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  1. 5-Lipoxygenase deficiency impairs innate and adaptive immune responses during fungal infection.

    PubMed

    Secatto, Adriana; Rodrigues, Lilian Cataldi; Serezani, Carlos Henrique; Ramos, Simone Gusmão; Dias-Baruffi, Marcelo; Faccioli, Lúcia Helena; Medeiros, Alexandra I

    2012-01-01

    5-Lipoxygenase-derived products have been implicated in both the inhibition and promotion of chronic infection. Here, we sought to investigate the roles of endogenous 5-lipoxygenase products and exogenous leukotrienes during Histoplasma capsulatum infection in vivo and in vitro. 5-LO deficiency led to increased lung CFU, decreased nitric oxide production and a deficient primary immune response during active fungal infection. Moreover, H. capsulatum-infected 5-LO(-/-) mice showed an intense influx of neutrophils and an impaired ability to generate and recruit effector T cells to the lung. The fungal susceptibility of 5-LO(-/-) mice correlated with a lower rate of macrophage ingestion of IgG-H. capsulatum relative to WT macrophages. Conversely, exogenous LTB4 and LTC4 restored macrophage phagocytosis in 5-LO deficient mice. Our results demonstrate that leukotrienes are required to control chronic fungal infection by amplifying both the innate and adaptive immune response during histoplasmosis.

  2. A Novel 5-Lipoxygenase-Activating Protein Inhibitor, AM679, Reduces Inflammation in the Respiratory Syncytial Virus-Infected Mouse Eye▿

    PubMed Central

    Musiyenko, Alla; Correa, Lucia; Stock, Nicholas; Hutchinson, John H.; Lorrain, Daniel S.; Bain, Gretchen; Evans, Jilly F.; Barik, Sailen

    2009-01-01

    Respiratory syncytial virus (RSV) is an important cause of viral respiratory disease in children, and RSV bronchiolitis has been associated with the development of asthma in childhood. RSV spreads from the eye and nose to the human respiratory tract. Correlative studies of humans and direct infection studies of BALB/c mice have established the eye as a significant pathway of entry of RSV to the lung. At the same time, RSV infection of the eye produces symptoms resembling allergic conjunctivitis. Cysteinyl leukotrienes (CysLTs) are known promoters of allergy and inflammation, and the first step in their biogenesis from arachidonic acid is catalyzed by 5-lipoxygenase (5-LO) in concert with the 5-LO-activating protein (FLAP). We have recently developed a novel compound, AM679, which is a topically applied and potent inhibitor of FLAP. Here we show with the BALB/c mouse eye RSV infection model that AM679 markedly reduced the RSV-driven ocular pathology as well as the synthesis of CysLTs in the eye. In addition, AM679 decreased the production of the Th2 cell cytokine interleukin-4 but did not increase the viral load in the eye or the lung. These results suggest that FLAP inhibitors may be therapeutic for RSV-driven eye disease and possibly other inflammatory eye indications. PMID:19759251

  3. Augmentation of 5-lipoxygenase activity and expression during dengue serotype-2 infection

    PubMed Central

    2013-01-01

    Background Leukotriene B4, a 5-lipoxygenase product of arachidonic acid with potent chemotactic effects on neutrophils, has not been assessed in dengue patients. In this study, plasma leukotriene B4 and serum high-sensitivity C-reactive protein levels were determined in adult patients during the febrile, convalescent and defervescent stages of dengue serotype-2 (DENV-2) infection, and compared with those of age--matched healthy and non-dengue febrile subjects. In vitro studies were performed to examine the effects of live and heat-inactivated DENV-2 on the activities and expression of 5-lipoxygenase in human neutrophils. Results Plasma leukotriene B4 was elevated during the febrile stages of dengue infection compared to levels during convalescence and in study controls. Plasma leukotriene B4 also correlated with serum high-sensitivity C-reactive protein in dengue patients (febrile, r = 0.91, p < 0.001; defervescence, r = 0.87, p < 0.001; convalescence, r = 0.87, p < 0.001). Exposure of human neutrophils to DENV-2 resulted in a significant rise in leukotriene B4; the extent of increase, however, did not differ between exposure to live and heat-inactivated DENV-2. Pre-incubation of either live or heat-inactivated DENV-2 resulted in reduced leukotriene B4 release by neutrophils, indicating that contact with dengue antigens (and not replication) triggers the neutrophil response. Production of leukotriene B4 was associated with an increase in 5-lipoxygenase expression in human neutrophils; addition of MK886 (a 5-lipoxygenase activating protein inhibitor) attenuated further increase in leukotriene B4 production. Conclusion These findings provide important clinical and mechanistic data on the involvement of 5-lipoxygenase and its metabolites in dengue infection. Further studies are needed to elucidate the therapeutic implications of these findings. PMID:24168271

  4. 5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders.

    PubMed

    Manev, Radmila; Manev, Hari

    2004-01-01

    There is evidence of an association between depression and anxiety and cardio- cerebro-vascular conditions, but the mechanisms of this association are unknown. Here we review a possible role for the 5-lipoxygenase (5-LOX) pathway. 5-LOX is an enzyme that, in association with 5-LOX-activating protein (FLAP), leads to the synthesis of leukotrienes from omega-6 arachidonic acid. Production of active leukotrienes can be reduced by dietary omega-3 fatty acids, which also are beneficial in cardiac and psychiatric (e.g., depression) pathologies. Human 5-LOX and FLAP gene polymorphisms are a risk factor in atherosclerosis and cardio-cerebro-vascular pathologies; an overactive 5-LOX pathway is found in these diseases. Studies with 5-LOX-deficient transgenic mice suggest that 5-LOX activity may contribute to anxiety- and depression-like behaviors. Future research should characterize the role of the 5-LOX pathway in comorbid cardio-cerebro-vascular and psychiatric disorders and in the therapeutic actions of dietary omega-3 fatty acids.

  5. 5-lipoxygenase knockout mice exhibit a resistance to acute pancreatitis induced by cerulein

    PubMed Central

    Cuzzocrea, Salvatore; Rossi, Antonietta; Serraino, Ivana; Di Paola, Rosanna; Dugo, Laura; Genovese, Tiziana; Britti, Domenico; Sciarra, Giuseppe; De Sarro, Angelina; Caputi, Achille P; Sautebin, Lidia

    2003-01-01

    Here we compare the degree of pancreatitis caused by cerulein in mice lacking 5-lipoxygenase (5-LO) and in the corresponding wild-type mice. Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by oedema, neutrophil infiltration and necrosis and elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in immunoreactivity for intracellular adhesion molecule-1 (ICAM-1), P-selectin and E-selectin in the pancreas and lung of cerulein-treated mice. In contrast, the degree of (1) pancreatic inflammation and tissue injury (histological score), (2) up-regulation/expression of P-selectin, E-selectin and ICAM-1, and (3) neutrophil infiltration was markedly reduced in pancreatic and lung tissue obtained from cerulein-treated 5-LO-deficient mice. These findings support the view that 5-LO plays an important, pro-inflammatory role in the acute pancreatitis caused by cerulein in mice. PMID:12941149

  6. The Protective Effect of Eupatilin against Hydrogen Peroxide-Induced Injury Involving 5-Lipoxygenase in Feline Esophageal Epithelial Cells

    PubMed Central

    Lim, Jae Chun; Park, Sun Young; Nam, Yoonjin; Nguyen, Thanh Thao

    2012-01-01

    In this study, we focused to identify whether eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone), an extract from Artemisia argyi folium, prevents H2O2-induced injury of cultured feline esophageal epithelial cells. Cell viability was measured by the conventional MTT reduction assay. Western blot analysis was performed to investigate the expression of 5-lipoxygenase by H2O2 treatment in the absence and presence of inhibitors. When cells were exposed to 600 µM H2O2 for 24 hours, cell viability was decreased to 40%. However, when cells were pretreated with 25~150 µM eupatilin for 12 hours, viability was significantly restored in a concentration-dependent manner. H2O2-treated cells were shown to express 5-lipoxygenase, whereas the cells pretreated with eupatilin exhibited reduction in the expression of 5-lipoxygenase. The H2O2-induced increase of 5-lipoxygenase expression was prevented by SB202190, SP600125, or NAC. We further demonstrated that the level of leukotriene B4 (LTB4) was also reduced by eupatilin, SB202190, SP600125, NAC, or nordihydroguaiaretic acid (a lipoxygenase inhibitor) pretreatment. H2O2 induced the activation of p38MAPK and JNK, this activation was inhibited by eupatilin. These results indicate that eupatilin may reduce H2O2-induced cytotoxicity, and 5-lipoxygenase expression and LTB4 production by controlling the p38 MAPK and JNK signaling pathways through antioxidative action in feline esophageal epithelial cells. PMID:23118554

  7. 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.

  8. Synthesis and 5-lipoxygenase inhibitory activity of new cinnamoyl and caffeoyl clusters.

    PubMed

    Doiron, Jérémie; Boudreau, Luc H; Picot, Nadia; Villebonet, Benoît; Surette, Marc E; Touaibia, Mohamed

    2009-02-15

    Novel cinnamoyl and caffeoyl clusters were synthesized by multiple Cu(I)-catalyzed [1,3]-dipolar cycloadditions and their anti-5-lipoxygenase inhibitory activity was tested. Caffeoyl cluster showed an improved 5-lipoxygenase inhibitory activity compared to caffeic acid, with caffeoyl trimer 16 and tetramer 19 showing the best 5-lipoxygenase inhibitory activity.

  9. 5-lipoxygenase mRNA and protein isoforms.

    PubMed

    Ochs, Meike J; Suess, Beatrix; Steinhilber, Dieter

    2014-01-01

    5-Lipoxygenase (5-LO) catalyses the two initial steps in the biosynthesis of leukotrienes, a group of inflammatory lipid mediators derived from arachidonic acid. An increased level of leukotrienes is associated with chronic inflammatory diseases such as asthma or atherosclerosis. In this MiniReview, we focus on recent findings regarding alternative splice variants of 5-LO with a special emphasis on two potential protein isoforms expressed in human B-lymphocytes which might be of interest as new drug targets.

  10. 5-lipoxygenase and 5-lipoxygenase-activating protein gene polymorphisms, dietary linoleic acid, and risk for breast cancer.

    PubMed

    Wang, Jun; John, Esther M; Ingles, Sue Ann

    2008-10-01

    The n-6 polyunsaturated fatty acid 5-lipoxygenase pathway has been shown to play a role in the carcinogenesis of breast cancer. We conducted a population-based case-control study among Latina, African-American, and White women from the San Francisco Bay area to examine the association of the 5-lipoxygenase gene (ALOX5) and 5-lipoxygenase-activating protein gene (ALOX5AP) with breast cancer risk. Three ALOX5AP polymorphisms [poly(A) microsatellite, -4900 A>G (rs4076128), and -3472 A>G (rs4073259)] and three ALOX5 polymorphisms [Sp1-binding site (-GGGCGG-) variable number of tandem repeat polymorphism, -1279 G>T (rs6593482), and 760 G>A (rs2228065)] were genotyped in 802 cases and 888 controls. We did not find significant main effects of ALOX5 and ALOX5AP genotypes on breast cancer risk that were consistent across race or ethnicity; however, there was a significant interaction between the ALOX5AP -4900 A>G polymorphism and dietary linoleic acid intake (P=0.03). Among women consuming a diet high in linoleic acid (top quartile of intake, >17.4 g/d), carrying the AA genotype was associated with higher breast cancer risk (age- and race-adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.9) compared with carrying genotypes AG or GG. Among women consuming

  11. Stress-induced nuclear export of 5-lipoxygenase

    SciTech Connect

    Hanaka, Hiromi; Shimizu, Takao; Izumi, Takashi . E-mail: takizumi@med.gunma-u.ac.jp

    2005-12-09

    A key enzyme for leukotriene biosynthesis is 5-lipoxygenase (5-LO), which we found is exported from the nucleus when p38 MAPK is activated. CHO-K1 cells stably express green fluorescent protein-5-lipoxygenase fusion protein (GFP-5LO), which is located predominantly in the nucleus, and is exported by anisomycin, hydrogen peroxide, and sorbitol, with activation of p38 MAPK. SB203580, an inhibitor of p38 MAPK, and Leptomycin B, an inhibitor of the nuclear export, blocked the anisomycin-induced export of GFP-5LO. When HEK293 cells were transformed with plasmids for wild-type GFP-5LO, GFP-5LO-S271A or GFP-5LO-S271E mutants, most wild-type GFP-5LO and GFP-5LO-S271A localized in the nucleus, but GFP-5LO-S271E localized in the cytosol. Thus, phosphorylation at Ser-271 of 5-LO is important for its export. Endogenous 5-LO in RBL cells stimulated with anisomycin was also exported from the nucleus. These results suggest that the nuclear export of 5-LO depends on the stress-induced activation of the p38 MAPK pathway.

  12. A23187-induced translocation of 5-lipoxygenase in osteosarcoma cells

    PubMed Central

    1992-01-01

    In a previous study, osteosarcoma cells expressing both 5-lipoxygenase (5-LO) and 5 lipoxygenase-activating protein (FLAP) synthesized leukotrienes upon A23187 stimulation (Dixon, R. A. F., R. E. Diehl, E. Opas, E. Rands, P. J. Vickers, J. F. Evans, J. W. Gillard, and D. K. Miller. 1990. Nature (Lond.). 343:282-284). Osteosarcoma cells expressing 5-LO but not expressing FLAP were unable to synthesize leukotrienes. Thus, it was determined that FLAP was required for the cellular synthesis of leukotrienes. To examine the role of FLAP in A23187-induced translocation of 5-LO to a membrane fraction, we have studied the A23187-stimulated translocation of 5-LO in osteosarcoma cells expressing both 5-LO and FLAP, and in osteosarcoma cells expressing 5-LO only. We demonstrate that in cells expressing both 5-LO and FLAP, 5-LO translocates to membranes in response to A23187 stimulation. This 5-LO translocation is inhibited when cells are stimulated in the presence of MK-886. In osteosarcoma cells expressing 5-LO but not expressing FLAP, 5-LO is able to associate with membranes following A23187 stimulation. In contrast to the cells containing both 5-LO and FLAP, MK-886 is unable to prevent 5-LO membrane association in cells transfected with 5-LO alone. Therefore, we have demonstrated that in this cell system, 5-LO membrane association and activation can be separated into at least two distinct steps: (1) calcium-dependent movement of 5-LO to membranes without product formation, which can occur in the absence of FLAP (membrane association), and (2) activation of 5-LO with product formation, which is FLAP dependent and inhibited by MK-886 (enzyme activation). PMID:1469057

  13. Expression of 5-lipoxygenase and 5-lipoxygenase-activating protein in human fetal membranes throughout pregnancy and at term.

    PubMed

    Brown, N L; Slater, D M; Alvi, S A; Elder, M G; Sullivan, M H; Bennett, P R

    1999-07-01

    Lipoxygenase metabolites may be involved in human parturition. 5-lipoxygenase (5-LOX) catalyses the first steps in the synthesis of leukotrienes from arachidonic acid, and its activity is dependent on 5-LOX activating protein (FLAP). The expression of 5-LOX and FLAP were investigated in fetal membranes to determine whether there are changes with gestational age or at term with the onset of labour. No significant differences were found in the expression of 5-LOX or FLAP mRNA in the amnion at different gestational ages or at term. In the chorion-decidua, 5-LOX mRNA expression was significantly higher in the first trimester of pregnancy than in the second and third trimesters. At term, there was a significant increase in both 5-LOX mRNA and protein expression in the chorion-decidua in the time after labour, compared with the time before labour. The expression of FLAP mRNA was also significantly higher in the chorion-decidua in the first trimester of pregnancy compared with the third trimester, and at term in the time after labour compared with the time before labour. Expression of FLAP protein was not studied, as an antibody is not currently available. These results are consistent with a role for 5-LOX and FLAP in the control of parturition at term, and also suggest an involvement earlier in pregnancy.

  14. 5-lipoxygenase-dependent recruitment of neutrophils and macrophages by eotaxin-stimulated murine eosinophils.

    PubMed

    Luz, Ricardo Alves; Xavier-Elsas, Pedro; de Luca, Bianca; Masid-de-Brito, Daniela; Cauduro, Priscila Soares; Arcanjo, Luiz Carlos Gondar; dos Santos, Ana Carolina Cordeiro Faria; de Oliveira, Ivi Cristina Maria; Gaspar-Elsas, Maria Ignez Capella

    2014-01-01

    The roles of eosinophils in antimicrobial defense remain incompletely understood. In ovalbumin-sensitized mice, eosinophils are selectively recruited to the peritoneal cavity by antigen, eotaxin, or leukotriene(LT)B4, a 5-lipoxygenase (5-LO) metabolite. 5-LO blockade prevents responses to both antigen and eotaxin. We examined responses to eotaxin in the absence of sensitization and their dependence on 5-LO. BALB/c or PAS mice and their mutants (5-LO-deficient ALOX; eosinophil-deficient GATA-1) were injected i.p. with eotaxin, eosinophils, or both, and leukocyte accumulation was quantified up to 24 h. Significant recruitment of eosinophils by eotaxin in BALB/c, up to 24 h, was accompanied by much larger numbers of recruited neutrophils and monocytes/macrophages. These effects were abolished by eotaxin neutralization and 5-LO-activating protein inhibitor MK886. In ALOX (but not PAS) mice, eotaxin recruitment was abolished for eosinophils and halved for neutrophils. In GATA-1 mutants, eotaxin recruited neither neutrophils nor macrophages. Transfer of eosinophils cultured from bone-marrow of BALB/c donors, or from ALOX donors, into GATA-1 mutant recipients, i.p., restored eotaxin recruitment of neutrophils and showed that the critical step dependent on 5-LO is the initial recruitment of eosinophils by eotaxin, not the secondary neutrophil accumulation. Eosinophil-dependent recruitment of neutrophils in naive BALB/c mice was associated with increased binding of bacteria.

