficient microglia showed reduced phagocytosis activity in both retina and acutely isolated cortical slices. Our study identifies GPR34 as an important signaling component controlling microglial function, morphology and phagocytosis. PMID:25142016

  11. 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. PMID:24235882

  12. Dermatopathy in juvenile Angus cattle due to vitamin A deficiency.

    PubMed

    Baldwin, Thomas J; Rood, Kerry A; Kelly, E Jane; Hall, Jeffery O

    2012-07-01

    In juvenile cattle, vitamin A deficiency is reported most commonly as a neurological condition; only rarely are there dermatologic manifestations. In the current study, alopecia, severe epidermal and follicular orthokeratosis, and acanthosis due to hypovitaminosis A are reported in 2 of 32 Angus calves, with a third animal suspected. Affected animals responded to vitamin A supplementation, and no additional calves displayed signs. Vitamin A acts on skin by regulating DNA transcription in keratinocytes, reducing the number of tonofilaments and desmosomes, both involved in cell-to-cell adhesion. Hence, adequate levels of dietary vitamin A are necessary for normal keratinocyte turnover, and deficiencies result in retention of keratinized cells (orthokeratosis). The present report reminds diagnosticians to consider vitamin A deficiency in cases of orthokeratotic dermatopathy in cattle. PMID:22585959

  13. Genetics Home Reference: 17β-hydroxysteroid dehydrogenase type 10 deficiency

    MedlinePlus

    ... involved in breaking down the protein building block ( amino acid ) isoleucine and a group of fats called branched- ... system. Mutations that cause HSD10 deficiency change single amino acids in HSD10, which reduces or eliminates the activity ...

  14. Iron refractory iron deficiency anemia

    PubMed Central

    De Falco, Luigia; Sanchez, Mayka; Silvestri, Laura; Kannengiesser, Caroline; Muckenthaler, Martina U.; Iolascon, Achille; Gouya, Laurent; Camaschella, Clara; Beaumont, Carole

    2013-01-01

    Iron refractory iron deficiency anemia is a hereditary recessive anemia due to a defect in the TMPRSS6 gene encoding Matriptase-2. This protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values. The anemia appears in the post-natal period, although in some cases it is only diagnosed in adulthood. The disease is refractory to oral iron treatment but shows a slow response to intravenous iron injections and partial correction of the anemia. To date, 40 different Matriptase-2 mutations have been reported, affecting all the functional domains of the large ectodomain of the protein. In vitro experiments on transfected cells suggest that Matriptase-2 cleaves Hemojuvelin, a major regulator of hepcidin expression and that this function is altered in this genetic form of anemia. In contrast to the low/undetectable hepcidin levels observed in acquired iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin is inappropriately high for the low iron status and accounts for the absent/delayed response to oral iron treatment. A challenge for the clinicians and pediatricians is the recognition of the disorder among iron deficiency and other microcytic anemias commonly found in pediatric patients. The current treatment of iron refractory iron deficiency anemia is based on parenteral iron administration; in the future, manipulation of the hepcidin pathway with the aim of suppressing it might become an alternative therapeutic approach. PMID:23729726

  15. Miro1 deficiency in amyotrophic lateral sclerosis

    PubMed Central

    Zhang, Fan; Wang, Wenzhang; Siedlak, Sandra L.; Liu, Yingchao; Liu, Jun; Jiang, Keji; Perry, George; Zhu, Xiongwei; Wang, Xinglong

    2015-01-01

    Proper transportation of mitochondria to sites with high energy demands is critical for neuronal function and survival. Impaired mitochondrial movement has been repeatedly reported in motor neurons of amyotrophic lateral sclerosis (ALS) patients and indicated as an important mechanism contributing to motor neuron degeneration in ALS. Miro1, a RhoGTPase also referred to as Rhot1, is a key regulator of mitochondrial movement linking mitochondria and motor proteins. In this study, we investigated whether the expression of Miro1 was altered in ALS patients and ALS animal models. Immunoblot analysis revealed that Miro1 was significantly reduced in the spinal cord tissue of ALS patients. Consistently, the decreased expression of Miro1 was also noted only in the spinal cord, and not in the brain tissue of transgenic mice expressing ALS-associated SOD1 G93A or TDP-43 M337V. Glutamate excitotoxicity is one of the major pathophysiological mechanisms implicated in the pathogenesis of ALS, and we found that excessive glutamate challenge lead to significant reduction of Miro1 expression in spinal cord motor neurons both in vitro and in mice. Taken together, these findings show Miro1 deficiency in ALS patients and ALS animal models and suggest glutamate excitotoxicity as a likely cause of Miro1 deficiency. PMID:26074815

  16. Iodine deficiency disorders (IDD) control in India

    PubMed Central

    Pandav, Chandrakant S.; Yadav, Kapil; Srivastava, Rahul; Pandav, Rijuta; Karmarkar, M.G.