  15. Accelerated fracture healing in mice lacking the 5-lipoxygenase gene

    PubMed Central

    2010-01-01

    Background and purpose Cyclooxygenase-2 (COX-2) promotes inflammation by synthesizing pro-inflammatory prostaglandins from arachidonic acid. Inflammation is an early response to bone fracture, and ablation of COX-2 activity impairs fracture healing. Arachidonic acid is also converted into leukotrienes by 5-lipoxygenase (5-LO). We hypothesized that 5-LO is a negative regulator of fracture healing and that in the absence of COX-2, excess leukotrienes synthesized by 5-LO will impair fracture healing. Methods Fracture healing was assessed in mice with a targeted 5-LO mutation (5-LOKO mice) and control mice by radiographic and histological observations, and measured by histomorphometry and torsional mechanical testing. To assess effects on arachidonic acid metabolism, prostaglandin E2, F2α, and leukotriene B4 levels were measured in the fracture calluses of control, 5-LOKO COX-1KO, and COX-2KO mice by enzyme linked immunoassays. Results Femur fractures in 5-LOKO mice rapidly developed a cartilaginous callus that was replaced with bone to heal fractures faster than in control mice. Femurs from 5-LOKO mice had substantially better mechanical properties after 1 month of healing than did control mice. Callus leukotriene levels were 4-fold higher in mice homozygous for a targeted mutation in the COX-2 gene (COX-2KO), which indicated that arachidonic acid was shunted into the 5-LO pathway in the absence of COX-2. Interpretation These experiments show that 5-LO negatively regulates fracture healing and that shunting of arachidonic acid into the 5-LO pathway may account, at least in part, for the impaired fracture healing response observed in COX-2KO mice. PMID:21067431

  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. 5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation.

    PubMed

    Bäck, Magnus; Sultan, Ariane; Ovchinnikova, Olga; Hansson, Göran K

    2007-04-13

    Transforming growth factor-beta (TGF-beta) is a major antiinflammatory mediator in atherosclerosis. Transgenic ApoE(-/-) mice with a dominant-negative TGFbeta type II receptor (dnTGFbetaRII) on CD4(+) and CD8(+) T cells display aggravated atherosclerosis. The aim of the present study was to elucidate the mechanisms involved in this enhanced inflammatory response. Gene array analyses identified the 5-lipoxygenase-activating protein (FLAP) among the most upregulated genes in both the aorta and adipose tissue of dnTGFbetaRII transgenic ApoE(-/-) mice compared with their ApoE(-/-) littermates, a finding that was confirmed by real-time quantitative RT-PCR. Aortas from the former mice in addition produced increased amounts of the lipoxygenase product leukotriene B(4) after ex vivo stimulation. FLAP protein expression in both the aorta and adipose tissue was detected in macrophages, but not in T cells. Four weeks of treatment with the FLAP inhibitor MK-886 (10 mg/kg in 1% tylose delivered by osmotic pumps) significantly reduced atherosclerotic lesion size and T-cell content. Finally, FLAP mRNA levels were upregulated approximately 8-fold in adipose tissue derived from obese ob/ob mice. In conclusion, the results of the present study suggest a key role for mediators of the 5-lipoxygenase pathway in inflammatory reactions of atherosclerosis and metabolic disease.

  18. 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.

  19. 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

  20. The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages

    PubMed Central

    Rossi, A; Pergola, C; Koeberle, A; Hoffmann, M; Dehm, F; Bramanti, P; Cuzzocrea, S; Werz, O; Sautebin, L

    2010-01-01

    BACKGROUND AND PURPOSE Zileuton is the only 5-lipoxygenase (5-LOX) inhibitor marketed as a treatment for asthma, and is often utilized as a selective tool to evaluate the role of 5-LOX and leukotrienes. The aim of this study was to investigate the effect of zileuton on prostaglandin (PG) production in vitro and in vivo. EXPERIMENTAL APPROACH Peritoneal macrophages activated with lipopolysaccharide (LPS)/interferon γ (LPS/IFNγ), J774 macrophages and human whole blood stimulated with LPS were used as in vitro models and rat carrageenan-induced pleurisy as an in vivo model. KEY RESULTS Zileuton suppressed PG biosynthesis by interference with arachidonic acid (AA) release in macrophages. We found that zileuton significantly reduced PGE2 and 6-keto prostaglandin F1α (PGF1α) levels in activated mouse peritoneal macrophages and in J774 macrophages. This effect was not related to 5-LOX inhibition, because it was also observed in macrophages from 5-LOX knockout mice. Notably, zileuton inhibited PGE2 production in LPS-stimulated human whole blood and suppressed PGE2 and 6-keto PGF1α pleural levels in rat carrageenan-induced pleurisy. Interestingly, zileuton failed to inhibit the activity of microsomal PGE2 synthase1 and of cyclooxygenase (COX)-2 and did not affect COX-2 expression. However, zileuton significantly decreased AA release in macrophages accompanied by inhibition of phospholipase A2 translocation to cellular membranes. CONCLUSIONS AND IMPLICATION Zileuton inhibited PG production by interfering at the level of AA release. Its mechanism of action, as well as its use as a pharmacological tool, in experimental models of inflammation should be reassessed. PMID:20880396

  1. Screening of some rare endemic Italian plants for inhibitory activity on 5-lipoxygenase.

    PubMed

    Prieto, José-María; Bader, Ammar; Martini, Francesca; Ríos, José-Luis; Morelli, Ivano

    2005-12-01

    The extracts of four rare plants found on the islands of Sicily, Vulcano and Marettimo, Southern Italy, were screened for their inhibitory effect on the production of leukotriene B4 by 5-lipoxygenase in intact cells. The methanol extracts of pods of Cytisus aeolicus and aerial parts of Thymus richardii were the most active extracts, inhibiting almost completely the leukotriene B4 production at 200 and 50 microg/ml, respectively.

  2. Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway

    PubMed Central

    Moore, Gillian Y.; Pidgeon, Graham P.

    2017-01-01

    5-lipoxygenase is an enzyme responsible for the synthesis of a range of bioactive lipids signalling molecules known collectively as eicosanoids. 5-lipoxygenase metabolites such as 5-hydroxyeicosatetraenoic acid (5-HETE) and a number of leukotrienes are mostly derived from arachidonic acid and have been shown to be lipid mediators of inflammation in different pathological states including cancer. Upregulated 5-lipoxygenase expression and metabolite production is found in a number of cancer types and has been shown to be associated with increased tumorigenesis. 5-lipoxygenase activity is present in a number of diverse cell types of the immune system and connective tissue. In this review, we discuss potential routes through which cancer cells may utilise the 5-lipoxygenase pathway to interact with the tumour microenvironment during the development and progression of a tumour. Furthermore, immune-derived 5-lipoxygenase signalling can drive both pro- and anti-tumour effects depending on the immune cell subtype and an overview of evidence for these opposing effects is presented. PMID:28125014

  3. 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

  4. Roles of 5-lipoxygenase and cysteinyl-leukotriene type 1 receptors in the hematological response to allergen challenge and its prevention by diethylcarbamazine in a murine model of asthma.

    PubMed

    Masid-de-Brito, Daniela; Queto, Túlio; Gaspar-Elsas, Maria Ignez C; Xavier-Elsas, Pedro

    2014-01-01

    Diethylcarbamazine (DEC), which blocks leukotriene production, abolishes the challenge-induced increase in eosinopoiesis in bone-marrow from ovalbumin- (OVA-) sensitized mice, suggesting that 5-lipoxygenase (5-LO) products contribute to the hematological responses in experimental asthma models. We explored the relationship between 5-LO, central and peripheral eosinophilia, and effectiveness of DEC, using PAS or BALB/c mice and 5-LO-deficient mutants. We quantified eosinophil numbers in freshly harvested or cultured bone-marrow, peritoneal lavage fluid, and spleen, with or without administration of leukotriene generation inhibitors (DEC and MK886) and cisteinyl-leukotriene type I receptor antagonist (montelukast). The increase in eosinophil numbers in bone-marrow, observed in sensitized/challenged wild-type mice, was abolished by MK886 and DEC pretreatment. In ALOX mutants, by contrast, there was no increase in bone-marrow eosinophil counts, nor in eosinophil production in culture, in response to sensitization/challenge. In sensitized/challenged ALOX mice, challenge-induced migration of eosinophils to the peritoneal cavity was significantly reduced relative to the wild-type PAS controls. DEC was ineffective in ALOX mice, as expected from a mechanism of action dependent on 5-LO. In BALB/c mice, challenge significantly increased spleen eosinophil numbers and DEC treatment prevented this increase. Overall, 5-LO appears as indispensable to the systemic hematological response to allergen challenge, as well as to the effectiveness of DEC.

  5. Effect of a 5-lipoxygenase inhibitor on nerve growth factor-induced thermal hyperalgesia in the rat.

    PubMed

    Amann, R; Schuligoi, R; Lanz, I; Peskar, B A

    1996-06-13

    Intraplantar injection of mouse beta (2.5S) nerve growth factor (NGF) caused thermal hyperalgesia and stimulated release of immunoreactive leukotriene B4 from the rat paw skin. Both effects of NGF were prevented by the 5-lipoxygenase inhibitor, (R)-2-[4-quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid (BAY X1005). BAY X1005 did not affect bradykinin-induced thermal hyperalgesia. These results suggest the participation of 5-lipoxygenase products of arachidonate in NGF-induced local thermal hyperalgesia.

  6. A fluorescence-based assay for measuring the redox potential of 5-lipoxygenase inhibitors.

    PubMed

    Lee, Sangchul; Park, Youngsam; Kim, Junghwan; Han, Sung-Jun

    2014-01-01

    The activities and side effects of 5-lipoxygenase (5-LO) inhibitors can be predicted by identifying their redox mechanisms. In this study, we developed a fluorescence-based method to measure the redox potential of 5-LO inhibitors and compared it to the conventional, absorbance-based method. After the pseudo-peroxidase reaction, the amount of remaining lipid peroxide was quantified using the H2DCFDA (2',7'-dichlorodihydrofluorescein diacetate) fluorescence dye. Our method showed large signal windows and provided comparable redox potential values. Importantly, the redox mechanisms of known inhibitors were accurately measured with the fluorescence assay, whereas the conventional, absorbance-based method showed contradictory results. Our findings suggest that our developed method is a better alternative for classifying the redox potential of 5-LO inhibitors, and the fluorescence assay can be effectively used to study the mechanisms of action that are related to redox cycling.

  7. Gene expression of 5-lipoxygenase and LTA4 hydrolase in renal tissue of nephrotic syndrome patients

    PubMed Central

    Menegatti, E; Roccatello, D; Fadden, K; Piccoli, G; De Rosa, G; Sena, L M; Rifai, A

    1999-01-01

    Leukotrienes (LT) of the 5-lipoxygenase pathway constitute a class of potent biological lipid mediators of inflammation implicated in the pathogenesis of different models of experimental glomerulonephritis. The key enzyme, 5-lipoxygenase (5-LO), catalyses oxygenation of arachidonic acid to generate the primary leukotriene LTA4. This LT, in turn, serves as a substrate for either LTA4 hydrolase, to form the potent chemoattractant LTB4, or LTC4 synthase, to produce the powerful vasoconstrictor LTC4. To investigate the potential role of LT in the pathogenesis of human glomerulonephritis with nephrotic syndrome, we examined the gene expression of 5-LO and LTA4 hydrolase in renal tissue of 21 adult patients with nephrotic syndrome and 11 controls. The patients consisted of 11 cases of membranous nephropathy (MN), seven focal and segmental glomerulosclerosis (FSGS), two non-IgA mesangial glomerulonephritis and one minimal change disease. Total RNA purified from renal tissue was reverse transcribed into cDNA and amplified with specific primers in a polymerase chain reaction (RT-PCR). Eight patients' renal tissue, four MN and four FSGS, co-expressed 5-LO and LTA4 hydrolase. In situ hybridization analysis revealed 5-LO expression and distribution limited to the interstitial cells surrounding the peritubular capillaries. Comparative clinical and immunohistological data showed that these eight patients had impaired renal function and interstitial changes that significantly correlated with 5-LO expression. These findings suggest that leukotrienes may play an important role in the pathogenesis of MN and FSGS. These results are also relevant to elucidating the pathophysiologic mechanisms which underlie progression to renal failure in these diseases. PMID:10337029

  8. Cylindol A, a novel biphenyl ether with 5-lipoxygenase inhibitory activity, and a related compound from Imperata Cylindrica.

    PubMed

    Matsunaga, K; Ikeda, M; Shibuya, M; Ohizumi, Y

    1994-09-01

    Cylindol A [1] and B [2], two novel substances, have been isolated from Imperata cylindrica, and their structures have been elucidated on the basis of their spectral data coupled with chemical evidence and total synthesis. Cylindol A [1] showed 5-lipoxygenase inhibitory activity.

  9. Regulation of leukotriene and 5oxoETE synthesis and the effect of 5-lipoxygenase inhibitors: a mathematical modeling approach

    PubMed Central

    2012-01-01

    Background 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes and 5-Oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (oxoETE). These inflammatory signaling molecules play a role in the pathology of asthma and so 5-LO inhibition is a promising target for asthma therapy. The 5-LO redox inhibitor zileuton (Zyflo IR/CR®) is currently marketed for the treatment of asthma in adults and children, but widespread use of zileuton is limited by its efficacy/safety profile, potentially related to its redox characteristics. Thus, a quantitative, mechanistic description of its functioning may be useful for development of improved anti-inflammatory targeting this mechanism. Results A mathematical model describing the operation of 5-LO, phospholipase A2, glutathione peroxidase and 5-hydroxyeicosanoid dehydrogenase was developed. The catalytic cycles of the enzymes were reconstructed and kinetic parameters estimated on the basis of available experimental data. The final model describes each stage of cys-leukotriene biosynthesis and the reactions involved in oxoETE production. Regulation of these processes by substrates (phospholipid concentration) and intracellular redox state (concentrations of reduced glutathione, glutathione (GSH), and lipid peroxide) were taken into account. The model enabled us to reveal differences between redox and non-redox 5-LO inhibitors under conditions of oxidative stress. Despite both redox and non-redox inhibitors suppressing leukotriene A4 (LTA4) synthesis, redox inhibitors are predicted to increase oxoETE production, thus compromising efficacy. This phenomena can be explained in terms of the pseudo-peroxidase activity of 5-LO and the ability of lipid peroxides to transform 5-LO into its active form even in the presence of redox inhibitors. Conclusions The mathematical model developed described quantitatively different mechanisms of 5-LO inhibition and simulations revealed differences between the potential therapeutic outcomes for these

  10. Ethanol Promotes Chemically Induced Oral Cancer in Mice through Activation of the 5-Lipoxygenase Pathway of Arachidonic Acid Metabolism

    PubMed Central

    Guo, Yizhu; Wang, Xin; Zhang, Xinyan; Sun, Zheng; Chen, Xiaoxin

    2011-01-01

    Alcohol drinking is a known risk factor for oral cancer in humans. However, previous animal studies on the promoting effect of ethanol on oral carcinogenesis were inconclusive. It is necessary to develop an animal model with which the molecular mechanism of ethanol-related oral carcinogenesis may be elucidated in order to develop effective prevention strategies. In this study, mice were first treated with 4-nitroquinoline-1-oxide (4NQO, 100μg/ml in drinking water) for 8 weeks, and then given water or ethanol (8%) as the sole drink for another 16 weeks. During the experiment, 8% ethanol was well tolerated by mice. The incidence of squamous cell carcinoma (SCC) increased from 20% (8/41) to 43% (17/40; p<0.05). Expression of 5-lipoxygenase (5-Lox) and cyclooxygenase 2 (Cox-2) was increased in dysplasia and SCC of 4NQO-treated tongues, and further enhanced by ethanol. Using this mouse model, we further demonstrated that fewer cancers were induced in Alox5−/− mice, as were cell proliferation, inflammation, and angiogenesis in the tongue, as compared with Alox5+/+ mice. Interestingly, Cox-2 expression was induced by ethanol in knockout mice, while 5-Lox and leukotriene A4 hydrolase (LTA4H) expression and leukotriene B4 (LTB4) biosynthesis were dramatically reduced. Moreover, ethanol enhanced expression and nuclear localization of 5-Lox and stimulated LTB4 biosynthesis in human tongue SCC cells (SCC-15 and SCC-4) in vitro. In conclusion, this study clearly demonstrated that ethanol promoted 4NQO-induced oral carcinogenesis, at least in part, through further activation of the 5-Lox pathway of arachidonic acid metabolism. PMID:21881027

  11. Clicked cinnamic/caffeic esters and amides as radical scavengers and 5-lipoxygenase inhibitors.

    PubMed

    Doiron, Jérémie A; Métayer, Benoît; Richard, Ryan R; Desjardins, Dany; Boudreau, Luc H; Levesque, Natalie A; Jean-François, Jacques; Poirier, Samuel J; Surette, Marc E; Touaibia, Mohamed

    2014-01-01

    5-Lipoxygenase (5-LO) is the key enzyme responsible for the conversion of arachidonic acid to leukotrienes, a class of lipid mediators implicated in inflammatory disorders. In this paper, we describe the design, synthesis, and preliminary activity studies of novel clicked caffeic esters and amides as radical scavengers and 5-LO inhibitors. From known 5-LO inhibitor 3 as a lead, cinnamic esters 8a-h and amides 9a-h as well as caffeic esters 15a-h and amides 16a-h were synthesized by Cu(I)-catalyzed [1,3]-dipolar cycloaddition with the appropriate azide precursors and terminal alkynes. All caffeic analogs are proved to be good radical scavengers (IC50: 10-20 μM). Esters 15g and 15f possessed excellent 5-LO inhibition activity in HEK293 cells and were equipotent with the known 5-LO inhibitor CAPE and more potent than Zileuton. Several synthesized esters possess activities rivaling Zileuton in stimulated human polymorphonuclear leukocytes.

  12. Clicked Cinnamic/Caffeic Esters and Amides as Radical Scavengers and 5-Lipoxygenase Inhibitors

    PubMed Central

    Doiron, Jérémie A.; Métayer, Benoît; Richard, Ryan R.; Desjardins, Dany; Boudreau, Luc H.; Levesque, Natalie A.; Jean-François, Jacques; Poirier, Samuel J.; Surette, Marc E.; Touaibia, Mohamed

    2014-01-01

    5-Lipoxygenase (5-LO) is the key enzyme responsible for the conversion of arachidonic acid to leukotrienes, a class of lipid mediators implicated in inflammatory disorders. In this paper, we describe the design, synthesis, and preliminary activity studies of novel clicked caffeic esters and amides as radical scavengers and 5-LO inhibitors. From known 5-LO inhibitor 3 as a lead, cinnamic esters 8a–h and amides 9a–h as well as caffeic esters 15a–h and amides 16a–h were synthesized by Cu(I)-catalyzed [1,3]-dipolar cycloaddition with the appropriate azide precursors and terminal alkynes. All caffeic analogs are proved to be good radical scavengers (IC50: 10–20 μM). Esters 15g and 15f possessed excellent 5-LO inhibition activity in HEK293 cells and were equipotent with the known 5-LO inhibitor CAPE and more potent than Zileuton. Several synthesized esters possess activities rivaling Zileuton in stimulated human polymorphonuclear leukocytes. PMID:25383225

  13. Structure-activity relationship of caffeic acid phenethyl ester analogs as new 5-lipoxygenase inhibitors.

    PubMed

    Doiron, Jérémie A; Leblanc, Luc M; Hébert, Martin J G; Levesque, Natalie A; Paré, Aurélie F; Jean-François, Jacques; Cormier, Marc; Surette, Marc E; Touaibia, Mohamed

    2016-09-26

    Leukotrienes (LTs) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester (CAPE) possesses potent anti-LTs activity through the inhibition of 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of LTs. In this study, we describe the design and synthesis of CAPE analogs as radical scavengers and 5-LO inhibitors. Caffeic esters bearing propargyl and allyl linkers between the caffeoyl and aryl moieties (4a-i and 5a-i, respectively) were synthesized by Sonogashira and Heck cross-coupling reactions to probe the effects of flexibility and aryl substitution on 5-LO inhibition. Caffeoyl alcohol and ethers (6, 7a-b) as well as caffeoyl aldehyde and ketones (8a-e) were synthesized to elucidate the importance of the ester linkage for inhibitory activity. All tested compounds proved to be good radical scavengers (IC50 of 10-30 μm). After preliminary anti-LTs activity screening in HEK293 cell models, 5-LO inhibition potential of selected compounds was determined in human polymorphonuclear leukocytes (PMNL). Most screened compounds outperformed CAPE 3 in concentration-dependent assays on PMNL, with ester dimers 4i and 5i along with caffeoyl ethers 7a-b being roughly eight-, seven-, and 16-fold more potent than Zileuton, with IC50 values of 0.36, 0.43, and 0.18 μm, respectively.

  14. The 5-Lipoxygenase Inhibitor Zileuton Confers Neuroprotection against Glutamate Oxidative Damage by Inhibiting Ferroptosis.

    PubMed

    Liu, Yang; Wang, Wei; Li, Yuyao; Xiao, Yunqi; Cheng, Jian; Jia, Jia

    2015-01-01

    5-Lipoxygenase (5-LOX) inhibitors have been shown to be protective in several neurodegenerative disease models; however, the underlying mechanisms remain unclear. We investigated whether 5-LOX inhibitor zileuton conferred direct neuroprotection against glutamate oxidative toxicity by inhibiting ferroptosis, a newly identified iron-dependent programmed cell death. Treatment of HT22 mouse neuronal cell line with glutamate resulted in significant cell death, which was inhibited by zileuton in a dose-dependent manner. Consistently, zileuton decreased glutamate-induced production of reactive oxygen species but did not restore glutamate-induced depletion of glutathione. Moreover, the pan-caspase inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone (ZVAD-fmk) neither prevented HT22 cell death induced by glutamate nor affected zileuton protection against glutamate oxidative toxicity, suggesting that zileuton did not confer neuroprotection by inhibiting caspase-dependent apoptosis. Interestingly, glutamate-induced HT22 cell death was significantly inhibited by the ferroptosis inhibitor ferrostatin-1. Moreover, zileuton protected HT22 neuronal cells from erastin-induced ferroptosis. However, we did not observe synergic protective effects of zileuton and ferrostatin-1 on glutamate-induced cell death. These results suggested that both the 5-LOX inhibitor zileuton and the ferropotosis inhibitor ferrostatin-1 acted through the same cascade to protect against glutamate oxidative toxicity. In conclusion, our results suggested that zileuton protected neurons from glutamate-induced oxidative stress at least in part by inhibiting ferroptosis.

  15. 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.

  16. 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

  17. Phosphodiesterase 4D and 5-Lipoxygenase Activating Protein in Ischemic Stroke

    PubMed Central

    Meschia, James F.; Brott, Thomas G.; Brown, Robert D.; Crook, Richard; Worrall, Bradford B.; Kissela, Brett; Brown, W. Mark; Rich, Stephen S.; Case, L. Douglas; Evans, E. Whitney; Hague, Stephen; Singleton, Andrew; Hardy, John

    2006-01-01

    Risk for ischemic stroke is mediated by both environmental and genetic factors. Although several environmental exposures have been implicated, relatively little is known about the genetic basis of predisposition to this disease. Recent studies in Iceland identified risk polymorphisms in two putative candidate genes for ischemic stroke: phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP). A collection of North American sibling pairs concordant for ischemic stroke and two cohorts of prospectively ascertained North American ischemic stroke cases and control subjects were used for evaluation of PDE4D and ALOX5AP. Although no evidence supported linkage of ischemic stroke with either of the two candidate genes, single-nucleotide polymorphisms and haplotypic associations were observed between PDE4D and ischemic stroke. There was no evidence of association between variants of ALOX5AP and ischemic stroke. These data suggest that common variants in PDE4D may contribute to the genetic risk for ischemic stroke in multiple populations. PMID:16130105

  18. Identification and Characterization of a New Protein Isoform of Human 5-Lipoxygenase

    PubMed Central

    Häfner, Ann-Kathrin; Beilstein, Kim; Graab, Philipp; Ball, Ann-Katrin; Saul, Meike J.; Hofmann, Bettina; Steinhilber, Dieter

    2016-01-01

    Leukotrienes (LTs) are inflammatory mediators that play a pivotal role in many diseases like asthma bronchiale, atherosclerosis and in various types of cancer. The key enzyme for generation of LTs is the 5-lipoxygenase (5-LO). Here, we present a novel putative protein isoform of human 5-LO that lacks exon 4, termed 5-LOΔ4, identified in cells of lymphoid origin, namely the Burkitt lymphoma cell lines Raji and BL41 as well as primary B and T cells. Deletion of exon 4 does not shift the reading frame and therefore the mRNA is not subjected to non-mediated mRNA decay (NMD). By eliminating exon 4, the amino acids Trp144 until Ala184 are omitted in the corresponding protein. Transfection of HEK293T cells with a 5-LOΔ4 expression plasmid led to expression of the corresponding protein which suggests that the 5-LOΔ4 isoform is a stable protein in eukaryotic cells. We were also able to obtain soluble protein after expression in E. coli and purification. The isoform itself lacks canonical enzymatic activity as it misses the non-heme iron but it still retains ATP-binding affinity. Differential scanning fluorimetric analysis shows two transitions, corresponding to the two domains of 5-LO. Whilst the catalytic domain of 5-LO WT is destabilized by calcium, addition of calcium has no influence on the catalytic domain of 5-LOΔ4. Furthermore, we investigated the influence of 5-LOΔ4 on the activity of 5-LO WT and proved that it stimulates 5-LO product formation at low protein concentrations. Therefore regulation of 5-LO by its isoform 5-LOΔ4 might represent a novel mechanism of controlling the biosynthesis of lipid mediators. PMID:27855198

  19. Homology modeling of 5-lipoxygenase and hints for better inhibitor design

    NASA Astrophysics Data System (ADS)

    Aparoy, P.; Reddy, R. N.; Guruprasad, Lalitha; Reddy, M. R.; Reddanna, P.

    2008-09-01

    Lipoxygenases (LOXs) are a group of enzymes involved in the oxygenation of polyunsaturated fatty acids. Among these 5-lipoxygenase (5-LOX) is the key enzyme leading to the formation of pharmacologically important leukotrienes and lipoxins, the mediators of inflammatory and allergic disorders. In view of close functional similarity to mammalian lipoxygenase, potato 5-LOX is used extensively. In this study, the homology modeling technique has been used to construct the structure of potato 5-LOX. The amino acid sequence identity between the target protein and sequence of template protein 1NO3 (soybean LOX-3) searched from NCBI protein BLAST was 63%. Based on the template structure, the protein model was constructed by using the Homology program in InsightII. The protein model was briefly refined by energy minimization steps and validated using Profile-3D, ERRAT and PROCHECK. The results showed that 99.3% of the amino acids were in allowed regions of Ramachandran plot, suggesting that the model is accurate and its stereochemical quality good. Like all LOXs, 5-LOX also has a two-domain structure, the small N-terminal β-barrel domain and a larger catalytic domain containing a single atom of non-heme iron coordinating with His525, His530, His716 and Ile864. Asn720 is present in the fifth coordination position of iron. The sixth coordination position faces the open cavity occupied here by the ligands which are docked. Our model of the enzyme is further validated by examining the interactions of earlier reported inhibitors and by energy minimization studies which were carried out using molecular mechanics calculations. Four ligands, nordihydroguaiaretic acid (NDGA) having IC50 of 1.5 μM and analogs of benzyl propargyl ethers having IC50 values of 760 μM, 45 μM, and no inhibition respectively were selected for our docking and energy minimization studies. Our results correlated well with the experimental data reported earlier, which proved the quality of the model. This

  20. 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.

  1. Common Polymorphisms in the 5-Lipoxygenase Pathway and Risk of Incident Myocardial Infarction: A Danish Case-Cohort Study

    PubMed Central

    Gammelmark, Anders; Nielsen, Michael S.; Lundbye-Christensen, Søren; Tjønneland, Anne; Schmidt, Erik B.; Overvad, Kim

    2016-01-01

    Background The 5-lipoxygenase pathway (5-LOX) has been implicated in the development of cardiovascular disease and studies have suggested that genetic polymorphisms related to key enzymes in this pathway may confer risk of myocardial infarction (MI). This study investigated the association of pre-selected genetic polymorphisms in four candidate genes of 5-LOX (arachidonate 5-lipoxygenase and its activating protein (ALOX-5 and FLAP), leukotriene A4 hydroxylase (LTA4-H) and leukotriene C4 synthase (LTC4-S)) with incident MI. Methods In a Danish cohort including 57,053 participants, aged 50–64 at enrolment and recruited from 1993–97, we conducted a case-cohort study including cases with incident MI and a randomly selected sub cohort of 3,000 participants. Cases were identified from national registries through July 2013. A total of 22 SNPs were selected and genotyped using the commercially available KASP™ assay. A tandem-repeat polymorphism, located in the ALOX-5 gene, was genotyped by multi-titre plate sequencing. Haplotypes were inferred using PHASE 2.1. Results During a median follow-up of 17.0 years we identified 3,089 cases of incident MI. In FLAP, two SNPs were negatively associated with incident MI (rs9551963 & rs17222842) while one SNP (rs2247570) located in LTA4-H, was associated with higher risk of MI when comparing subjects with two copies of the variant allele to homozygotes for the wild type. However, only rs17222842 remained significantly associated with MI after correcting for multiple testing. Furthermore, the promoter polymorphism rs59439148 was associated with risk of MI in men. For male carriers of two variant alleles we found a hazard ratio of 1.63 (95% CI: 1.06;2.52) compared to homozygotes for the wild type. Previously described haplotypes (Hap-A -B, -E and -K) were not associated with MI in our population. Conclusion In conclusion, some common polymorphisms in the 5-lipoxygenase pathway were modestly associated with incident MI, suggesting

  2. 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.

  3. Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B4 synthesis by inhibiting a calcium-activated kinase pathway

    PubMed Central

    Fredman, Gabrielle; Ozcan, Lale; Spolitu, Stefano; Hellmann, Jason; Spite, Matthew; Backs, Johannes; Tabas, Ira

    2014-01-01

    Imbalances between proinflammatory and proresolving mediators can lead to chronic inflammatory diseases. The balance of arachidonic acid-derived mediators in leukocytes is thought to be achieved through intracellular localization of 5-lipoxygenase (5-LOX): nuclear 5-LOX favors the biosynthesis of proinflammatory leukotriene B4 (LTB4), whereas, in theory, cytoplasmic 5-LOX could favor the biosynthesis of proresolving lipoxin A4 (LXA4). This balance is shifted in favor of LXA4 by resolvin D1 (RvD1), a specialized proresolving mediator derived from docosahexaenoic acid, but the mechanism is not known. Here we report a new pathway through which RvD1 promotes nuclear exclusion of 5-LOX and thereby suppresses LTB4 and enhances LXA4 in macrophages. RvD1, by activating its receptor formyl peptide receptor2/lipoxin A4 receptor, suppresses cytosolic calcium and decreases activation of the calcium-sensitive kinase calcium-calmodulin-dependent protein kinase II (CaMKII). CaMKII inhibition suppresses activation P38 and mitogen-activated protein kinase-activated protein kinase 2 kinases, which reduces Ser271 phosphorylation of 5-LOX and shifts 5-LOX from the nucleus to the cytoplasm. As such, RvD1’s ability to decrease nuclear 5-LOX and the LTB4:LXA4 ratio in vitro and in vivo was mimicked by macrophages lacking CaMKII or expressing S271A-5-LOX. These findings provide mechanistic insight into how a specialized proresolving mediator from the docosahexaenoic acid pathway shifts the balance toward resolution in the arachidonic acid pathway. Knowledge of this mechanism may provide new strategies for promoting inflammation resolution in chronic inflammatory diseases. PMID:25246560

  4. 5-Lipoxygenase-dependent apoptosis of human lymphocytes in the International Space Station: data from the ROALD experiment.

    PubMed

    Battista, Natalia; Meloni, Maria A; Bari, Monica; Mastrangelo, Nicolina; Galleri, Grazia; Rapino, Cinzia; Dainese, Enrico; Agrò, Alessandro Finazzi; Pippia, Proto; Maccarrone, Mauro

    2012-05-01

    The functional adaptation of the immune system to the surrounding environment is also a fundamental issue in space. It has been suggested that a decreased number of lymphocytes might be a cause of immunosuppression, possibly due to the induction of apoptosis. Early activation of 5-lipoxygenase (5-LOX) might play a central role in the initiation of the apoptotic program. The goal of the role of apoptosis in lymphocyte depression (ROALD) experiment, flown on the International Space Station as part of the BIO-4 mission of the European Space Agency, was to ascertain the induction of apoptosis in human lymphocytes under authentic microgravity, and to elucidate the possible involvement of 5-LOX. Our results demonstrate that exposure of human lymphocytes to microgravity for 48 h onboard the ISS remarkably increased apoptotic hallmarks such as DNA fragmentation (∼3-fold compared to ground-based controls) and cleaved-poly (ADP-ribose) polymerase (PARP) protein expression (∼3-fold), as well as mRNA levels of apoptosis-related markers such as p53 (∼3-fold) and calpain (∼4-fold); these changes were paralleled by an early increase of 5-LOX activity (∼2-fold). Our findings provide a molecular background for the immune dysfunction observed in astronauts during space missions, and reveal potential new markers to monitor health status of ISS crew members.

  5. 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.

  6. 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

  7. Involvement of eicosanoids in the pathogenesis of pancreatic cancer: the roles of cyclooxygenase-2 and 5-lipoxygenase.

    PubMed

    Knab, Lawrence M; Grippo, Paul J; Bentrem, David J

    2014-08-21

    The interplay between inflammation and cancer progression is a growing area of research. A combination of clinical, epidemiological, and basic science investigations indicate that there is a relationship between inflammatory changes in the pancreas and neoplastic progression. Diets high in ω-6 polyunsaturated fatty acids provide increased substrate for arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) to form eicosanoids. These eicosanoids directly contribute to pancreatic cancer cell proliferation. Both COX-2 and 5-LOX are upregulated in multiple cancer types, including pancreatic cancer. In vitro studies using pancreatic cancer cell lines have demonstrated upregulation of COX-2 and 5-LOX at both the mRNA and protein levels. When COX-2 and 5-LOX are blocked via a variety of mechanisms, cancer cell proliferation is abrogated both in vitro and in vivo. The mechanism of COX-2 has been shown to include effects on apoptosis as well as angiogenesis. 5-LOX has been implicated in apoptosis. The use of COX-2 and 5-LOX inhibitors in clinical studies in patients with pancreatic cancer has been limited. Patient enrollment has been restricted to those with advanced disease which makes evaluation of these drugs as chemopreventive agents difficult. COX-2 and 5-LOX expression have been shown to be present during the early neoplastic changes of pancreatic cancer, well before progression to invasive disease. This indicates that the ideal role for these interventions is early in the disease process as preventive agents, perhaps in patients with chronic pancreatitis or hereditary pancreatitis.

  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. Suppression of oxidative stress and 5-lipoxygenase activation by edaravone improves depressive-like behavior after concussion.

    PubMed

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

    2014-10-15

    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 OS and 5

  10. 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

  11. STAT4 deficiency reduces the development of atherosclerosis in mice.

    PubMed

    Taghavie-Moghadam, Parésa L; Gjurich, Breanne N; Jabeen, Rukhsana; Krishnamurthy, Purna; Kaplan, Mark H; Dobrian, Anca D; Nadler, Jerry L; Galkina, Elena V

    2015-11-01

    Atherosclerosis is a chronic inflammatory process that leads to plaque formation in large and medium sized vessels. T helper 1 (Th1) cells constitute the majority of plaque infiltrating pro-atherogenic T cells and are induced via IFNγ-dependent activation of T-box (Tbet) and/or IL-12-dependent activation of signal transducer and activator of transcription 4 (STAT4). We thus aimed to define a role for STAT4 in atherosclerosis. STAT4-deficiency resulted in a ∼71% reduction (p < 0.001) in plaque burden in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice fed chow diet and significantly attenuated atherosclerosis (∼31%, p < 0.01) in western diet fed Stat4(-/-)Apoe(-/-) mice. Surprisingly, reduced atherogenesis in Stat4(-/-)Apoe(-/-) mice was not due to attenuated IFNγ production in vivo by Th1 cells, suggesting an at least partially IFNγ-independent pro-atherogenic role of STAT4. STAT4 is expressed in T cells, but also detected in macrophages (MΦs). Stat4(-/-)Apoe(-/-)in vitro differentiated M1 or M2 MΦs had reduced cytokine production compare to Apoe(-/-) M1 and M2 MΦs that was accompanied by reduced induction of CD69, I-A(b), and CD86 in response to LPS stimulation. Stat4(-/-)Apoe(-/-) MΦs expressed attenuated levels of CCR2 and demonstrated reduced migration toward CCL2 in a transwell assay. Importantly, the percentage of aortic CD11b(+)F4/80(+)Ly6C(hi) MΦs was reduced in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice. Thus, this study identifies for the first time a pro-atherogenic role of STAT4 that is at least partially independent of Th1 cell-derived IFNγ, and primarily involving the modulation of MΦ responses.