    2013-01-01

    Iodine deficiency disorders (IDD) constitute the single largest cause of preventable brain damage worldwide. Majority of consequences of IDD are invisible and irreversible but at the same time these are preventable. In India, the entire population is prone to IDD due to deficiency of iodine in the soil of the subcontinent and consequently the food derived from it. To combat the risk of IDD, salt is fortified with iodine. However, an estimated 350 million people do not consume adequately iodized salt and, therefore, are at risk for IDD. Of the 325 districts surveyed in India so far, 263 are IDD-endemic. The current household level iodized salt coverage in India is 91 per cent with 71 per cent households consuming adequately iodized salt. The IDD control goal in India was to reduce the prevalence of IDD below 10 per cent in the entire country by 2012. What is required is a “mission approach” with greater coordination amongst all stakeholders of IDD control efforts in India. Mainstreaming of IDD control in policy making, devising State specific action plans to control IDD, strict implementation of Food Safety and Standards (FSS) Act, 2006, addressing inequities in iodized salt coverage (rural-urban, socio-economic), providing iodized salt in Public Distribution System, strengthening monitoring and evaluation of IDD programme and ensuring sustainability of IDD control activities are essential to achieve sustainable elimination of IDD in India. PMID:24135192

  17. Potential Mechanisms of Progranulin-deficient FTLD

    PubMed Central

    Ward, Michael Emmerson

    2013-01-01

    Frontotemporal lobar dementia (FTLD) is the most common cause of dementia in patients younger than 60 years of age, and causes progressive neurodegeneration of the frontal and temporal lobes usually accompanied by devastating changes in language or behavior in affected individuals. Mutations in the progranulin (GRN) gene account for a significant fraction of familial FTLD, and in the vast majority of cases, these mutations lead to reduced expression of progranulin via nonsense-mediated mRNA decay. Progranulin is a secreted glycoprotein that regulates a diverse range of cellular functions including cell proliferation, cell migration, and inflammation. Recent fundamental discoveries about progranulin biology, including the findings that sortilin and tumor necrosis factor receptor (TNFR) are high affinity progranulin receptors, are beginning to shed light on the mechanism(s) by which progranulin deficiency causes FTLD. This review will explore how alterations in basic cellular functions due to PGRN deficiency, both intrinsic and extrinsic to neurons, might lead to the development of FTLD. PMID:21892758

  18. Genetic disorders coupled to ROS deficiency.

    PubMed

    O'Neill, Sharon; Brault, Julie; Stasia, Marie-Jose; Knaus, Ulla G

    2015-12-01

    Maintaining the redox balance between generation and elimination of reactive oxygen species (ROS) is critical for health. Disturbances such as continuously elevated ROS levels will result in oxidative stress and development of disease, but likewise, insufficient ROS production will be detrimental to health. Reduced or even complete loss of ROS generation originates mainly from inactivating variants in genes encoding for NADPH oxidase complexes. In particular, deficiency in phagocyte Nox2 oxidase function due to genetic variants (CYBB, CYBA, NCF1, NCF2, NCF4) has been recognized as a direct cause of chronic granulomatous disease (CGD), an inherited immune disorder. More recently, additional diseases have been linked to functionally altered variants in genes encoding for other NADPH oxidases, such as for DUOX2/DUOXA2 in congenital hypothyroidism, or for the Nox2 complex, NOX1 and DUOX2 as risk factors for inflammatory bowel disease. A comprehensive overview of novel developments in terms of Nox/Duox-deficiency disorders is presented, combined with insights gained from structure-function studies that will aid in predicting functional defects of clinical variants. PMID:26210446

  19. Genetic disorders coupled to ROS deficiency

    PubMed Central

    O’Neill, Sharon; Brault, Julie; Stasia, Marie-Jose; Knaus, Ulla G.

    2015-01-01

    Maintaining the redox balance between generation and elimination of reactive oxygen species (ROS) is critical for health. Disturbances such as continuously elevated ROS levels will result in oxidative stress and development of disease, but likewise, insufficient ROS production will be detrimental to health. Reduced or even complete loss of ROS generation originates mainly from inactivating variants in genes encoding for NADPH oxidase complexes. In particular, deficiency in phagocyte Nox2 oxidase function due to genetic variants (CYBB, CYBA, NCF1, NCF2, NCF4) has been recognized as a direct cause of chronic granulomatous disease (CGD), an inherited immune disorder. More recently, additional diseases have been linked to functionally altered variants in genes encoding for other NADPH oxidases, such as for DUOX2/DUOXA2 in congenital hypothyroidism, or for the Nox2 complex, NOX1 and DUOX2 as risk factors for inflammatory bowel disease. A comprehensive overview of novel developments in terms of Nox/Duox-deficiency disorders is presented, combined with insights gained from structure–function studies that will aid in predicting functional defects of clinical variants. PMID:26210446