  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. Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening

    PubMed Central

    Temml, Veronika; Garscha, Ulrike; Romp, Erik; Schubert, Gregor; Gerstmeier, Jana; Kutil, Zsofia; Matuszczak, Barbara; Waltenberger, Birgit; Stuppner, Hermann; Werz, Oliver; Schuster, Daniela

    2017-01-01

    Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N’-(3,4-dichlorophenyl)urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay. PMID:28218273

  14. Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening

    NASA Astrophysics Data System (ADS)

    Temml, Veronika; Garscha, Ulrike; Romp, Erik; Schubert, Gregor; Gerstmeier, Jana; Kutil, Zsofia; Matuszczak, Barbara; Waltenberger, Birgit; Stuppner, Hermann; Werz, Oliver; Schuster, Daniela

    2017-02-01

    Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N’-(3,4-dichlorophenyl)urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay.

  15. Manassantin A isolated from Saururus chinensis inhibits 5-lipoxygenase-dependent leukotriene C4 generation by blocking mitogen-activated protein kinase activation in mast cells.

    PubMed

    Kim, Su Jeong; Lu, Yue; Kwon, Okyun; Hwangbo, Kyoung; Seo, Chang-Seob; Lee, Seung Ho; Kim, Cheorl-Ho; Chang, Young-Chae; Son, Jong Keun; Chang, Hyeun Wook

    2011-01-01

    In this study, manassantin A (Man A), an herbal medicine isolated from Saururus chinensis (S. chinensis), markedly inhibited 5-lipoxygenase (5-LO)-dependent leukotriene C(4) (LTC(4)) generation in bone marrow-derived mast cells (BMMCs) in a concentration-dependent manner. To investigate the molecular mechanisms underlying the inhibition of LTC(4) generation by Man A, we assessed the effects of Man A on phosphorylation of cytosolic phospholipase A(2) (cPLA(2)) and mitogen-activated protein kinases (MAPKs). Inhibition of LTC(4) generation by Man A was accompanied by a decrease in cPLA(2) phosphorylation, which occurred via the MAPKs including extracellular signal-regulated protein kinase-1/2 (ERK1/2) as well as p38 and c-Jun N-terminal kinase (JNK) pathways. Taken together, the present study suggests the Man A represents a potential therapeutic approach for the treatment of airway allergic-inflammatory diseases.

  16. Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency.

    PubMed

    Burrage, Lindsay C; Sun, Qin; Elsea, Sarah H; Jiang, Ming-Ming; Nagamani, Sandesh C S; Frankel, Arthur E; Stone, Everett; Alters, Susan E; Johnson, Dale E; Rowlinson, Scott W; Georgiou, George; Lee, Brendan H

    2015-11-15

    Arginase deficiency is caused by deficiency of arginase 1 (ARG1), a urea cycle enzyme that converts arginine to ornithine. Clinical features of arginase deficiency include elevated plasma arginine levels, spastic diplegia, intellectual disability, seizures and growth deficiency. Unlike other urea cycle disorders, recurrent hyperammonemia is typically less severe in this disorder. Normalization of plasma arginine levels is the consensus treatment goal, because elevations of arginine and its metabolites are suspected to contribute to the neurologic features. Using data from patients enrolled in a natural history study conducted by the Urea Cycle Disorders Consortium, we found that 97% of plasma arginine levels in subjects with arginase deficiency were above the normal range despite conventional treatment. Recently, arginine-degrading enzymes have been used to deplete arginine as a therapeutic strategy in cancer. We tested whether one of these enzymes, a pegylated human recombinant arginase 1 (AEB1102), reduces plasma arginine in murine models of arginase deficiency. In neonatal and adult mice with arginase deficiency, AEB1102 reduced the plasma arginine after single and repeated doses. However, survival did not improve likely, because this pegylated enzyme does not enter hepatocytes and does not improve hyperammonemia that accounts for lethality. Although murine models required dosing every 48 h, studies in cynomolgus monkeys indicate that less frequent dosing may be possible in patients. Given that elevated plasma arginine rather than hyperammonemia is the major treatment challenge, we propose that AEB1102 may have therapeutic potential as an arginine-reducing agent in patients with arginase deficiency.

  17. 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.

  18. Synthesis and biological evaluation of 1-(benzenesulfonamido)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene regioisomers: a novel class of 5-lipoxygenase inhibitors.

    PubMed

    Chowdhury, Morshed Alam; Chen, Hua; Abdellatif, Khaled R A; Dong, Ying; Petruk, Kenneth C; Knaus, Edward E

    2008-07-15

    A hitherto unknown class of linear acetylene regioisomers were designed such that a SO(2)NH(2) group was located at the ortho-, meta-, or para-position of the acetylene C-1 phenyl ring, and a N-hydroxypyridin-2(1H)-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). All three regioisomers inhibited 5-lipoxygenase (5-LOX), where the relative potency order was 2-SO(2)NH(2) (IC(50)=10 microM) >3-SO(2)NH(2) (IC(50)=15 microM) >4-SO(2)NH(2) (IC(50)=68 microM) relative to the reference drug nordihydroguaiaretic acid (NDGA; IC(50)=35 microM). The 2-SO(2)NH(2) regioisomer (ED(50)=86.0mg/kg po) exhibited excellent oral anti-inflammatory (AI) activity that was more potent than aspirin (ED(50)=128.9 mg/kg) and marginally less potent than ibuprofen (ED(50)=67.4 mg/kg). The N-hydroxypyridin-2(1H)one moiety provides a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of chelating 5-LOX iron for exploitation in the design of 5-LOX inhibitory AI drugs.

  19. Compounded PHOSPHO1/ALPL deficiencies reduce dentin mineralization.

    PubMed

    McKee, M D; Yadav, M C; Foster, B L; Somerman, M J; Farquharson, C; Millán, J L

    2013-08-01

    Phosphatases are involved in bone and tooth mineralization, but their mechanisms of action are not completely understood. Tissue-nonspecific alkaline phosphatase (TNAP, ALPL) regulates inhibitory extracellular pyrophosphate through its pyrophosphatase activity to control mineral propagation in the matrix; mice without TNAP lack acellular cementum, and have mineralization defects in dentin, enamel, and bone. PHOSPHO1 is a phosphatase found within membrane-bounded matrix vesicles in mineralized tissues, and double ablation of Alpl and Phospho1 in mice leads to a complete absence of skeletal mineralization. Here, we describe mineralization abnormalities in the teeth of Phospho1(-/-) mice, and in compound knockout mice lacking Phospho1 and one allele of Alpl (Phospho1(-/-);Alpl(+/-) ). In wild-type mice, PHOSPHO1 and TNAP co-localized to odontoblasts at early stages of dentinogenesis, coincident with the early mineralization of mantle dentin. In Phospho1 knockout mice, radiography, micro-computed tomography, histology, and transmission electron microscopy all demonstrated mineralization abnormalities of incisor dentin, with the most remarkable findings being reduced overall mineralization coincident with decreased matrix vesicle mineralization in the Phospho1(-/-) mice, and the almost complete absence of matrix vesicles in the Phospho1(-/-);Alpl(+/-) mice, whose incisors showed a further reduction in mineralization. Results from this study support prominent non-redundant roles for both PHOSPHO1 and TNAP in dentin mineralization.

  20. Compounded PHOSPHO1/ALPL Deficiencies Reduce Dentin Mineralization

    PubMed Central

    McKee, M.D.; Yadav, M.C.; Foster, B.L.; Somerman, M.J.; Farquharson, C.; Millán, J.L.

    2013-01-01

    Phosphatases are involved in bone and tooth mineralization, but their mechanisms of action are not completely understood. Tissue-nonspecific alkaline phosphatase (TNAP, ALPL) regulates inhibitory extracellular pyrophosphate through its pyrophosphatase activity to control mineral propagation in the matrix; mice without TNAP lack acellular cementum, and have mineralization defects in dentin, enamel, and bone. PHOSPHO1 is a phosphatase found within membrane-bounded matrix vesicles in mineralized tissues, and double ablation of Alpl and Phospho1 in mice leads to a complete absence of skeletal mineralization. Here, we describe mineralization abnormalities in the teeth of Phospho1-/- mice, and in compound knockout mice lacking Phospho1 and one allele of Alpl (Phospho1-/-;Alpl+/-). In wild-type mice, PHOSPHO1 and TNAP co-localized to odontoblasts at early stages of dentinogenesis, coincident with the early mineralization of mantle dentin. In Phospho1 knockout mice, radiography, micro-computed tomography, histology, and transmission electron microscopy all demonstrated mineralization abnormalities of incisor dentin, with the most remarkable findings being reduced overall mineralization coincident with decreased matrix vesicle mineralization in the Phospho1-/- mice, and the almost complete absence of matrix vesicles in the Phospho1-/-;Alpl+/- mice, whose incisors showed a further reduction in mineralization. Results from this study support prominent non-redundant roles for both PHOSPHO1 and TNAP in dentin mineralization. PMID:23694930

  1. 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.

  2. Omega-3 fatty acid deficiency during brain maturation reduces neuronal and behavioral plasticity in adulthood.

    PubMed

    Bhatia, Harsharan Singh; Agrawal, Rahul; Sharma, Sandeep; Huo, Yi-Xin; Ying, Zhe; Gomez-Pinilla, Fernando

    2011-01-01

    Omega-3-fatty acid DHA is a structural component of brain plasma membranes, thereby crucial for neuronal signaling; however, the brain is inefficient at synthesizing DHA. We have asked how levels of dietary n-3 fatty acids during brain growth would affect brain function and plasticity during adult life. Pregnant rats and their male offspring were fed an n-3 adequate diet or n-3 deficient diets for 15 weeks. Results showed that the n-3 deficiency increased parameters of anxiety-like behavior using open field and elevated plus maze tests in the male offspring. Behavioral changes were accompanied by a level reduction in the anxiolytic-related neuropeptide Y-1 receptor, and an increase in the anxiogenic-related glucocorticoid receptor in the cognitive related frontal cortex, hypothalamus and hippocampus. The n-3 deficiency reduced brain levels of docosahexaenoic acid (DHA) and increased the ratio n-6/n-3 assessed by gas chromatography. The n-3 deficiency reduced the levels of BDNF and signaling through the BDNF receptor TrkB, in proportion to brain DHA levels, and reduced the activation of the BDNF-related signaling molecule CREB in selected brain regions. The n-3 deficiency also disrupted the insulin signaling pathways as evidenced by changes in insulin receptor (IR) and insulin receptor substrate (IRS). DHA deficiency during brain maturation reduces plasticity and compromises brain function in adulthood. Adequate levels of dietary DHA seem crucial for building long-term neuronal resilience for optimal brain performance and aiding in the battle against neurological disorders.

  3. Modulation of arachidonic acid metabolism by curcumin and related beta-diketone derivatives: effects on cytosolic phospholipase A(2), cyclooxygenases and 5-lipoxygenase.

    PubMed

    Hong, Jungil; Bose, Mousumi; Ju, Jihyeung; Ryu, Jae-Ha; Chen, Xiaoxin; Sang, Shengmin; Lee, Mao-Jung; Yang, Chung S

    2004-09-01

    Aberrant arachidonic acid metabolism is involved in the inflammatory and carcinogenic processes. In this study, we investigated the effects of curcumin, a naturally occurring chemopreventive agent, and related beta-diketone derivatives on the release of arachidonic acid and its metabolites in the murine macrophage RAW264.7 cells and in HT-29 human colon cancer cells. We also examined their effects on the catalytic activities and protein levels of related enzymes: cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenases (COX) as well as 5-lipoxygenase (5-LOX). At 10 micro M, dibenzoylmethane (DBM), trimethoxydibenzoylmethane (TDM), tetrahydrocurcumin (THC) and curcumin effectively inhibited the release of arachidonic acid and its metabolites in lipopolysaccharide (LPS)-stimulated RAW cells and A23187-stimulated HT-29 cells. Inhibition of phosphorylation of cPLA(2), the activation process of this enzyme, rather than direct inhibition of cPLA(2) activity appears to be involved in the effect of curcumin. All the curcuminoids (10 micro M) potently inhibited the formation of prostaglandin E(2) (PGE(2)) in LPS-stimulated RAW cells. Curcumin (20 micro M) significantly inhibited LPS-induced COX-2 expression; this effect, rather than the catalytic inhibition of COX, may contribute to the decreased PGE(2) formation. Without LPS-stimulation, however, curcumin increased the COX-2 level in the macrophage cells. Studies with isolated ovine COX-1 and COX-2 enzymes showed that the curcuminoids had significantly higher inhibitory effects on the peroxidase activity of COX-1 than that of COX-2. Curcumin and THC potently inhibited the activity of human recombinant 5-LOX, showing estimated IC(50) values of 0.7 and 3 micro M, respectively. The results suggest that curcumin affects arachidonic acid metabolism by blocking the phosphorylation of cPLA(2), decreasing the expression of COX-2 and inhibiting the catalytic activities of 5-LOX. These activities may contribute to the anti

  4. A Novel Inhibitor of 5-Lipoxygenase (5-LOX) Prevents Oxidative Stress–Induced Cell Death of Retinal Pigment Epithelium (RPE) Cells

    PubMed Central

    Subramanian, Preeti; Mendez, Emily F.; Becerra, S. Patricia

    2016-01-01

    Purpose 5-Lipoxygenase (5-LOX) oxygenates arachidonic acid to form 5-hydroperoxyeicosatetraenoic acid, which is further converted into biologically detrimental leukotrienes, such as leukotriene B4 (LTB4). The RPE and retina express the PNPLA2 gene for pigment epithelium–derived factor receptor (PEDF-R), a lipase involved in cell survival. The purpose here was to investigate the role of PEDF-R on the 5-LOX pathway in oxidative stress of RPE. Methods Lipoxygenase activity assays were performed with soybean and potato lipoxygenase. Binding was evaluated by peptide-affinity chromatography and pull-down assays with PEDF-R–derived synthetic peptides or recombinant protein. Oxidative stress was induced in human ARPE-19 and primary pig RPE cells with indicated concentrations of H2O2/TNF-α. Reverse transcription–PCR of ALOX5 and PNPLA2 genes was performed. Cell viability and death rates were determined using respective biomarkers. Leukotriene B4 levels were measured by ELISA. Results Among five peptides spanning between positions Leu159 and Met325 of human PEDF-R polypeptide, only two overlapping peptides, E5b and P1, bound and inhibited lipoxygenase activity. Human recombinant 5-LOX bound specifically to peptide P1 and to His6/Xpress-tagged PEDF-R via ionic interactions. The two inhibitor peptides E5b and P1 promoted cell viability and decreased cell death of RPE cells undergoing oxidative stress. Oxidative stress decreased the levels of PNPLA2 transcripts with no effect on ALOX5 expression. Exogenous additions of P1 peptide or overexpression of the PNPLA2 gene decreased both LTB4 levels and death of RPE cells undergoing oxidative stress. Conclusions A novel peptide region of PEDF-R inhibits 5-LOX, which intersects with RPE cell death pathways induced by oxidative stress. PMID:27635633

  5. 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.

  6. Levels of prostaglandin E metabolite and leukotriene E(4) are increased in the urine of smokers: evidence that celecoxib shunts arachidonic acid into the 5-lipoxygenase pathway.

    PubMed

    Duffield-Lillico, Anna J; Boyle, Jay O; Zhou, Xi Kathy; Ghosh, Aradhana; Butala, Geera S; Subbaramaiah, Kotha; Newman, Robert A; Morrow, Jason D; Milne, Ginger L; Dannenberg, Andrew J

    2009-04-01

    Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) play a role in inflammation and carcinogenesis. Biomarkers that reflect tobacco smoke-induced tissue injury are needed. In this study, levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E(4) (LTE(4)), biomarkers of the COX and 5-LO pathways, were compared in never smokers, former smokers, and current smokers. The effects of celecoxib, a selective COX-2 inhibitor, on levels of PGE-M and LTE(4) were determined. Baseline levels of PGE-M and LTE(4) were positively associated with smoking status; levels of PGE-M and LTE(4) were higher in current versus never smokers. Treatment with 200 mg celecoxib twice daily for 6 +/- 1 days led to a reduction in urinary PGE-M levels in all groups but exhibited the greatest effect among subjects with high baseline PGE-M levels. Thus, high baseline PGE-M levels in smokers reflected increased COX-2 activity. In individuals with high baseline PGE-M levels, treatment with celecoxib led to a significant increase in levels of urinary LTE(4), an effect that was not found in individuals with low baseline PGE-M levels. In conclusion, increased levels of urinary PGE-M and LTE(4) were found in human smokers, a result that may reflect subclinical lung inflammation. In individuals with high baseline levels of PGE-M (elevated COX-2 activity), celecoxib administration shunted arachidonic acid into the proinflammatory 5-LO pathway. Because 5-LO activity and LTE(4) have been suggested to play a role in cardiovascular disease, these results may help to explain the link between use of COX-2 inhibitors and cardiovascular complications.

  7. Differences in the modulation of reactive species, lipid bodies, cyclooxygenase-2, 5-lipoxygenase and PPAR-γ in cerebral malaria-susceptible and resistant mice.

    PubMed

    Borges, Tatiana K S; Alves, Érica A R; Vasconcelos, Henda A R; Carneiro, Fabiana P; Nicola, André M; Magalhães, Kelly G; Muniz-Junqueira, Maria Imaculada

    2017-04-01

    Proinflammatory responses are associated with the severity of cerebral malaria. NO, H2O2, eicosanoid and PPAR-γ are involved in proinflammatory responses, but regulation of these factors is unclear in malaria. This work aimed to compare the expression of eicosanoid-forming-enzymes in cerebral malaria-susceptible CBA and C57BL/6 and -resistant BALB/c mice. Mice were infected with Plasmodium berghei ANKA, and the survival rates and parasitemia curves were assessed. On the sixth day post-infection, cyclooxygenase-2 and 5-lipoxygenase in brain sections were assessed by immunohistochemistry, and, NO, H2O2, lipid bodies, and PPAR-γ expression were assessed in peritoneal macrophages. The C57BL/6 had more severe disease with a lower survival time, higher parasitemia and lower production of plasmodicidal NO and H2O2 molecules than BALB/c. Enhanced COX-2 and 5-LOX expression were observed in brain tissue cells and vessels from C57BL/6 mice, and these mice expressed higher constitutive PPAR-γ levels. There was no translocation of PPAR-γ from cytoplasm to nucleus in macrophages from these mice. CBA mice had enhanced COX-2 expression in brain tissue cells and vessels and also lacked PPAR-γ cytoplasm-to-nucleus translocation. The resistant BALB/c mice presented higher survival time, lower parasitemia and higher NO and H2O2 production on the sixth day post-infection. These mice did not express either COX-2 or 5-LOX in brain tissue cells and vessels. Our data showed that besides the high parasite burden and lack of microbicidal molecules, an imbalance with high COX-2 and 5-LOX eicosanoid expression and a lack of regulatory PPAR-γ cytoplasm-to-nucleus translocation in macrophages were observed in mice that develop cerebral malaria.

  8. Prediction of comparative inhibition efficiency for a novel natural ligand, galangin against human brain acetylcholinesterase, butyrylcholinesterase and 5-lipoxygenase: a neuroinformatics study.

    PubMed

    Shaikh, Sibhghatulla; Ahmad, Syed S; Ansari, Mohammad A; Shakil, Shazi; Rizvi, Syed M D; Shakil, Shahnawaz; Tabrez, Shams; Akhtar, Salman; Kamal, Mohammad A

    2014-04-01

    The present study elucidates molecular interactions of human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and 5-lipoxygenase (5-LPO) with a novel natural ligand Galangin (GAL); and also with the well-known ligands Bisnorcymserine (BNC) and Cymserine for comparison. Docking between these ligands and enzymes were performed using 'Autodock4.2'. It was found that hydrophobic interactions play an important role in the correct positioning of BNC within the 'catalytic site' of AChE, BuChE and 5-LPO to permit docking while hydrogen bonds are significant in case of cymserine for the same. However, only polar interactions are significant in the correct positioning of GAL within the 'catalytic site' of AChE, BuChE and 5-LPO to permit docking. Such information may aid in the design of versatile AChE, BuChE and 5 LPO-inhibitors, and is expected to aid in safe clinical use of above ligands. Scope still remains in the determination of the three-dimensional structure of AChE-GAL, BuChE-GAL and 5-LPO-GAL complex by X-ray crystallography to certify the described data. Moreover, the present study confirms that GAL is a more efficient inhibitor of human brain AChE compared to BNC and cymserine, while in case of 5-LPO and human brain BuChE, BNC is a more efficient inhibitor compared to GAL and cymserine with reference to ΔG and Ki values.

  9. Effects of novel 5-lipoxygenase inhibitors on the incidence of pulmonary adenomas in the A/J murine model when administered via nose-only inhalation.

    PubMed

    Myrdal, P B; Karlage, K; Kuehl, P J; Angersbach, B S; Merrill, B A; Wightman, P D

    2007-05-01

    The objective of this study was to determine the effects of 5-lipoxygenase (5-LO) inhibitors on the incidence of benzo(a)pyrene-induced pulmonary adenomas in female A/J mice. Two novel compounds, S-29606 and S-30621, and the Food and Drug Administration-approved Zileuton were investigated. S-29606 and S-30621 were selected from a group of similar active structures on the basis of local versus systemic 5-LO inhibitory activity. Preliminary studies found them to lack oral bioavailability, in direct contrast to Zileuton. Treatment was initiated 1 week following exposure to the carcinogen benzo(a)pyrene. Both S-29606 and S-30621 were dosed via nose-only inhalation 5 days a week, for 16 weeks, whereas Zileuton was administered orally. Dose levels for S-29606 and S-30621 were determined to be 220 and 430 microg/kg for the low- and high-dose groups, respectively, whereas the dose of Zileuton was 245 mg/kg. Both test compounds exhibited a significant reduction of pulmonary adenomas, compared with a positive control for high and low doses, P < 0.05. Additionally, a dose response for both S-29606 and S-30621 was observed when compared with placebo. Despite a dose 575 times greater than that of the novel test compounds, orally administered Zileuton did not produce a reduction in adenoma occurrence. The findings of this study offer compelling preliminary data for the use of S-29606 and S-30621 in further investigations of the treatment of pulmonary adenomas and support the use of inhalation drug delivery as an alternate to oral delivery for these compounds.

  10. Females with FVIII and FIX deficiency have reduced joint range of motion

    PubMed Central

    Sidonio, Robert F.; Mili, Fatima D.; Li, Tengguo; Miller, Connie H.; Hooper, William C.; DeBaun, Michael R.; Soucie, Michael

    2015-01-01

    Little is known about rates of joint bleeding among females with FVIII/FIX deficiency or hemophilia carriers. In a cross-sectional study, we tested the hypothesis that females with FVIII or FIX deficiency enrolled in the Universal Data Collection (UDC) project had a reduced mean overall joint range of motion (ROM) compared with historic controls from the Normal Joint Study. Demographics, clinical characteristics, and joint ROM measurements on 303 females without a bleeding disorder and 148 females with FVIII and FIX deficiency, respectively, between the ages of 2–69 years and a body mass index (BMI) ≤35 were compared. Multivariate linear regression was performed with the overall joint ROM (sum of the right and left ROM measurements of five joints) as the dependent variable and FVIII or FIX activity as the independent variable adjusting for age, race, BMI, and number of joint bleeds reported over the last 6 months. As FVIII and FIX activity decreased, the mean overall joint ROM became reduced and in most cases was significantly lower than that of the controls regardless of age and clinical hemophilia severity. Further investigation of reduced joint ROM as evidence of subclinical joint bleeding in females with FVIII and FIX deficiency is warranted. PMID:24838518

  11. 11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis.

    PubMed

    Kipari, Tiina; Hadoke, Patrick W F; Iqbal, Javaid; Man, Tak-Yung; Miller, Eileen; Coutinho, Agnes E; Zhang, Zhenguang; Sullivan, Katie M; Mitic, Tijana; Livingstone, Dawn E W; Schrecker, Christopher; Samuel, Kay; White, Christopher I; Bouhlel, M Amine; Chinetti-Gbaguidi, Giulia; Staels, Bart; Andrew, Ruth; Walker, Brian R; Savill, John S; Chapman, Karen E; Seckl, Jonathan R

    2013-04-01

    11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11β-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11β-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11β-HSD1 inhibitor or crossed with 11β-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11β-HSD1 inhibition or deficiency attenuated atherosclerosis (74-76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11β-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11β-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11β-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages.

  12. Zinc deficiency with reduced mastication impairs spatial memory in young adult mice.

    PubMed

    Kida, Kumiko; Tsuji, Tadataka; Tanaka, Susumu; Kogo, Mikihiko

    2015-12-01

    Sufficient oral microelements such as zinc and fully chewing of foods are required to maintain cognitive function despite aging. No knowledge exists about the combination of factors such as zinc deficiency and reduced mastication on learning and memory. Here we show that tooth extraction only in 8-week-old mice did not change the density of glial fibrillary acidic protein-labeled astrocytes in the hippocampus or spatial memory parameters. However, tooth extraction followed by zinc deprivation strongly impaired spatial memory and led to an increase in astrocytic density in the hippocampal CA1 region. The impaired spatial performance in the zinc-deficient only (ZD) mice also coincided well with the increase in the astrocytic density in the hippocampal CA1 region. After switching both zinc-deficient groups to a normal diet with sufficient zinc, spatial memory recovered, and more time was spent in the quadrant with the goal in the probe test in the mice with tooth extraction followed by zinc deprivation (EZD) compared to the ZD mice. Interestingly, we found no differences in astrocytic density in the CA1 region among all groups at 22 weeks of age. Furthermore, the escape latency in a visible probe test at all times was longer in zinc-deficient groups than the others and demonstrated a negative correlation with body weight. No significant differences in escape latency were observed in the visible probe test among the ZD, EZD, and normal-fed control at 4 weeks (CT4w) groups in which body weight was standardized to that of the EZD group, or in the daily reduction in latency between the normal-fed control and CT4w groups. Our data showed that zinc-deficient feeding during a young age impairs spatial memory performance and leads to an increase in astrocytic density in the hippocampal CA1 region and that zinc-sufficient feeding is followed by recovery of the impaired spatial memory along with changes in astrocytic density. The combination of the two factors, zinc deficiency

  13. Reduced cardiac remodelling and prevention of glutathione deficiency after omega-3 supplementation in chronic heart failure.

    PubMed

    Fang, Yuehua; Favre, Julie; Vercauteren, Magalie; Laillet, Brigitte; Remy-Jouet, Isabelle; Skiba, Mohamed; Lallemand, Françoise; Dehaudt, Cathy; Monteil, Christelle; Thuillez, Christian; Mulder, Paul

    2011-06-01

    n-3 polyunsaturated fatty acids (omega-3) supplementation is associated with reduced cardiovascular mortality and post-infarction death. However, the impact of omega-3 supplementation in congestive heart failure (CHF) is still unknown. This study assesses the effects of omega-3 supplementation on left ventricular (LV) function and remodelling. We assessed, in rats with CHF induced by left coronary ligation, the effects of a 1-week and a 12-week supplementation with omega-3 (450 mg/kg per day) on LV hemodynamics, function and structure. Chronic omega-3 reduces total peripheral resistance due to an increase in cardiac output without modification of arterial pressure. Only chronic omega-3 reduces LV end-diastolic pressure and LV relaxation constant. Moreover, chronic omega-3 decreases LV systolic and diastolic diameters, LV weight and collagen density. Acute and chronic omega-3 increase LV γ-glutamyl-cysteine synthetase and oppose glutathione deficiency resulting in a reduction of myocardial oxidized glutathione. In experimental CHF, long-term omega-3 supplementation improves LV hemodynamics and function and prevents LV remodelling and glutathione deficiency. The latter might be one of the mechanisms involved, but whether other mechanism, independent of myocardial redox 'status', such as reduced inflammation, are implicated remains to be confirmed.

  14. Adiponectin deficiency promotes tumor growth in mice by reducing macrophage infiltration.

    PubMed

    Sun, Yutong; Lodish, Harvey F

    2010-08-05

    Adiponectin is an adipocyte-derived plasma protein that has been implicated in regulating angiogenesis, but the role of adiponectin in regulating this process is still controversial. In this study, in order to determine whether adiponectin affects tumor growth and tumor induced vascularization, we implanted B16F10 melanoma and Lewis Lung Carcinoma cells subcutaneously into adiponectin knockout and wild-type control mice, and found that adiponectin deficiency markedly promoted the growth of both tumors. Immunohistochemical analyses indicated that adiponectin deficiency reduced macrophage recruitment to the tumor, but did not affect cancer cell mitosis, apoptosis, or tumor-associated angiogenesis. In addition, treatment with recombinant adiponectin did not affect the proliferation of cultured B16F10 tumor cells. Importantly, the restoration of microphage infiltration at an early stage of tumorigenesis by means of co-injection of B16F10 cells and macrophages reversed the increased tumor growth in adiponectin knockout mice. Thus, we conclude that the enhanced tumor growth observed in adiponectin deficient mice is likely due to the reduction of macrophage infiltration rather than enhanced angiogenesis.

  15. Galectin-3 Gene Inactivation Reduces Atherosclerotic Lesions and Adventitial Inflammation in ApoE-Deficient Mice

    PubMed Central

    Nachtigal, Maurice; Ghaffar, Abdul; Mayer, Eugene P.

    2008-01-01

    This study has examined the role of galectin-3 (GaL3), a multicompartmented N-acetyllactosamine-binding chimeric lectin, on atherogenesis in the ApoE-deficient mouse model of atherosclerosis. Pathological changes consisting of atheromatous plaques, atherosclerotic microaneurysms extending into periaortic vascular channels, and adventitial and periaortic inflammatory infiltrates were assessed in an equal number (n = 36) of apolipoprotein (Apo)E-deficient mice and ApoE-GaL3 double-knockout mice. These mice were divided into three age groups, 21 to 23 weeks, 25 to 31 weeks, and 36 to 44 weeks of age. Results of this morphological analysis have shown an age-related increase in the incidence of aorta atheromatous plaques and periaortic vascular channels in ApoE-deficient mice. By contrast ApoE/GaL3 double-knockout mice did not show an increase in pathological changes with age. The 36- to 44-week group of ApoE−/−/GaL3−/− mice had a significantly lower number of atherosclerotic lesions (P < 0.004) and fewer atheromatous plaques (P < 0.008) when compared with ApoE−/−/GaL3+/+ mice of the same age. ApoE−/−/GaL3−/− mice had a lower number of perivascular inflammatory infiltrates and mast cells than those found in ApoE−/−/GaL3+/+ mice. The reduced number of perivascular mast cells may have resulted in a low level of interleukin-4 that contributed to the reduction in the morphological parameters of atherogenesis correlated with the lack of GaL3 expression. The effect of GaL3 deficiency on atherogenesis decrease could be related to its function as a multifunctional protein implicated in macrophage chemotaxis, angiogenesis, lipid loading, and inflammation. PMID:18156214

  16. Zinc deficiency reduces fertility in C. elegans hermaphrodites and disrupts oogenesis and meiotic progression.

    PubMed

    Hester, James; Hanna-Rose, Wendy; Diaz, Francisco

    2017-01-01

    Zinc is necessary for successful gametogenesis in mammals; however the role of zinc in the gonad function of non-mammalian species has not been investigated. The genetic tractability, short generation time, and hermaphroditic reproduction of the nematode C. elegans offer distinct advantages for the study of impaired gametogenesis as a result of zinc deficiency. However the phenotypic reproductive effects arising from zinc restriction have not been established in this model. We therefore examined the effect of zinc deficiency on C. elegans reproduction by exposing worms to the zinc chelator N,N,N',N'-tetrakis (2-pyridylmethyl)ethane-1,2-diamine (TPEN). Treatment began at the early larval stage and continued until reproductive senescence. TPEN treatment reduced the total number of progeny produced by C. elegans hermaphrodites compared with control subjects, with the largest difference in output observed 48h after larval stage 4. At this time-point, zinc deficient worms displayed fewer embryos in the uterus and disorganized oocyte development when observed under DIC microscopy. DAPI staining revealed impaired oogenesis and chromosome dynamics with an expanded region of pachytene stage oocytes extending into the proximal arm of the gonad. This phenotype was not seen in control or zinc-rescue subjects. This study demonstrates that reproduction in C. elegans is sensitive to environmental perturbations in zinc, indicating that this is a good model for future studies in zinc-mediated subfertility. Aberrant oocyte development and disruption of the pachytene-diplotene transition indicate that oogenesis in particular is affected by zinc deficiency in this model.

  17. Executioner Caspase-3 and 7 Deficiency Reduces Myocyte Number in the Developing Mouse Heart

    PubMed Central

    Cardona, Maria; López, Juan Antonio; Serafín, Anna; Rongvaux, Anthony; Inserte, Javier; García-Dorado, David; Flavell, Richard; Llovera, Marta; Cañas, Xavier; Vázquez, Jesús; Sanchis, Daniel

    2015-01-01

    Executioner caspase-3 and -7 are proteases promoting cell death but non-apoptotic roles are being discovered. The heart expresses caspases only during development, suggesting they contribute to the organ maturation process. Therefore, we aimed at identifying novel functions of caspases in heart development. We induced simultaneous deletion of executioner caspase-3 and -7 in the mouse myocardium and studied its effects. Caspase knockout hearts are hypoplastic at birth, reaching normal weight progressively through myocyte hypertrophy. To identify the molecular pathways involved in these effects, we used microarray-based transcriptomics and multiplexed quantitative proteomics to compare wild type and executioner caspase-deficient myocardium at different developmental stages. Transcriptomics showed reduced expression of genes promoting DNA replication and cell cycle progression in the neonatal caspase-deficient heart suggesting reduced myocyte proliferation, and expression of non-cardiac isoforms of structural proteins in the adult null myocardium. Proteomics showed reduced abundance of proteins involved in oxidative phosphorylation accompanied by increased abundance of glycolytic enzymes underscoring retarded metabolic maturation of the caspase-null myocardium. Correlation between mRNA expression and protein abundance of relevant genes was confirmed, but transcriptomics and proteomics indentified complementary molecular pathways influenced by caspases in the developing heart. Forced expression of wild type or proteolytically inactive caspases in cultured cardiomyocytes induced expression of genes promoting cell division. The results reveal that executioner caspases can modulate heart’s cellularity and maturation during development, contributing novel information about caspase biology and heart development. PMID:26121671

  18. Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency.

    PubMed

    Yao, Yucheng; Yao, Jiayi; Radparvar, Melina; Blazquez-Medela, Ana M; Guihard, Pierre J; Jumabay, Medet; Boström, Kristina I

    2013-11-19

    Cerebral arteriovenous malformations (AVMs) are common vascular malformations, which may result in hemorrhagic strokes and neurological deficits. Bone morphogenetic protein (BMP) and Notch signaling are both involved in the development of cerebral AVMs, but the cross-talk between the two signaling pathways is poorly understood. Here, we show that deficiency of matrix Gla protein (MGP), a BMP inhibitor, causes induction of Notch ligands, dysregulation of endothelial differentiation, and the development of cerebral AVMs in MGP null (Mgp(-/-)) mice. Increased BMP activity due to the lack of MGP induces expression of the activin receptor-like kinase 1, a BMP type I receptor, in cerebrovascular endothelium. Subsequent activation of activin receptor-like kinase 1 enhances expression of Notch ligands Jagged 1 and 2, which increases Notch activity and alters the expression of Ephrin B2 and Ephrin receptor B4, arterial and venous endothelial markers, respectively. Reducing the expression of Jagged 1 and 2 in the Mgp(-/-) mice by crossing them with Jagged 1 or 2 deficient mice reduces Notch activity, normalizes endothelial differentiation, and prevents cerebral AVMs, but not pulmonary or renal AVMs. Our results suggest that Notch signaling mediates and can modulate changes in BMP signaling that lead to cerebral AVMs.