  20. Iodine deficiency in vegetarians and vegans.

    PubMed

    Krajcovicová-Kudlácková, M; Bucková, K; Klimes, I; Seboková, E

    2003-01-01

    Iodine content in food of plant origin is lower in comparison with that of animal origin due to a low iodine concentration in soil. Urinary iodine excretion was assessed in 15 vegans, 31 lacto- and lacto-ovovegetarians and 35 adults on a mixed diet. Iodine excretion was significantly lower in alternative nutrition groups - 172 microg/l in vegetarians and 78 microg/l in vegans compared to 216 microg/l in subjects on a mixed diet. One fourth of the vegetarians and 80% of the vegans suffer from iodine deficiency (iodine excretion value below 100 microg/l) compared to 9% in the persons on a mixed nutrition. The results show that under conditions of alternative nutrition, there is a higher prevalence of iodine deficiency, which might be a consequence of exclusive or prevailing consumption of food of plant origin, no intake of fish and other sea products, as well as reduced iodine intake in the form of sea salt. PMID:12748410

  1. Norepinephrine deficiency in Parkinson's disease: the case for noradrenergic enhancement.

    PubMed

    Espay, Alberto J; LeWitt, Peter A; Kaufmann, Horacio

    2014-12-01

    The dramatic response of most motor and some nonmotor symptoms to dopaminergic therapies has contributed to maintaining the long-established identity of Parkinson's disease (PD) as primarily a nigrostriatal dopamine (DA) deficiency syndrome. However, DA neurotransmission may be neither the first nor the major neurotransmitter casualty in the neurodegenerative sequence of PD. Growing evidence supports earlier norepinephrine (NE) deficiency resulting from selective degeneration of neurons of the locus coeruleus and sympathetic ganglia. Dopaminergic replacement therapy therefore would seem to neglect some of the motor, behavioral, cognitive, and autonomic impairments that are directly or indirectly associated with the marked deficiency of NE in the brain and elsewhere. Therapeutic strategies to enhance NE neurotransmission have undergone only limited pharmacological testing. Currently, these approaches include selective NE reuptake inhibition, presynaptic α2 -adrenergic receptor blockade, and an NE prodrug, the artificial amino acid L-threo-3,4-dihydroxyphenylserine. In addition to reducing the consequences of deficient noradrenergic signaling, enhancement strate gies have the potential for augmenting the effects of dopaminergic therapies in PD. Furthermore, early recognition of the various clinical manifestations associated with NE deficiency, which may precede development of motor symptoms, could provide a window of opportunity for neuroprotective interventions. PMID:25297066

  2. Replication fork stability confers chemoresistance in BRCA-deficient cells.

    PubMed

    Ray Chaudhuri, Arnab; Callen, Elsa; Ding, Xia; Gogola, Ewa; Duarte, Alexandra A; Lee, Ji-Eun; Wong, Nancy; Lafarga, Vanessa; Calvo, Jennifer A; Panzarino, Nicholas J; John, Sam; Day, Amanda; Crespo, Anna Vidal; Shen, Binghui; Starnes, Linda M; de Ruiter, Julian R; Daniel, Jeremy A; Konstantinopoulos, Panagiotis A; Cortez, David; Cantor, Sharon B; Fernandez-Capetillo, Oscar; Ge, Kai; Jonkers, Jos; Rottenberg, Sven; Sharan, Shyam K; Nussenzweig, André

    2016-07-21

    Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2-deficient tumour cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexities by which tumour cells evade chemotherapeutic interventions and acquire drug resistance. PMID:27443740

  3. Caspase-2 Deficiency Enhances Aging-Related Traits in Mice

    PubMed Central

    Zhang, Yingpei; Padalecki, Susan S; Chaudhuri, Asish R; Waal, Eric De; Goins, Beth A; Grubbs, Barry; Ikeno, Yuji; Richardson, Arlan; Mundy, Gregory R; Herman, Brian

    2007-01-01

    Alteration of apoptotic activity has been observed in a number of tissues in aging mammals, but it remains unclear whether and/or how apoptosis may affect aging. Caspase-2 is a member of the cysteine protease family that plays a critical role in apoptosis. To understand the impact of compromised apoptosis function on mammalian aging, we conducted a comparative study on caspase-2 deficient mice and their wild-type littermates with a specific focus on the aging-related traits at advanced ages. We found that caspase-2 deficiency enhanced a number of traits commonly seen in premature aging animals. Loss of caspase-2 was associated with shortened maximum lifespan, impaired hair growth, increased bone loss, and reduced body fat content. In addition, we found that the livers of caspase-2 deficient mice had higher levels of oxidized proteins than those of age-matched wild-type mice, suggesting that caspase-2 deficiency compromised the animal's ability to clear oxidatively damaged cells. Collectively, these results suggest that caspase-2 deficiency affects aging in the mice. This study thus demonstrates for the first time that disruption of a key apoptotic gene has a significant impact on aging. PMID:17188333

  4. Genetics Home Reference: complement factor I deficiency

    MedlinePlus

    ... Page Baracho GV, Nudelman V, Isaac L. Molecular characterization of homozygous hereditary factor I deficiency. Clin Exp ... G, Sánchez-Corral P, López-Trascasa M. Molecular characterization of Complement Factor I deficiency in two Spanish ...