  19. Moderate zinc deficiency reduces testicular Zip6 and Zip10 abundance and impairs spermatogenesis in mice.

    PubMed

    Croxford, Thomas P; McCormick, Nicholas H; Kelleher, Shannon L

    2011-03-01

    Male infertility accounts for ~40% of cases of failure to conceive. Testes have a strict zinc (Zn) requirement and severe Zn deficiency compromises spermatogenesis, sperm viability, and motility, compromising fertility in men. Despite the high prevalence of marginal Zn deficiency in humans, less emphasis has been placed on understanding the consequences on male reproduction. Swiss Webster mice were used to visualize Zip protein expression during spermatogenesis using immunohistochemistry. Data suggest Zip5 imports Zn into Sertoli cells and spermatocytes, augmented by Zip10 (primary spermatocytes) and Zip8 (secondary spermatocytes). Zip6, 8, and 10 expression was retained in round spermatids, although Zip8 and Zip10 expression disappears during spermatid maturation. Zip1 and Zip6 expression was detected in mature, elongated spermatids. Zip14 was detected in undifferentiated spermatogonia and Leydig cells. Mice fed diets (n = 10/group) reduced in Zn concentration [marginal-Zn diet (MZD), 10 mg Zn/kg; low-Zn diet (ZD), 7 mg Zn/kg] for 30 d had >35% lower liver Zn concentrations than mice fed the control diet (C; 30 mg Zn/kg) (P < 0.05). Plasma Zn and testosterone concentrations and the testes Zn concentration and weight were not significantly lower than in controls. Plasma Zn was greater in the ZD group than in the C and MZD groups. Mice fed ZD had a reduced number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells (~50%; P < 0.05), compromised seminiferous tubule structure, and reduced Zip10 and Zip6 abundance (>50%; P < 0.5) compared with mice fed C. Our data provide compelling evidence that reduced Zn intake may be associated with infertility in men, perhaps independent of decreased levels of circulating Zn or testosterone, which warrants further investigation in human populations.

  20. Leukocyte TLR5 deficiency inhibits atherosclerosis by reduced macrophage recruitment and defective T-cell responsiveness

    PubMed Central

    Ellenbroek, Guilielmus H.J.M.; van Puijvelde, Gijs H.M.; Anas, Adam A.; Bot, Martine; Asbach, Miriam; Schoneveld, Arjan; van Santbrink, Peter J.; Foks, Amanda C.; Timmers, Leo; Doevendans, Pieter A.; Pasterkamp, Gerard; Hoefer, Imo E.; van der Poll, Tom; Kuiper, Johan; de Jager, Saskia C.A.

    2017-01-01

    Toll-like receptors (TLR) provide a critical link between innate and adaptive immunity, both important players in atherosclerosis. Since evidence for the role of TLR5 is lacking, we aimed to establish this in the immune axis of atherosclerosis. We assessed the effect of the TLR5-specific ligand Flagellin on macrophage maturation and T-cell polarisation. Next, we generated TLR5−/−LDLr−/− chimeras to study the effect of hematopoietic TLR5 deficiency on atherosclerosis formation. Flagellin stimulation did not influence wildtype or TLR5−/− macrophage maturation. Only in wildtype macrophages, Flagellin exposure increased MCP-1 and IL6 expression. Flagellin alone reduced T-helper 1 proliferation, which was completely overruled in the presence of T-cell receptor activation. In vivo, hematopoietic TLR5 deficiency attenuated atherosclerotic lesion formation by ≈25% (1030*103 ± 63*103 vs. 792*103 ± 61*103 μm2; p = 0.013) and decreased macrophage area (81.3 ± 12.0 vs. 44.2 ± 6.6 μm2; p = 0.011). In TLR5−/− chimeric mice, we observed lower IL6 plasma levels (36.4 ± 5.6 vs. 15.1 ± 2.2 pg/mL; p = 0.003), lower (activated) splenic CD4+ T-cell content (32.3 ± 2.1 vs. 21.0 ± 1.2%; p = 0.0018), accompanied by impaired T-cell proliferative responses. In conclusion, hematopoietic TLR5 deficiency inhibits atherosclerotic lesion formation by attenuated macrophage accumulation and defective T-cell responsiveness. PMID:28202909

  1. 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

  2. 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.

  3. MEC-17 deficiency leads to reduced α-tubulin acetylation and impaired migration of cortical neurons.

    PubMed

    Li, Lei; Wei, Dan; Wang, Qiong; Pan, Jing; Liu, Rong; Zhang, Xu; Bao, Lan

    2012-09-12

    Neuronal migration is a fundamental process during the development of the cerebral cortex and is regulated by cytoskeletal components. Microtubule dynamics can be modulated by posttranslational modifications to tubulin subunits. Acetylation of α-tubulin at lysine 40 is important in regulating microtubule properties, and this process is controlled by acetyltransferase and deacetylase. MEC-17 is a newly discovered α-tubulin acetyltransferase that has been found to play a major role in the acetylation of α-tubulin in different species in vivo. However, the physiological function of MEC-17 during neural development is largely unknown. Here, we report that MEC-17 is critical for the migration of cortical neurons in the rat. MEC-17 was strongly expressed in the cerebral cortex during development. MEC-17 deficiency caused migratory defects in the cortical projection neurons and interneurons, and perturbed the transition of projection neurons from the multipolar stage to the unipolar/bipolar stage in the intermediate zone of the cortex. Furthermore, knockdown of α-tubulin deacetylase HDAC6 or overexpression of tubulin(K40Q) to mimic acetylated α-tubulin could reduce the migratory and morphological defects caused by MEC-17 deficiency in cortical projection neurons. Thus, MEC-17, which regulates the acetylation of α-tubulin, appears to control the migration and morphological transition of cortical neurons. This finding reveals the importance of MEC-17 and α-tubulin acetylation in cortical development.

  4. DNA Methyltransferase protein synthesis is reduced in CXXC finger protein 1-deficient embryonic stem cells.

    PubMed

    Butler, Jill S; Palam, Lakshmi R; Tate, Courtney M; Sanford, Jeremy R; Wek, Ronald C; Skalnik, David G

    2009-05-01

    CXXC finger protein 1 (CFP1) binds to unmethylated CpG dinucleotides and is required for embryogenesis. CFP1 is also a component of the Setd1A and Setd1B histone H3K4 methyltransferase complexes. Murine embryonic stem (ES) cells lacking CFP1 fail to differentiate, and exhibit a 70% reduction in global genomic cytosine methylation and a 50% reduction in DNA methyltransferase (DNMT1) protein and activity. This study investigated the underlying mechanism for reduced DNMT1 expression in CFP1-deficient ES cells. DNMT1 transcript levels were significantly elevated in ES cells lacking CFP1, despite the observed reduction in DNMT1 protein levels. To address the posttranscriptional mechanisms by which CFP1 regulates DNMT1 protein activity, pulse/chase analyses were carried out, demonstrating a modest reduction in DNMT1 protein half-life in CFP1-deficient ES cells. Additionally, global protein synthesis was decreased in ES cells lacking CFP1, contributing to a reduction in the synthesis of DNMT1 protein. ES cells lacking CFP1 were found to contain elevated levels of phosphorylated eIF2alpha, and an accompanying reduction in translation initiation as revealed by a lower level of polyribosomes. These results reveal a novel role for CFP1 in the regulation of translation initiation, and indicate that loss of CFP1 function leads to decreased DNMT1 protein synthesis and half-life.

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

    PubMed Central

    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

  6. Interleukin-18 deficiency reduces neuropeptide gene expressions in the mouse amygdala related with behavioral change.

    PubMed

    Yamamoto, Yuta; Tanahashi, Toshihito; Katsuura, Sakurako; Kurokawa, Ken; Nishida, Kensei; Kuwano, Yuki; Kawai, Tomoko; Teshima-Kondo, Shigetada; Chikahisa, Sachiko; Tsuruo, Yoshihiro; Sei, Hiroyoshi; Rokutan, Kazuhito

    2010-12-15

    In this study, we examined the effects of IL-18 deficiency on behaviors and gene expression profiles in 6 brain regions. IL-18(-/-) mice reduced depressive-like behavior and changed gene expressions predominantly in the amygdala compared with wild-type mice. Pathway analysis of the differentially expressed genes ranked behavior as the top-scored biological function. Of note, the absence of IL-18 decreased Avp, Hcrt, Oxt, and Pmch mRNA levels and the number of arginine vasopressin- and oxytocin-positive cells in the amygdala, but not in the hypothalamus. Our results suggest that IL-18-dependent vasopressinergic and oxytocinergic circuitry in the amygdala may regulate depressive-like behaviors in mice.

  7. "Tall oil"-derived phytosterols reduce atherosclerosis in ApoE-deficient mice.

    PubMed

    Moghadasian, M H; McManus, B M; Pritchard, P H; Frohlich, J J

    1997-01-01

    We investigated the effects of a "tall oil"-derived phytosterol mixture (TODPM) on the formation of atherosclerotic lesions in apoE-deficient mice. TODPM was added at 2% (wt/wt) to the chow of nine mice; the control group had six animals. The diet of all animals contained 9% (wt/wt) fat and 0.15% (wt/wt) cholesterol. After 4 weeks, plasma total cholesterol levels were significantly reduced in the TODPM-treated mice (26.6 versus 42.0 mmol/L, P < .0001). The mean body weight of the TODPM-supplemented group was significantly higher at week 5 and throughout the study (29.4 versus 27.7 g, P < .05). The experiment was terminated at 18 weeks. Histological examination showed mature atherosclerotic lesions composed of foam cells underlying the endothelium, a mosaic of extracellular glycosaminoglycans, numerous apparently proliferative smooth muscle cells, and foci of cholesterol clefts in the control animals. By contrast, the TODPM-treated mice showed only early lesions containing mainly superficial foam cells. As assessed by morphometry, the lesion area in the aortic sinuses of TODPM-treated animals was less than half that of control animals (P < .0001). This reduced lesion area was accompanied by a substantial reduction in all lesional components, reflecting a delay in progression of atheromatous changes. A strong positive correlation (r = .69, P < .01) was found between plasma total cholesterol levels and lesion area in the aortic sinuses. TODPM also prevented the occurrence of xanthomatosis. We conclude that supplementation of a cholesterol-enriched diet with TODPM significantly lowers plasma cholesterol and retards development of atherosclerosis in apoE-deficient mice, suggesting a therapeutic potential for the mixture of phytosterols studied.

  8. Factor XI-deficient mice display reduced inflammation, coagulopathy, and bacterial growth during listeriosis.

    PubMed

    Luo, Deyan; Szaba, Frank M; Kummer, Lawrence W; Johnson, Lawrence L; Tucker, Erik I; Gruber, Andras; Gailani, David; Smiley, Stephen T

    2012-01-01

    In mice infected sublethally with Listeria monocytogenes, fibrin is deposited at low levels within hepatic tissue, where it functions protectively by limiting bacterial growth and suppressing hemorrhagic pathology. Here we demonstrate that mice infected with lethal doses of L. monocytogenes produce higher levels of fibrin and display evidence of systemic coagulopathy (i.e., thrombocytopenia, fibrinogen depletion, and elevated levels of thrombin-antithrombin complexes). When the hepatic bacterial burden exceeds 1×10(6) CFU, levels of hepatic fibrin correlate with the bacterial burden, which also correlates with levels of hepatic mRNA encoding the hemostatic enzyme factor XI (FXI). Gene-targeted FXI-deficient mice show significantly improved survival upon challenge with high doses of L. monocytogenes and also display reduced levels of hepatic fibrin, decreased evidence of coagulopathy, and diminished cytokine production (interleukin-6 [IL-6] and IL-10). While fibrin limits the bacterial burden during sublethal listeriosis in wild-type mice, FXI-deficient mice display a significantly improved capacity to restrain the bacterial burden during lethal listeriosis despite their reduced fibrin levels. They also show less evidence of hepatic necrosis. In conjunction with suboptimal antibiotic therapy, FXI-specific monoclonal antibody 14E11 improves survival when administered therapeutically to wild-type mice challenged with high doses of L. monocytogenes. Together, these findings demonstrate the utility of murine listeriosis as a model for dissecting qualitative differences between protective and pathological host responses and reveal novel roles for FXI in exacerbating inflammation and pathogen burden during a lethal bacterial infection.

  9. TTC39B Deficiency Stabilizes LXR Reducing both Atherosclerosis and Steatohepatitis

    PubMed Central

    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.

    2016-01-01

    Summary Cellular mechanisms that mediate steato-hepatitis, an increasingly prevalent condition in the Western world for which no therapies are available1, are poorly understood. Despite the fact 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. We discovered that tetratricopeptide repeat (TPR) domain protein 39B (Ttc39b, C9orf52) (T39), a high density lipoprotein (HDL) gene discovered in human genome wide association studies (GWAS)2, promotes the ubiquitination and degradation of LXR. Chow-fed T39-/- mice displayed increased HDL cholesterol levels associated with increased enterocyte ATP binding cassette transporter A1 (Abca1) expression and increased LXR protein without change in LXR mRNA. When challenged with a high fat/high cholesterol/bile salt (HF/HC/BS) diet, T39-/- mice or mice with hepatocyte-specific T39 deficiency showed increased hepatic LXR protein and target gene expression, and unexpectedly protection from steato-hepatitis and death. Western Type Diet (WTD)-fed Low density lipoprotein receptor (Ldlr)-/-T39-/- mice showed decreased fatty liver, increased HDL, decreased LDL and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibited hepatic sterol regulatory element binding protein 1 (SREBP-1, ADD1) processing. This was explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids (PUFA), linked to an LXRα-dependent increase in expression of enzymes mediating PC biosynthesis and incorporation of PUFA 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 be an effective strategy for reducing both steato-hepatitis and atherosclerosis. PMID

  10. Accelerated wound healing in tumor necrosis factor receptor p55-deficient mice with reduced leukocyte infiltration.

    PubMed

    Mori, Ryoichi; Kondo, Toshikazu; Ohshima, Tohru; Ishida, Yuko; Mukaida, Naofumi

    2002-07-01

    To clarify biological roles of tumor necrosis factor receptor p55 (TNF-Rp55) -mediated signals in wound healing, skin excisions were prepared in BALB/c (WT) and TNF-Rp55-deficient (KO) mice. In WT mice, the wound area was reduced to 50% of the original area 6 days after injury, with angiogenesis and collagen accumulation. Histopathologically, reepithelialization rate was approximately 80% 6 days. Myeloperoxidase activity and macrophage recruitment were the most evident 1 and 6 days after injury, respectively. Gene expression of adhesion molecules, interleukin 1alpha (IL-1alpha), IL-1beta, monocyte chemoattractant protein 1, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-2, transforming growth factor beta1 (TGF-beta1) connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), Flt-1, and Flk-1 was enhanced at the wound site. In KO mice, an enhancement in angiogenesis, collagen content, and reepithelialization was accelerated with the increased gene expression of TGF-beta1, CTGF, VEGF, Flt-1, and Flk-1 at the wound sites, resulting in accelerated wound healing compared with WT mice. In contrast, leukocyte infiltration, mRNA expression of adhesion molecules, and cytokines were significantly reduced in KO mice. These observations suggest that TNF-Rp55-mediated signals have some role in promoting leukocyte infiltration at the wound site and negatively affect wound healing, probably by reducing angiogenesis and collagen accumulation.

  11. Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice

    PubMed Central

    Larmonier, Claire B.; Laubitz, Daniel; Hill, Faihza M.; Shehab, Kareem W.; Lipinski, Leszek; Midura-Kiela, Monica T.; McFadden, Rita-Marie T.; Ramalingam, Rajalakshmy; Hassan, Kareem A.; Golebiewski, Marcin; Besselsen, David G.; Ghishan, Fayez K.

    2013-01-01

    Chronic inflammation and enteric infections are frequently associated with epithelial Na+/H+ exchange (NHE) inhibition. Alterations in electrolyte transport and in mucosal pH associated with inflammation may represent a key mechanism leading to changes in the intestinal microbial composition. NHE3 expression is essential for the maintenance of the epithelial barrier function. NHE3−/− mice develop spontaneous distal chronic colitis and are highly susceptible to dextran sulfate (DSS)-induced mucosal injury. Spontaneous colitis is reduced with broad-spectrum antibiotics treatment, thus highlighting the importance of the microbiota composition in NHE3 deficiency-mediated colitis. We herein characterized the colonic microbiome of wild-type (WT) and NHE3−/− mice housed in a conventional environment using 454 pyrosequencing. We demonstrated a significant decrease in the phylogenetic diversity of the luminal and mucosal microbiota of conventional NHE3−/− mice compared with WT. Rederivation of NHE3−/− mice from conventional to a barrier facility eliminated the signs of colitis and decreased DSS susceptibility. Reintroduction of the conventional microflora into WT and NHE3−/− mice from the barrier facility resulted in the restoration of the symptoms initially described in the conventional environment. Interestingly, qPCR analysis of the microbiota composition in mice kept in the barrier facility compared with reconventionalized mice showed a significant reduction of Clostridia classes IV and XIVa. Therefore, the gut microbiome plays a prominent role in the pathogenesis of colitis in NHE3−/− mice, and, reciprocally, NHE3 also plays a critical role in shaping the gut microbiota. NHE3 deficiency may be a critical contributor to dysbiosis observed in patients with inflammatory bowel disease. PMID:24029465

  12. Mitochondrial membrane potential is reduced in copper-deficient C2C12 cells in the absence of apoptosis.

    PubMed

    Chen, Xiulian; Medeiros, Denis M; Jennings, Dianne

    2005-07-01

    Mitochondrial membrane potential is reduced in copper-deficient rat hearts, but it is uncertain if this will lead to the onset of apoptosis. To determine if copper deficiency per se leads to apoptosis, C2C12 cells were made copper deficient by treatment with the copper chelator tetraethylenepentamine (TEPA). In TEPA-treated cells, the activity of Cu, Zn-superoxide dismutase and cytochrome-c oxidase decreased dramatically. The protein levels of nuclear-encoded subunits of the cytochromie-c oxidase decreased, but the mitochondrial-encoded subunits remained unchanged. Decreased mitochondrial membrane potential was indicated in TEPA-treated cells, but further investigation of the potential induction of apoptosis by measuring caspase-3 activity, protein concentrations of Bcl-2 and Bax, and DNA fragmentation suggested that apoptosis is not induced in TEPA-treated C2C12 cells. Cells with decreased mitochondrial membrane potential were not destined to apoptosis as a result of copper deficiency.