  5. Genetics Home Reference: GM3 synthase deficiency

    MedlinePlus

    ... GM3 synthase deficiency is characterized by recurrent seizures (epilepsy) and problems with brain development. Within the first ... diagnosis or management of GM3 synthase deficiency: American Epilepsy Society: Find a Doctor Clinic for Special Children ( ...

  6. Genetics Home Reference: familial glucocorticoid deficiency

    MedlinePlus

    ... familial glucocorticoid deficiency type 1 lead to defective trafficking of the receptor to the cell surface. J ... short stature, and natural killer cell deficiency in humans. J Clin Invest. 2012 Mar;122(3):814- ...

  7. Genetics Home Reference: 21-hydroxylase deficiency

    MedlinePlus

    ... deficiency is an inherited disorder that affects the adrenal glands . The adrenal glands are located on top of the kidneys and ... body. In people with 21-hydroxylase deficiency , the adrenal glands produce excess androgens, which are male sex hormones. ...

  8. Monocular Elevation Deficiency - Double Elevator Palsy

    MedlinePlus

    ... Eye Terms Conditions Frequently Asked Questions Español Condiciones Chinese Conditions Monocular Elevation Deficiency/ Double Elevator Palsy En Español Read in Chinese What is monocular elevation deficiency (Double Elevator Palsy)? ...

  9. How Is Alpha-1 Antitrypsin Deficiency Treated?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Alpha-1 Antitrypsin Deficiency Treated? Alpha-1 antitrypsin (AAT) deficiency has no cure, but its ... of these treatments are the same as the ones used for a lung disease called COPD (chronic ...

  10. Cobalamin deficiency, hyperhomocysteinemia, and dementia

    PubMed Central

    Werder, Steven F

    2010-01-01

    Introduction Although consensus guidelines recommend checking serum B12 in patients with dementia, clinicians are often faced with various questions: (1) Which patients should be tested? (2) What test should be ordered? (3) How are inferences made from such testing? (4) In addition to serum B12, should other tests be ordered? (5) Is B12 deficiency compatible with dementia of the Alzheimer’s type? (6) What is to be expected from treatment? (7) How is B12 deficiency treated? Methods On January 31st, 2009, a Medline search was performed revealing 1,627 citations related to cobalamin deficiency, hyperhomocysteinemia, and dementia. After limiting the search terms, all abstracts and/or articles and other references were categorized into six major groups (general, biochemistry, manifestations, associations and risks, evaluation, and treatment) and then reviewed in answering the above questions. Results The six major groups above are described in detail. Seventy-five key studies, series, and clinical trials were identified. Evidence-based suggestions for patient management were developed. Discussion Evidence is convincing that hyperhomocysteinemia, with or without hypovitaminosis B12, is a risk factor for dementia. In the absence of hyperhomocysteinemia, evidence is less convincing that hypovitaminosis B12 is a risk factor for dementia. B12 deficiency manifestations are variable and include abnormal psychiatric, neurological, gastrointestinal, and hematological findings. Radiological images of individuals with hyperhomocysteinemia frequently demonstrate leukoaraiosis. Assessing serum B12 and treatment of B12 deficiency is crucial for those cases in which pernicious anemia is suspected and may be useful for mild cognitive impairment and mild to moderate dementia. The serum B12 level is the standard initial test: 200 picograms per milliliter or less is low, and 201 to 350 picograms per milliliter is borderline low. Other tests may be indicated, including plasma

  11. Multiple Carboxylase Deficiency (Late Onset) Due to Deficiency of Biotinidase

    PubMed Central

    Mukhopadhyay, Debadatta; Das, Manoj Kumar; Dhar, Sandipan; Mukhopadhyay, Maya

    2014-01-01

    Biotinidase is a ubiquitous mammalian cell enzyme occurring in liver, serum and kidney. It cleaves biotin from biocytin, which is a cofactor for biotin dependent enzymes, namely the human carboxylases. Biotinidase deficiency is associated with a wide spectrum of neurological, dermatological, immunological and ophthalmological abnormalities. This is a case of a 3-year-old boy presenting with delayed developmental milestones, tachypnea, progressively increasing ataxia, alopecia and dermatitis, all which dramatically responded to high doses of biotin. PMID:25284861

  12. Deficiency or dementia? Exploring B12 deficiency after urostomy.

    PubMed

    Boucher, Michelle; Bryan, Sandra; Dukes, Suzie

    Vitamin B12 deficiency can be misdiagnosed as a variety of other illnesses, and if left untreated can lead to irreversible damage to the brain and nervous system. This article discusses the case of a 70-year-old female with a urostomy, well known to the stoma care department, who shortly after a routine parastomal hernia repair developed severe confusion, immobility and was unable to communicate. Subsequent investigations ruled out a cerebrovascular accident (CVA) and a diagnosis of rapidly progressing vascular dementia was made. An incidental finding of a low vitamin B12 level was identified and treatment commenced. She was transferred to a community hospital and her family were told to 'prepare for the worst'. It was, in fact, the vitamin B12 deficiency that was causing her symptoms of vascular dementia, and once treatment was established she underwent a 'miraculous' improvement, returning to normal life. This article discusses vitamin B12 deficiency and why patients with a urostomy are at risk of developing it; highlights the key role of the stoma care nurse and his or her knowledge of the patient; explores the importance of testing vitamin B12 levels in this group of patients; and discusses key learning and recommendations for practice. PMID:26067796

  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. Iron Deficiency in Autism and Asperger Syndrome.

    ERIC Educational Resources Information Center

    Latif, A.; Heinz, P.; Cook, R.

    2002-01-01

    Retrospective analysis of the full blood count and, when available, serum ferritin measurements of 96 children (52 with autism and 44 with Asperger syndrome) found six autistic children had iron deficiency and 12 of the 23 autistic children with serum ferritin measures were iron deficient. Far fewer Asperger children were iron deficient. Results…

  15. Protective effects of zinc on oxidative stress enzymes in liver of protein-deficient rats.

    PubMed

    Sidhu, Pardeep; Garg, M L; Dhawan, D K

    2005-01-01

    Persons afflicted with protein malnutrition are generally deficient in a variety of essential micronutrients like zinc, copper, iron, and selenium, which in turn affects number of metabolic processes in the body. To evaluate the protective effects of zinc on the enzymes involved in oxidative stress induced in liver of protein-deficient rats, the current study was designed. Zinc sulfate at a dose level of 227 mg/L zinc in drinking water was administered to female Sprague-Dawley normal control as well as protein-deficient rats for a total duration of 8 weeks. The effects of zinc treatment in conditions of protein deficiency were studied on rat liver antioxidant enzymes, which included catalase, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), glutathione reduced (GSH), and glutathione-S-transferase (GST). Protein deficiency in normal rats resulted in a significant increase in hepatic activities of catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase and the levels of lipid peroxidation. A significant inhibition in the levels of reduced glutathione and the enzyme activity of superoxide dismutase has been observed after protein deficiency in normal rats. Interestingly, Zn treatment to protein-deficient animals lowered already raised activity catalase, glutathione peroxidase, and glutathione-S-transferase and levels of lipid peroxidation to significant levels when compared to protein-deficient animals. Also, Zn treatment to the protein-deficient animals resulted in a significant elevation in the levels of GSH and SOD activity as compared to their respective controls, thereby indicating its effectiveness in regulating their levels in adverse conditions. It has also been observed that concentrations of zinc, copper, iron, and selenium were found to be decreased significantly in protein-deficient animals. However, the levels of these elements came back to within normal limits when zinc was administrated

  16. Hyperammonemic Encephalopathy Caused by Carnitine Deficiency

    PubMed Central

    Zucker, Stephen D.

    2007-01-01

    Carnitine is an essential co-factor in fatty acid metabolism. Carnitine deficiency can impair fatty acid oxidation, rarely leading to hyperammonemia and encephalopathy. We present the case of a 35-year-old woman who developed acute mental status changes, asterixis, and diffuse muscle weakness. Her ammonia level was elevated at 276 μg/dL. Traditional ammonia-reducing therapies were initiated, but proved ineffective. Pharmacologic, microbial, and autoimmune causes for the hyperammonemia were excluded. The patient was severely malnourished and her carnitine level was found to be extremely low. After carnitine supplementation, ammonia levels normalized and the patient’s mental status returned to baseline. In the setting of refractory hyperammonemia, this case illustrates how careful investigation may reveal a treatable condition. PMID:18080167

  17. Maternal vitamin D deficiency alters fetal brain development in the BALB/c mouse.

    PubMed

    Hawes, Jazmin E; Tesic, Dijana; Whitehouse, Andrew J; Zosky, Graeme R; Smith, Jeremy T; Wyrwoll, Caitlin S

    2015-06-01

    Prenatal exposure to vitamin D is thought to be critical for optimal fetal neurodevelopment, yet vitamin D deficiency is apparent in a growing proportion of pregnant women. The aim of this study was to determine whether a mouse model of vitamin D-deficiency alters fetal neurodevelopment. Female BALB/c mice were placed on either a vitamin D control (2,195 IU/kg) or deficient (0 IU/kg) diet for 5 weeks prior to and during pregnancy. Fetal brains were collected at embryonic day (E) 14.5 or E17.5 for morphological and gene expression analysis. Vitamin D deficiency during pregnancy reduced fetal crown-rump length and head size. Moreover, lateral ventricle volume was reduced in vitamin D-deficient foetuses. Expression of neurotrophin genes brain-derived neurotrophic factor (Bdnf) and transforming growth factor-β1 (Tgf-β1) was altered, with Bdnf reduced at E14.5 and increased at E17.5 following vitamin D deficiency. Brain expression of forkhead box protein P2 (Foxp2), a gene known to be important in human speech and language, was also altered. Importantly, Foxp2 immunoreactive cells in the developing cortex were reduced in vitamin D-deficient female foetuses. At E17.5, brain tyrosine hydroxylase (TH) gene expression was reduced in females, as was TH protein localization (to identify dopamine neurons) in the substantia nigra of vitamin D-deficient female foetuses. Overall, we show that prenatal vitamin D-deficiency leads to alterations in fetal mouse brain morphology and genes related to neuronal survival, speech and language development, and dopamine synthesis. Vitamin D appears to play an important role in mouse neurodevelopment. PMID:25753408

  18. Intracellular in vitro probe acylcarnitine assay for identifying deficiencies of carnitine transporter and carnitine palmitoyltransferase-1.