  13. 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

  14. Nitric oxide-releasing agent, LA419, reduces atherogenesis in apolipoprotein E-deficient mice.

    PubMed

    Carnicer, Ricardo; Guillén, Natalia; Arbonés-Mainar, José M; Navarro, María A; Guzmán, Mario A; Barranquero, Cristina; Arnal, Carmen; Gascón, Sonia; Acín, Sergio; Mourelle, Marisabel; Osada, Jesús

    2009-05-01

    LA419 is a novel nitric oxide-donor with antioxidant properties. The effect of this compound on the development of atherosclerosis was investigated in apolipoprotein E-deficient mice. Male mice were randomized to receive vehicle or 5 mg/kg/day LA419 for 12 weeks. At the end of this period, plasma lipid and lipoprotein parameters, oxidative stress markers and hepatic fat, and mRNA levels were measured as well as en face and cross-sectional lesion areas of the aorta. Data showed that LA419 administration reduced atherosclerotic foci and cross-sectional lesion areas by decreasing the intimae presence of macrophage-derived foam cells despite an increase in plasma cholesterol. This agent induced a significant reduction in body weight gain and mass of adipose tissue. Furthermore, compared with placebo, LA419 administration significantly reduced plasma triglycerides and apolipoprotein C-III levels as well as systemic oxidative stress, estimated by plasma 8-isoprostane. Conversely, nonesterified fatty acid and HDL cholesterol levels remained unchanged, as well as apolipoproteins A-I, A-IV, and B and paraoxonase activity. Plasma triglycerides were significantly associated with plasma levels of apolipoprotein C-III and hepatic Fsp27 mRNA expression. These results indicate that administration of LA419 modulates lesion development. These actions are partly independent of total cholesterol as well as HDL particles and related to triglyceridemia and oxidative stress. Hypotriglyceridemia is associated with an equal number of apoB-containing particles. Hence, LA419 administration could be used as a safe alternative to control the metabolic syndrome and atherosclerosis.

  15. 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.

  16. 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.

  17. Reduced food intake and body weight in mice deficient for the G protein-coupled receptor GPR82.

    PubMed

    Engel, Kathrin M Y; Schröck, Kristin; 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.

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

    PubMed

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

    2008-08-01

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

  19. Congenital brain serotonin deficiency leads to reduced ethanol sensitivity and increased ethanol consumption in mice.

    PubMed

    Sachs, Benjamin D; Salahi, A Ayten; Caron, Marc G

    2014-02-01

    Serotonergic dysfunction has been hypothesized to play an important role in the pathophysiology of alcoholism. However, whether congenital serotonin (5-HT) deficiency leads to increased alcohol consumption or affects ethanol-related behaviors has not been established. Here, we use a transgenic mouse line that expresses a hypofunctional variant of the 5-HT synthesis enzyme, tryptophan hydroxylase 2, to examine the impact of 5-HT deficiency on responses to alcohol. We demonstrate that these 5-HT-deficient transgenic animals (Tph2KI mice) recover their righting reflex more rapidly than wild-type controls following a high dose of ethanol and exhibit blunted locomotor retardation in response to repeated ethanol administration. In addition, compared to WT controls, 5-HT-deficient animals consume significantly more ethanol and exhibit increased preference for ethanol in two-bottle choice tests. Our data also suggest that 5-HT plays a critical role in mediating the effects of ethanol on Akt/GSK3β signaling in the nucleus accumbens. Overall, our results corroborate previous theories regarding the importance of brain 5-HT levels in mediating responsiveness to alcohol and demonstrate, for the first time, that congenital 5-HT deficiency leads to increased ethanol consumption and decreased sensitivity to the sedative-like effects of ethanol, perhaps in part through modulating Akt/GSK3β signaling.

  20. A micronutrient-fortified beverage prevents iron deficiency, reduces anemia and improves the hemoglobin concentration of pregnant Tanzanian women.

    PubMed

    Makola, Diklar; Ash, Deborah M; Tatala, Simon R; Latham, Michael C; Ndossi, Godwin; Mehansho, Haile

    2003-05-01

    Maternal malnutrition continues to be a major contributor to adverse reproductive outcomes in developing countries, despite longstanding efforts to fortify foods or to distribute medicinal supplements to pregnant women. The objective of this study was to test the effect of a micronutrient-fortified beverage containing 11 micronutrients (iron, iodine, zinc, vitamin A, vitamin C, niacin, riboflavin, folate, vitamin B-12, vitamin B-6 and vitamin E) on the hemoglobin, iron and vitamin A status of pregnant women in Tanzania. A group of 259 pregnant women with gestational ages of 8 to 34 wk were enrolled in a randomized double-blind controlled trial in which study women received 8 wk of supplementation. Hemoglobin, ferritin and dried blood spot retinol were measured at baseline and at the end of the supplementation period. The supplement resulted in a 4.16 g/L increase in hemoglobin concentration and a 3 micro g/L increase in ferritin and reduced the risk of anemia and iron deficiency anemia by 51 and 56%, respectively. The risk of iron deficiency was reduced by 70% among those who had iron deficiency at baseline and by 92% among those who had adequate stores. The micronutrient-fortified beverage may be a useful and convenient preventative measure, one that could help improve the nutritional status of women both before and during pregnancy and thereby help avoid some of the potential maternal and fetal consequences of micronutrient deficiencies.

  1. 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.

  2. 5-Lipoxygenase and cyclooxygenase inhibitory dammarane triterpenoid 1 from Borassus flabellifer seed coat inhibits tumor necrosis factor-α secretion in LPSInduced THP-1 human monocytes and induces apoptosis in MIA PaCa-2 pancreatic cancer cells.

    PubMed

    Yarla, Nagendra Sastry; Azad, Rajaram; Basha, Mahaboob; Rajack, Abdul; Kaladhar, D S V G K; Allam, Bharat Kumar; Pragada, Rajeswara Rao; Singh, Krishna Nand; K, Sunanda Kumari; Pallu, Reddanna; Parimi, Umadevi; Bishayee, Anupam; Duddukuri, Govinda Rao

    2015-01-01

    Phospholipase A2 (PLA2), Cyclooxygenase (COX) and 5-Lipoxygenase (5-LOX) are arachidonic acid metabolizing enzymes and their inhibitors have been developed as therapeutic molecules for cancer and inflammation related disorders. In the present study, PLA2, COX 1&2 and 5-LOX inhibitory studies of Borassus flabellifer seed coat extract were carried out and substantial 5-LOX inhibitory activity was found. Dammarane triterpenoid 1 (Dammara-20,23-diene-3,25-diol) was isolated according to 5-LOX activity guided isolation, and screened for COX (1 & 2) inhibitory activities. Dammarane triterpenoid 1 inhibited carrageenan-induced rat paw edema and TNF-α secretion levels in lipopolysaccharide (LPS)-induced THP-1 human monocytes. Anticancer activity studies demonstrated the antiproliferative effect of dammarane triterpenoid 1 on various cancer cell lines including MIA PaCa-2 pancreatic, DU145 prostate, HL-60 leukemia and Caco-2 colon cancers. Dammarane triterpenoid 1 showed good antiproliferative activity on MIA PaCa-2 pancreatic cancer cell line with IC50 of 12.36±0.33 µM, among other tested cell lines. Apoptosis inducing activity of dammarane triterpenoid 1 was confirmed based on increased sub-G0 phase cell population in cell cycle analysis, loss of mitochondrian membrane potential, elevated levels of cytochrome c, nuclear morphological changes and DNA fragmentation in MIA PaCa-2 pancreatic cancer cells. Therefore, dammarane triterpenoid skeleton may raise the hope of developing novel anti-inflammatory and anticancer drugs in the future.

  3. Design and synthesis of ten biphenyl-neolignan derivatives and their in vitro inhibitory potency against cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4-formation.

    PubMed

    Schühly, Wolfgang; Hüfner, Antje; Pferschy-Wenzig, Eva M; Prettner, Elke; Adams, Michael; Bodensieck, Antje; Kunert, Olaf; Oluwemimo, Asije; Haslinger, Ernst; Bauer, Rudolf

    2009-07-01

    A set of ten derivatives of methylhonokiol, an anti-inflammatory active biphenyl-type neolignan from Magnolia grandiflora, has been evaluated for their in vitro cyclooxygenase-1/2 (COX-1/2) inhibitory activity using assays with purified prostaglandin H synthase (PGHS)-1 and PGHS-2 enzymes as well as for their 5-lipoxygenase (5-LOX) mediated LTB(4) formation inhibitory activity using an assay with activated human polymorphonuclear leukocytes. The derivatization reactions included methylation, acetylation, hydrogenation, epoxydation and isomerization. Five of the derivatives are new to science. The most active compound against COX-1 and COX-2 was methylhonokiol with IC(50) values of 0.1 microM, whereas the most active compound against LTB(4) formation was (E)-3'-propenyl-5-(2-propenyl)-biphenyl-2,4'-diol with an IC(50) value of 1.0 microM. Structure-activity relationship studies showed that the polarity of the derivatives plays a crucial role in their activity towards COX-1/2 enzyme and 5-LOX mediated LTB(4) formation.

  4. Glycosylation inhibition reduces cholesterol accumulation in NPC1 protein-deficient cells.

    PubMed

    Li, Jian; Deffieu, Maika S; Lee, Peter L; Saha, Piyali; Pfeffer, Suzanne R

    2015-12-01

    Lysosomes are lined with a glycocalyx that protects the limiting membrane from the action of degradative enzymes. We tested the hypothesis that Niemann-Pick type C 1 (NPC1) protein aids the transfer of low density lipoprotein-derived cholesterol across this glycocalyx. A prediction of this model is that cells will be less dependent upon NPC1 if their glycocalyx is decreased in density. Lysosome cholesterol content was significantly lower after treatment of NPC1-deficient human fibroblasts with benzyl-2-acetamido-2-deoxy-α-D-galactopyranoside, an inhibitor of O-linked glycosylation. Direct biochemical measurement of cholesterol showed that lysosomes purified from NPC1-deficient fibroblasts contained at least 30% less cholesterol when O-linked glycosylation was blocked. As an independent means to modify protein glycosylation, we used Chinese hamster ovary ldl-D cells defective in UDP-Gal/UDP-GalNAc 4-epimerase in which N- and O-linked glycosylation can be controlled. CRISPR generated, NPC1-deficient ldl-D cells supplemented with galactose accumulated more cholesterol than those in which sugar addition was blocked. In the absence of galactose supplementation, NPC1-deficient ldl-D cells also transported more cholesterol from lysosomes to the endoplasmic reticulum, as monitored by an increase in cholesteryl [(14)C]-oleate levels. These experiments support a model in which NPC1 protein functions to transfer cholesterol past a lysosomal glycocalyx.

  5. Vitamin D Deficiency Reduces the Immune Response, Phagocytosis Rate, and Intracellular Killing Rate of Microglial Cells

    PubMed Central

    Onken, Marie Luise; Schütze, Sandra; Redlich, Sandra; Götz, Alexander; Hanisch, Uwe-Karsten; Bertsch, Thomas; Ribes, Sandra; Hanenberg, Andrea; Schneider, Simon; Bollheimer, Cornelius; Sieber, Cornel; Nau, Roland

    2014-01-01

    Meningitis and meningoencephalitis caused by Escherichia coli are associated with high rates of mortality and neurological sequelae. A high prevalence of neurological disorders has been observed in geriatric populations at risk of hypovitaminosis D. Vitamin D has potent effects on human immunity, including induction of antimicrobial peptides (AMPs) and suppression of T-cell proliferation, but its influence on microglial cells is unknown. The purpose of the present study was to determine the effects of vitamin D deficiency on the phagocytosis rate, intracellular killing, and immune response of murine microglial cultures after stimulation with the Toll-like receptor (TLR) agonists tripalmitoyl-S-glyceryl-cysteine (TLR1/2), poly(I·C) (TLR3), lipopolysaccharide (TLR4), and CpG oligodeoxynucleotide (TLR9). Upon stimulation with high concentrations of TLR agonists, the release of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was decreased in vitamin D-deficient compared to that in vitamin D-sufficient microglial cultures. Phagocytosis of E. coli K1 after stimulation of microglial cells with high concentrations of TLR3, -4, and -9 agonists and intracellular killing of E. coli K1 after stimulation with high concentrations of all TLR agonists were lower in vitamin D-deficient microglial cells than in the respective control cells. Our observations suggest that vitamin D deficiency may impair the resistance of the brain against bacterial infections. PMID:24686054

  6. 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

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

    PubMed

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

    1997-01-01

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

  8. 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

  9. 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.

  10. 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.

  11. Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2‐deficient mice

    PubMed Central

    Zhou, Mei; Learned, R. Marc; Rossi, Stephen J.; DePaoli, Alex M.; Tian, Hui

    2016-01-01

    Defects in multidrug resistance 3 gene (MDR3), which encodes the canalicular phospholipid flippase, cause a wide spectrum of cholangiopathy phenotypes in humans. Mice deficient in Mdr2 (murine ortholog of MDR3) develop liver diseases that closely reproduce the biochemical, histological, and clinical features of human cholangiopathies such as progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. We hypothesized that modulating bile acid metabolism by the gut hormone fibroblast growth factor 19 (FGF19) may represent a novel approach for treating cholangiopathy and comorbidities. We introduced adeno‐associated virus carrying the gene for either the endocrine hormone FGF19 or engineered FGF19 variant M70 to 12‐week old Mdr2‐deficient mice with fully established disease. Effects on serum levels of liver enzymes, liver histology, and bile acid homeostasis were evaluated. FGF19 and M70 rapidly and effectively reversed liver injury, decreased hepatic inflammation, attenuated biliary fibrosis, and reduced cholecystolithiasis in Mdr2‐deficient mice. Mechanistically, FGF19 and M70 significantly inhibited hepatic expression of Cyp7a1 and Cyp27a1, which encode enzymes responsible for the rate‐limiting steps in the classic and alternate bile acid synthetic pathways, thereby reducing the hepatic bile acid pool and blood levels of bile acids. Importantly, prolonged exposure to FGF19, but not M70, led to the formation of hepatocellular carcinomas in the Mdr2‐deficient mice. Furthermore, M70 ameliorated the hepatosplenomegaly and ductular proliferation that are associated with cholangiopathy. Conclusion: These results demonstrate the potential for treating cholangiopathy by safely harnessing FGF19 biology to suppress bile acid synthesis. (Hepatology 2016;63:914–929) PMID:26418580

  12. Enhanced viral clearance and reduced leukocyte infiltration in experimental herpes encephalitis after intranasal infection of CXCR3-deficient mice.

    PubMed

    Zimmermann, J; Hafezi, W; Dockhorn, A; Lorentzen, Eva U; Krauthausen, M; Getts, Daniel R; Müller, M; Kühn, Joachim E; King, Nicholas J C

    2017-01-23

    Herpes simplex virus type 1 (HSV-1) encephalitis (HSE) is the most common fatal sporadic encephalitis in developed countries. There is evidence from HSE animal models that not only direct virus-mediated damage caused but also the host's immune response contributes to the high mortality of the disease. Chemokines modulate and orchestrate this immune response. Previous experimental studies in HSE models identified the chemokine receptor CXCR3 and its ligands as molecules with a high impact on the course of HSE in mouse models. In this study, the role of the chemokine receptor CXCR3 was evaluated after intranasal infection with the encephalitogenic HSV-1 strain 17 syn(+) using CXCR3-deficient mice (CXCR3(-/-)) and wild-type controls. We demonstrated a neurotropic viral spread into the CNS of after intranasal infection. Although viral load and histological distribution of infected neurons were independent from CXCR3 signaling early after infection, CXCR3-deficient mice cleared HSV-1 more efficiently 14 days after infection. Furthermore, CXCR3 deficiency led to a decreased weight loss in mice after HSV-1 infection. T cell infiltration and microglial activation was prominently reduced by inhibition of CXCR3 signaling. Quantitative PCR of proinflammatory cytokines and chemokines confirmed the reduced neuroinflammatory response in CXCR3-deficient mice during HSE. Our results demonstrate that the recruitment of peripheral immune cells into the CNS, induction of neuroinflammation, and consecutive weight loss during herpes encephalitis is modulated by CXCR3 signaling. Interruption of the CXCR3 pathway ameliorates the detrimental host immune response and in turn, leads paradoxically to an enhanced viral clearance after intranasal infection. Our data gives further insight into the role of CXCR3 during HSE after intranasal infection.

  13. 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.

  14. In vitro metabolism of 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid (licofelone, ML3000), an inhibitor of cyclooxygenase-1 and -2 and 5-lipoxygenase.

    PubMed

    Albrecht, Wolfgang; Unger, Anke; Nussler, Andreas K; Laufer, Stefan

    2008-05-01

    2-[6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid (licofelone) is a dual inhibitor of both cyclooxygenase isoforms and 5-lipoxygenase and under development for treatment of osteoarthritis. In conventional in vitro assays using liver microsomes and NADPH as cosubstrate, a high metabolic stability of licofelone was observed. In the presence of UDP-glucuronic acid, licofelone is rapidly converted into the corresponding acyl glucuronide, M1. These results are in conflict with data from clinical studies. After administration of licofelone to humans, M1 plasma concentrations were negligibly low, whereas the exposure of the hydroxy-metabolite M2 achieved values of approximately 20% compared with that of the parent drug. Metabolism studies with human hepatocytes and dual-activity assays with microsomes, which allowed the simultaneous monitoring of hydroxylation and glucuronidation reactions, were performed, and the metabolic pathway of licofelone was elucidated. After glucuronidation, predominantly catalyzed by UDP glucuronosyltransferase (UGT) isoforms UGT2B7, UGT1A9, and UGT1A3, M1 is converted into the hydroxy-glucuronide M3 in a CYP2C8-dependent reaction. The enzyme specificities were investigated using recombinant human cytochrome P450 and UGT isoforms as test systems. In vitro drug-interaction studies using the 6alpha-hydroxylation of paclitaxel as control reaction confirmed that neither licofelone nor M1 is a relevant inhibitor of CYP2C8. The formation of M3 was also observed with liver microsomes from cynomolgus monkeys, but in incubations with mouse and rat liver microsomes, M1 remained unchanged. The clinical relevance of these findings is discussed.

  15. Molecular cloning and functional characterization of arachidonate 5-lipoxygenase (Alox5), and its expression in response to the ratio of linolenic acid to linoleic acid in diets of large yellow croaker (Larmichthys crocea).