    PubMed

    Purevsuren, Jamiyan; Kobayashi, Hironori; Hasegawa, Yuki; Yamada, Kenji; Takahashi, Tomoo; Takayanagi, Masaki; Fukao, Toshiyuki; Fukuda, Seiji; Yamaguchi, Seiji

    2013-02-01

    Mitochondrial fatty acid oxidation (FAO) disorders are caused by defects in one of the FAO enzymes that regulates cellular uptake of fatty acids and free carnitine. An in vitro probe acylcarnitine (IVP) assay using cultured cells and tandem mass spectrometry is a tool to diagnose enzyme defects linked to most FAO disorders. Extracellular acylcarnitine (AC) profiling detects carnitine palmitoyltransferase-2, carnitine acylcarnitine translocase, and other FAO deficiencies. However, the diagnosis of primary carnitine deficiency (PCD) or carnitine palmitoyltransferase-1 (CPT1) deficiency using the conventional IVP assay has been hampered by the presence of a large amount of free carnitine (C0), a key molecule deregulated by these deficiencies. In the present study, we developed a novel IVP assay for the diagnosis of PCD and CPT1 deficiency by analyzing intracellular ACs. When exogenous C0 was reduced, intracellular C0 and total AC in these deficiencies showed specific profiles clearly distinguishable from other FAO disorders and control cells. Also, the ratio of intracellular to extracellular C0 levels showed a significant difference in cells with these deficiencies compared with control. Hence, intracellular AC profiling using the IVP assay under reduced C0 conditions is a useful method for diagnosing PCD or CPT1 deficiency. PMID:23143007

  19. Clinical, endocrinological and biochemical effects of zinc deficiency.

    PubMed

    Prasad, A S

    1985-08-01

    The essentiality of zinc for humans was recognized in the early 1960s. The causes of zinc deficiency include malnutrition, alcoholism, malabsorption, extensive burns, chronic debilitating disorders, chronic renal disease, certain diuretics, the use of chelating agents such as penicillamine for Wilson's disease, and genetic disorders such as acrodermatitis enteropathica and sickle cell disease. The requirement of zinc is increased in pregnancy and during the growing age period. The clinical manifestations in severe cases of zinc deficiency included bullous-pustular dermatitis, alopecia, diarrhoea, emotional disorder, weight loss, intercurrent infections, hypogonadism in males and it is fatal if untreated. A moderate deficiency of zinc is characterized by growth retardation and delayed puberty in adolescents, hypogonadism in males, rough skin, poor appetite, mental lethargy, delayed wound healing, taste abnormalities and abnormal dark adaptation. In mild cases of zinc deficiency in human subjects, we have observed oligospermia, slight weight loss and hyperammonaemia. Zinc is a growth factor. As a result of its deficiency, growth is affected adversely in many animal species and in man. Inasmuch as zinc is needed for protein and DNA synthesis and cell division, it is believed that the growth effect of zinc is related to its effect on protein synthesis. Testicular functions are affected adversely as a result of zinc deficiency in both humans and experimental animals. This effect of zinc is at the end organ level and the hypothalamic--pituitary axis is intact in zinc-deficient subjects. Inasmuch as zinc is intimately involved in a cell division, its deficiency may adversely affect testicular size and thus its function. In mice, the incidence of degenerate oocytes, and hypohaploidy and hyperhaploidy in metaphase II oocytes were increased due to zinc deficiency. Zinc at physiological concentrations reduced prolactin secretion from the pituitary in vitro and it has been

  20. Iodine deficiency disorders in Europe.

    PubMed Central

    Delange, F.; Bürgi, H.

    1989-01-01

    Recent data on iodine excretion in the urine of adults, adolescents and newborns and on the iodine content of breast milk indicate a high prevalence of iodine deficiency (moderate in many cases and severe in a few) in many European countries. These cases may manifest as subclinical hypothyroidism in neonates and as goitre in adolescents and adults. Lack of iodine causes not only goitre, but also mental deficiency, hearing loss and other neurological impairments, and short stature due to thyroid insufficiency during fetal development and childhood. Although iodinated salt is available theoretically in most countries where it is needed, its quality and share of the market are often unsatisfactory. In many countries where only household salt is iodinated the iodine content has been set too low owing to an overestimation of household salt consumption. Governments are therefore urged to pass legislation and provide means for efficient iodination of salt wherever this is necessary. PMID:2670299

  1. Iodine: deficiency and therapeutic considerations.

    PubMed

    Patrick, Lyn

    2008-06-01

    Iodine deficiency is generally recognized as the most commonly preventable cause of mental retardation and the most common cause of endocrinopathy (goiter and primary hypothyroidism). Iodine deficiency becomes particularly critical in pregnancy due to the consequences for neurological damage during fetal development as well as during lactation. The safety of therapeutic doses of iodine above the established safe upper limit of 1 mg is evident in the lack of toxicity in the Japanese population that consumes 25 times the median intake of iodine consumption in the United States. Japan's population suffers no demonstrable increased incidence of autoimmune thyroiditis or hypothyroidism. Studies using 3.0- to 6.0-mg doses to effectively treat fibrocystic breast disease may reveal an important role for iodine in maintaining normal breast tissue architecture and function. Iodine may also have important antioxidant functions in breast tissue and other tissues that concentrate iodine via the sodium iodide symporter. PMID:18590348

  2. Iron deficiency anemia in pregnancy.

    PubMed

    Di Renzo, Gian Carlo; Spano, Filippo; Giardina, Irene; Brillo, Eleonora; Clerici, Graziano; Roura, Luis Cabero

    2015-11-01

    Anemia is the most frequent derailment of physiology in the world throughout the life of a woman. It is a serious condition in countries that are industrialized and in countries with poor resources. The main purpose of this manuscript is to give the right concern of anemia in pregnancy. The most common causes of anemia are poor nutrition, iron deficiencies, micronutrients deficiencies including folic acid, vitamin A and vitamin B12, diseases like malaria, hookworm infestation and schistosomiasis, HIV infection and genetically inherited hemoglobinopathies such as thalassemia. Depending on the severity and duration of anemia and the stage of gestation, there could be different adverse effects including low birth weight and preterm delivery. Treatment of mild anemia prevents more severe forms of anemia, strictly associated with increased risk of fetal-maternal mortality and morbidity. PMID:26472066

  3. Mitochondrial deficiency in Cockayne syndrome

    PubMed Central

    Scheibye-Knudsen, Morten; Croteau, Deborah L.; Bohr, Vilhelm A.

    2013-01-01

    Cockayne syndrome is a rare inherited disorder characterized by accelerated aging, cachectic dwarfism and many other features. Recent work has implicated mitochondrial dysfunction in the pathogenesis of this disease. This is particularly interesting since mitochondrial deficiencies are believed to be important in the aging process. In this review, we will discuss recent findings of mitochondrial pathology in Cockayne syndrome and suggest possible mechanisms for the mitochondrial dysfunction. PMID:23435289

  4. Functional consequences of zinc deficiency.

    PubMed

    McClain, C J; Kasarskis, E J; Allen, J J

    1985-01-01

    Zinc is an essential trace element necessary for over 200 zinc metalloenzymes and required for normal nucleic acid, protein, and membrane metabolism. During the past two decades there has been a rapid expansion of knowledge concerning zinc metabolism in both normal and disease situations, including mechanisms for zinc absorption, excretion and internal redistribution of zinc after stress or trauma. Acrodermatitis enteropathica has been recognized to be a disease of impaired zinc absorption in man. A host of disease processes now are recognized to be complicated by zinc deficiency including alcoholic liver disease, sickle cell anemia, protein calorie malnutrition, and a variety of intestinal diseases including Crohn's disease, sprue, short bowel syndrome and after jejunal ileal bypass. Zinc has proved to be an extremely interesting mineral to nutritionists and physicians because of its importance in normal physiology and biochemistry and because of the diverse presenting features of zinc deficiency. This paper reviews ten functional consequences of zinc deficiency and emphasizes certain consequences in which there have been new discoveries concerning their mechanism (e.g., anorexia) or their clinical importance (e.g., immune dysfunction). PMID:3911268

  5. Vitamin D recommendations: beyond deficiency.

    PubMed

    Biesalski, Hans K

    2011-01-01

    Vitamin D plays an important role in regular bone growth and in adequate function of the innate immune system, including barrier functions of mucous membranes. A sufficient supply during pregnancy and lactation protects the child from infectious diseases. Clinical symptoms of severe vitamin D deficiency (rickets) are well known and can be easily detected. Signs and symptoms beyond deficiency, however, remain to be elucidated. Based on clinical and observational data, the plasma level of 25(OH)D may serve as a 'marker' to detect or define a subclinical deficiency. Levels below 50 nmol/l might be insufficient to maintain the non-bone-related activities of vitamin D. Finally, it has to be considered that all of the nonbone activities of vitamin D are in concert with vitamin A (9-cis retinoic acid). Studies combining both vitamins in sufficient amounts (cod liver oil) demonstrated a beneficial effect on the prevention of respiratory tract infections. Consequently, it should be strongly recommended to increase the intake of vitamin D and to ensure a daily intake of vitamin A as counseled. PMID:22123631

  6. Mitochondrial Cytochrome c Oxidase Deficiency

    PubMed Central

    Rak, Malgorzata; Bénit, Paule; Chrétien, Dominique; Bouchereau, Juliette; Schiff, Manuel; El-Khoury, Riyad; Tzagoloff, Alexander; Rustin, Pierre

    2016-01-01

    As with other mitochondrial respiratory chain components, marked clinical and genetic heterogeneity is observed in patients with a cytochrome c oxidase deficiency. This constitutes a considerable diagnostic challenge and raises a number of puzzling questions. So far, pathological mutations have been reported in more than 30 genes, in both mitochondrial and nuclear DNA, affecting either structural subunits of the enzyme or proteins involved in its biogenesis. In this review, we discuss the possible causes of the discrepancy between the spectacular advances made in the identification of the molecular bases of cytochrome oxidase deficiency and the lack of any efficient treatment in diseases resulting from such deficiencies. This brings back many unsolved questions related to the frequent delay of clinical manifestation, variable course and severity, and tissue-involvement often associated with these diseases. In this context, we stress the importance to study different models of these diseases, but also discuss the limitations encountered in most available disease models. In the future, with the possible exception of replacement therapy using genes, cells or organs, a better understanding of underlying mechanism(s) of these mitochondrial diseases is presumably required to develop efficient therapy. PMID:26846578

  7. The Meniscus-Deficient Knee

    PubMed Central

    Rao, Allison J.; Erickson, Brandon J.; Cvetanovich, Gregory L.; Yanke, Adam B.; Bach, Bernard R.; Cole, Brian J.

    2015-01-01

    Meniscal tears are the most common knee injury, and partial meniscectomies are the most common orthopaedic surgical procedure. The injured meniscus has an impaired ability to distribute load and resist tibial translation. Partial or complete loss of the meniscus promotes early development of chondromalacia and osteoarthritis. The primary goal of treatment for meniscus-deficient knees is to provide symptomatic relief, ideally to delay advanced joint space narrowing, and ultimately, joint replacement. Surgical treatments, including meniscal allograft transplantation (MAT), high tibial osteotomy (HTO), and distal femoral osteotomy (DFO), are options that attempt to decrease the loads on the articular cartilage of the meniscus-deficient compartment by replacing meniscal tissue or altering joint alignment. Clinical and biomechanical studies have reported promising outcomes for MAT, HTO, and DFO in the postmeniscectomized knee. These procedures can be performed alone or in conjunction with ligament reconstruction or chondral procedures (reparative, restorative, or reconstructive) to optimize stability and longevity of the knee. Complications can include fracture, nonunion, patella baja, compartment syndrome, infection, and deep venous thrombosis. MAT, HTO, and DFO are effective options for young patients suffering from pain and functional limitations secondary to meniscal deficiency. PMID:26779547

  8. Nutritional Deficiencies and Phospholipid Metabolism

    PubMed Central

    Gimenez, María S.; Oliveros, Liliana B.; Gomez, Nidia N.

    2011-01-01

    Phospholipids are important components of the cell membranes of all living species. They contribute to the physicochemical properties of the membrane and thus influence the conformation and function of membrane-bound proteins, such as receptors, ion channels, and transporters and also influence cell function by serving as precursors for prostaglandins and other signaling molecules and modulating gene expression through the transcription activation. The components of the diet are determinant for cell functionality. In this review, the effects of macro and micronutrients deficiency on the quality, quantity and metabolism of different phospholipids and their distribution in cells of different organs is presented. Alterations in the amount of both saturated and polyunsaturated fatty acids, vitamins A, E and folate, and other micronutrients, such as zinc and magnesium, are discussed. In all cases we observe alterations in the pattern of phospholipids, the more affected ones being phosphatidylcholine, phosphatidylethanolamine and sphingomyelin. The deficiency of certain nutrients, such as essential fatty acids, fat-soluble vitamins and some metals may contribute to a variety of diseases that can be irreversible even after replacement with normal amount of the nutrients. Usually, the sequelae are more important when the deficiency is present at an early age. PMID:21731449

  9. Flu Vaccine Guidance for Patients with Immune Deficiency

    MedlinePlus

    ... Guidance for Patients with Immune Deficiency Share | Flu Vaccine Guidance for Patients with Immune Deficiency This article ... should patients with immune deficiency be given the vaccine? Immune deficient patients have a decreased resistance to ...

  10. Developmental vitamin D deficiency causes abnormal brain development.

    PubMed

    Eyles, D W; Feron, F; Cui, X; Kesby, J P; Harms, L H; Ko, P; McGrath, J J; Burne, T H J

    2009-12-01

    There is now clear evidence that vitamin D is involved in brain development. Our group is interested in environmental factors that shape brain development and how this may be relevant to neuropsychiatric diseases including schizophrenia. The origins of schizophrenia are considered developmental. We hypothesised that developmental vitamin D (DVD) deficiency may be the plausible neurobio