    PubMed

    Wang, Tianjiao; Zuo, Rantao; Mai, Kangsen; Xu, Wei; Ai, Qinghui

    2016-11-01

    This study was conducted to clone and functionally characterize a full-length cDNA encoding arachidonate 5-lipoxygenase (Alox5) from large yellow croaker (Larmichthys crocea) and investigate its gene expression in response to graded dietary ratio of linolenic acid (ALA) to linoleic acid (LNA) (0.03, 0.06, 0.45, 0.90 and 1.51). An isolated 2372bp cDNA clone of Alox5 contained an open reading frame spanning 2025bp encoding a protein with the ability to modify arachidonate acid (AA) to 5-hydroxyeicosatetraenoic (5-HETE). In the liver, the Alox5 mRNA expression levels significantly increased to the maximum when the dietary ALA/LNA increased from 0.03 to 0.06, and then significantly decreased with dietary ALA/LNA increased to 1.51 (P<0.05). In the kidney, the expression levels of Alox5 of fish fed diets with low dietary ALA/LNA (0.03-0.06) were significantly higher than those of fish fed diets with high dietary ALA/LNA (0.45-1.51) (P<0.05). The dual-luciferase reporter assays showed that the nuclear factor kappa B (NF-κB) could act on cognate cis-acting elements in the promoter of Alox5 and increased the transcription of Alox5. Results of the present study suggested that the expression of Alox5 is higher in croakers fed high concentrations of LNA compared to those fed high concentrations of ALA, which might be regulated by NF-κB and contribute to the inflammation process by catalyzing the dioxygenation of AA.

  16. Ebola Virus Makona Shows Reduced Lethality in an Immune-deficient Mouse Model.

    PubMed

    Smither, Sophie J; Eastaugh, Lin; Ngugi, Sarah; O'Brien, Lyn; Phelps, Amanda; Steward, Jackie; Lever, Mark Stephen

    2016-10-15

    Ebola virus Makona (EBOV-Makona; from the 2013-2016 West Africa outbreak) shows decreased virulence in an immune-deficient mouse model, compared with a strain from 1976. Unlike other filoviruses tested, EBOV-Makona may be slightly more virulent by the aerosol route than by the injected route, as 2 mice died following aerosol exposure, compared with no mortality among mice that received intraperitoneal injection of equivalent or higher doses. Although most mice did not succumb to infection, the detection of an immunoglobulin G antibody response along with observed clinical signs suggest that the mice were infected but able to clear the infection and recover. We hypothesize that this may be due to the growth rates and kinetics of the virus, which appear slower than that for other filoviruses and consequently give more time for an immune response that results in clearance of the virus. In this instance, the immune-deficient mouse model is unlikely to be appropriate for testing medical countermeasures against this EBOV-Makona stock but may provide insight into pathogenesis and the immune response to virus.

  17. Adaptive immune response in JAM-C-deficient mice: normal initiation but reduced IgG memory.

    PubMed

    Zimmerli, Claudia; Lee, Boris P L; Palmer, Gaby; Gabay, Cem; Adams, Ralf; Aurrand-Lions, Michel; Imhof, Beat A

    2009-04-15

    We have recently shown that junctional adhesion molecule (JAM)-C-deficient mice have leukocytic pulmonary infiltrates, disturbed neutrophil homeostasis, and increased postnatal mortality. This phenotype was partially rescued when mice were housed in ventilated isolators, suggesting an inability to cope with opportunistic infections. In the present study, we further examined the adaptive immune responses in JAM-C(-/-) mice. We found that murine conventional dendritic cells express in addition to Mac-1 and CD11c also JAM-B as ligand for JAM-C. By in vitro adhesion assay, we show that murine DCs can interact with recombinant JAM-C via Mac-1. However, this interaction does not seem to be necessary for dendritic cell migration and function in vivo, even though JAM-C is highly expressed by lymphatic sinuses of lymph nodes. Nevertheless, upon immunization and boosting with a protein Ag, JAM-C-deficient mice showed decreased persistence of specific circulating Abs although the initial response was normal. Such a phenotype has also been observed in a model of Ag-induced arthritis, showing that specific IgG2a Ab titers are reduced in the serum of JAM-C(-/-) compared with wild-type mice. Taken together, these data suggest that JAM-C deficiency affects the adaptive humoral immune response against pathogens, in addition to the innate immune system.

  18. Growth hormone replacement therapy reduces risk of cancer in adult with growth hormone deficiency: A meta-analysis

    PubMed Central

    Li, Zhanzhan; Zhou, Qin; Li, Yanyan; Fu, Jun; Huang, Xinqiong; Shen, Liangfang

    2016-01-01

    The risk of growth hormone on cancer in adult with growth hormone deficiency remains unclear. We carried out a meta-analysis to evaluate the risk of cancer in adult with and without growth hormone replacement therapy. We searched PubMed, Web of Science, China National Knowledge Infrastructure, and WanFang databases up to 31 July 2016 for eligible studies. Pooled risk ratio (RR) with 95% confidence interval (CI) was calculated using fixed-or random-effects models if appropriate. The Newcastle-Ottawa Scale was used to assess the study quality. Two retrospective and seven prospective studies with a total of 11191 participants were included in the final analysis. The results from fixed-effects model showed this therapy was associated with the deceased risk of cancer in adult with growth hormone deficiency (RR=0.69, 95%CI: 0.59-0.82), with low heterogeneity within studies (I2=39.0%, P=0.108). We performed sensitivity analyses by sequentially omitting one study each time, and the pooled RRs did not materially change, indicating that our results were statistically stable. Begger's and Egger's tests suggested that there was no publication bias (Z=-0.63, P=0.520; t=0.16, P=0.874). Our study suggests that growth hormone replacement therapy could reduce risk of cancer in adult with growth hormone deficiency. PMID:27835910

  19. Clinical and immunological correction of DOCK8 deficiency by allogeneic hematopoietic stem cell transplantation following a reduced toxicity conditioning regimen.

    PubMed

    Boztug, Heidrun; Karitnig-Weiß, Cäcilia; Ausserer, Bernd; Renner, Ellen D; Albert, Michael H; Sawalle-Belohradsky, Julie; Belohradsky, Bernd H; Mann, Georg; Horcher, Ernst; Rümmele-Waibel, Alexandra; Geyeregger, Rene; Lakatos, Karoly; Peters, Christina; Lawitschka, Anita; Matthes-Martin, Susanne

    2012-10-01

    Dedicator of cytokinesis 8 protein (DOCK8) deficiency is a combined immunodeficiency disorder characterized by an expanding clinical picture with typical features of recurrent respiratory or gastrointestinal tract infections, atopic eczema, food allergies, chronic viral infections of the skin, and blood eosinophilia often accompanied by elevated serum IgE levels. The only definitive treatment option is allogeneic hematopoietic stem cell transplantation (HSCT). We report a patient with early severe manifestation of DOCK8 deficiency, who underwent unrelated allogeneic HSCT at the age of 3 years following a reduced toxicity conditioning regimen. The transplant course was complicated by pulmonary aspergilloma pretransplantation, adenovirus (ADV) reactivation, and cytomegalovirus (CMV) pneumonitis 4 weeks after transplantation. With antifungal and antiviral treatment the patient recovered. Seven months after transplantation the patient is in excellent clinical condition. Eczematous rash, chronic viral skin infections, and food allergies have subsided, associated with normalization of IgE levels and absolute numbers of eosinophils. Chimerism analysis shows stable full donor chimerism. DOCK8 deficiency can be successfully cured by allogeneic HSCT. This treatment option should be considered early after diagnosis, as opportunistic infections and malignancies that occur more frequently during the natural course of the disease are associated with higher morbidity and mortality.

  20. Impairment of skin wound healing in beta-1,4-galactosyltransferase-deficient mice with reduced leukocyte recruitment.

    PubMed

    Mori, Ryoichi; Kondo, Toshikazu; Nishie, Toshikazu; Ohshima, Tohru; Asano, Masahide

    2004-04-01

    Cell-surface carbohydrate chains are known to contribute to cell migration, interactions, and proliferation, but their roles in skin wound healing have not been evaluated. We examined the biological roles of beta4-galactosylated carbohydrate chains in skin wound healing using mutant mice that lack beta-1,4-galactosyltransferase-I (beta4GalT-I), which is responsible for the biosynthesis of the type 2 chain in N-glycans and the core 2 branch in O-glycans. beta4GalT-I-deficient mice showed significantly delayed wound healing with reduced re-epithelialization, collagen synthesis, and angiogenesis, compared with control mice. Neutrophil and macrophage recruitment at wound sites was also impaired in these mice probably because of selectin-ligand deficiency. In accordance with the reduced leukocyte infiltration, the expression levels of macrophage-derived chemokines, transforming growth factor-beta1, and vascular endothelial growth factor were all reduced in beta4GalT-I(-/-) mice. These results demonstrate that beta4-galactosylated carbohydrate chains play a critical role in skin wound healing by mediating leukocyte infiltration and epidermal cell growth, which affects the production of chemokines and growth factors. This study introduces a suitable mouse model for investigating the molecular mechanisms of skin wound healing and is the first report showing that carbohydrate chains have a strong influence on skin wound healing.

  1. Deficiency of CCAAT/Enhancer Binding Protein-Epsilon Reduces Atherosclerotic Lesions in LDLR−/− Mice

    PubMed Central

    Okamoto, Ryoko; Gery, Sigal; Gombart, Adrian F.; Wang, Xuping; Castellani, Lawrence W.; Akagi, Tadayuki; Chen, Shuang; Arditi, Moshe; Ho, Quoc; Lusis, Aldons J.; Li, Quanlin; Koeffler, H. Phillip

    2014-01-01

    The CCAAT/enhancer binding proteins (C/EBPs) are transcription factors involved in hematopoietic cell development and induction of several inflammatory mediators. C/EBPε is expressed only in myeloid cells including monocytes/macrophages. Atherosclerosis is an inflammatory disorder of the vascular wall and circulating immune cells such as monocytes/macrophages. Mice deficient in the low density lipoprotein (LDL) receptor (Ldlr−/−) fed on a high cholesterol diet (HCD) show elevated blood cholesterol levels and are widely used as models to study human atherosclerosis. In this study, we generated Ldlr and Cebpe double-knockout (llee) mice and compared their atherogenic phenotypes to Ldlr single deficient (llEE) mice after HCD. Macrophages from llee mice have reduced lipid uptake by foam cells and impaired phagokinetic motility in vitro compared to macrophages from llEE mice. Also, compared to llEE mice, llee mice have alterations of lipid metabolism, and reduced atheroma and obesity, particularly the males. Peritoneal macrophages of llee male mice have reduced mRNA expression of FABP4, a fatty acid binding protein implicated in atherosclerosis. Overall, our study suggests that the myeloid specific factor C/EBPε is involved in systemic lipid metabolism and that silencing of C/EBPε could decrease the development of atherosclerosis. PMID:24489659

  2. Diet-Induced Obesity and Reduced Skin Cancer Susceptibility in Matrix Metalloproteinase 19-Deficient Mice

    PubMed Central

    Pendás, Alberto M.; Folgueras, Alicia R.; Llano, Elena; Caterina, John; Frerard, Françoise; Rodríguez, Francisco; Astudillo, Aurora; Noël, Agnès; Birkedal-Hansen, Henning; López-Otín, Carlos

    2004-01-01

    Matrix metalloproteinase 19 (MMP-19) is a member of the MMP family of endopeptidases that, in contrast to most MMPs, is widely expressed in human tissues under normal quiescent conditions. MMP-19 has been found to be associated with ovulation and angiogenic processes and is deregulated in diverse pathological conditions such as rheumatoid arthritis and cancer. To gain further insights into the in vivo functions of this protease, we have generated mutant mice deficient in Mmp19. These mice are viable and fertile and do not display any obvious abnormalities. However, Mmp19-null mice develop a diet-induced obesity due to adipocyte hypertrophy and exhibit decreased susceptibility to skin tumors induced by chemical carcinogens. Based on these results, we suggest that this enzyme plays an in vivo role in some of the tissue remodeling events associated with adipogenesis, as well as in pathological processes such as tumor progression. PMID:15169894

  3. 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

    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.

  4. Ovarian hormone deficiency reduces intrinsic excitability and abolishes acute estrogen sensitivity in hippocampal CA1 pyramidal neurons

    PubMed Central

    Wu, Wendy W.; Adelman, John P.; Maylie, James

    2011-01-01

    Premature and uncompensated loss of ovarian hormones following ovariectomy (OVX) elevates the risks of cognitive impairment and dementia. These risks are prevented with estrogen (E2)-containing hormone replacement therapy initiated shortly following OVX but not after substantial delay. Currently the cellular bases underlying these clinical findings are unknown. At the cellular level, intrinsic membrane properties regulate the efficiency of synaptic inputs to initiate output action potentials (APs), thereby affecting neuronal communication hence cognitive processing. This study tested the hypothesis that in CA1 pyramidal neurons, intrinsic membrane properties and their acute regulation by E2 require ovarian hormones for maintenance. Whole-cell current clamp recordings were performed on neurons from ~7 months old OVX rats that experienced either short-term (10 days, control OVX) or long-term (5 months, OVXLT) ovarian hormone deficiency. The results reveal that long-term hormone deficiency reduced intrinsic membrane excitability (IE) as measured by the number of evoked action potentials (APs) and firing duration for a given current injection. This was accompanied by AP broadening, an increased slow afterhyperpolarization (sAHP), and faster accumulation of NaV channel inactivation during repetitive firing. In the control OVX neurons, E2 acutely increased IE and reduced the sAHP. In contrast, acute regulation of IE by E2 was absent in the OVXLT neurons. Since the degree of IE of hippocampal pyramidal neurons is positively related with hippocampus-dependent learning ability, and modulation of IE is observed following successful learning, these findings provide a framework for understanding hormone deficiency-related cognitive impairment and the critical window for therapy initiation. PMID:21325532

  5. 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.

  6. 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.

  7. Impaired ovarian development and reduced fertility in female mice deficient in Skp2

    PubMed Central

    Fotovati, Abbas; Abu-Ali, Samah; Nakayama, Keiko; Nakayama, Keiichi I

    2011-01-01

    p27 is a major negative regulator of somatic cellular proliferation, and its down-regulation has been shown to be associated with cancer development. Targeted disruption ofp27 results in complete loss of fertility in female mice, suggesting that it plays a significant role in the development of female gametes and the surrounding environment. We have now investigated the effect of loss of Skp2, an F-box protein that mediates ubiquitin-dependent degradation of p27, on female gamete production. The female Skp2-deficient mice showed accumulation of p27 in the ovary and severely compromised gamete development from the embryonic stage to follicular growth in the adult ovary, eventually leading to a decreased functional gamete reserve. Additional deletion of p27 resulted in relatively normal ovarian folliculogenesis, suggesting that accumulating p27 is primarily responsible for the compromised ovarian development. Embryonic ovaries of Skp2−/− mice manifested massive apoptosis as evidenced by cleavage of pro-caspase 3 and poly(ADP-ribose) polymerase-1. This in turn resulted in a significant decrease in the remaining pool of functional gametes in Skp2−/− mice shortly after sexual maturity and premature ovarian failure. The increased apoptosis seemed to be attributable to the polyploidy of granulosa cells. These results suggest that proper progression of the cell cycle, regulated by the p27-Skp2 axis, is pivotal for the maintenance of fertility, and that defects in this system may underlie the pathogenesis of abnormal gamete production and premature ovarian failure during the reproductive life of women. PMID:21450015

  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. Reducing incapacitating symptoms during space flight: is postural deficiency syndrome an applicable model?

    PubMed

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

    2008-08-01

    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.

  10. 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.

  11. 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.

  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.

  13. Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain

    PubMed Central

    Chen, Wanqiu; Guo, Yi; Walker, Espen J.; Shen, Fanxia; Jun, Kristine; Oh, S. Paul; Degos, Vincent; Lawton, Michael T.; Tihan, Tarik; Davalos, Dimitrios; Akassoglou, Katerina; Nelson, Jeffrey; Pile-Spellman, John; Su, Hua; Young, William L.

    2013-01-01

    Objective Vessels in brain arteriovenous malformations (bAVM) are prone to rupture. The underlying pathogenesis is not clear. Hereditary hemorrhagic telangiectasia type 2 (HHT2) patients with activin receptor-like kinase 1 (Alk1) mutation have a higher incidence of bAVM than the general population. We tested the hypothesis that vascular endothelial growth factor (VEGF) impairs vascular integrity in the Alk1-deficient brain through reduction of mural cell-coverage. Methods and Results Adult Alk11f/2f mice (loxP sites flanking exons 4-6) and wild-type (WT) mice were injected with 2×107 PFU Ad-Cre and 2×109 genome copies of AAV-VEGF to induce focal homozygous Alk1 deletion (in Alk11f/2f mice) and angiogenesis. Brain vessels were analyzed eight weeks later. Compared to WT mice, the Alk1-deficient brain had more fibrin (99±30×103 pixels/mm2 vs. 40±13×103, P=0.001), iron deposition (508±506 pixels/mm2 vs. 6 ±49, P=0.04), and Iba1+ microglia/macrophage infiltration (888±420 Iba1+ cells/mm2 vs. 240±104 Iba1+, P=0.001) after VEGF stimulation. In the angiogenic foci, the Alk1-deficient brain had more α-SMA- vessels (52±9% vs. 12±7%, P<0.001), fewer vascular associated pericytes (503±179/mm2 vs. 931±115, P<0.001), and reduced PDGFR-β expression (26±9%, P<0.001). Conclusion Reduction of mural cell coverage in response to VEGF stimulation is a potential mechanism for the impairment of vessel wall integrity in HHT2-associated bAVM. PMID:23241407

  14. Vitamin D deficiency is associated with insulin resistance in nondiabetics and reduced insulin production in type 2 diabetics.

    PubMed

    Esteghamati, A; Aryan, Z; Esteghamati, Ar; Nakhjavani, M

    2015-04-01

    It is not known whether the association of serum 25-hydroxyvitamin D [25(OH)D] with glycemic measurements of individuals without diabetes is similar to those with diabetes or not. This study is aimed to investigate the association of serum 25(OH)D with glycemic markers of diabetics, nondiabetics, and prediabetics. A case-control study was conducted on age and sex matched 1,195 patients with type 2 DM, 121 prediabetics, and 209 healthy controls. Anthropometric variables, lipid profile, glycemic measurements, and serum 25(OH)D levels were recorded. Serum insulin and C-peptide levels were also measured. All glycemic measurements were compared between diabetics and nondiabetics and prediabetics at different vitamin D status. Patients with DM had lower serum 25(OH)D compared to prediabetics and healthy controls. Endogenous insulin production in response to food intake and in fasting was significantly lower in vitamin D deficient patients with DM compared to those with serum 25(OH)D>40 ng/ml. Diabetic women with serum 25(OH)D<20 ng/ml had lower beta cell function as estimated by lower HOMA-B compared to their counterparts with serum 25(OH)D>40 ng/ml. Healthy individuals with serum 25(OH)D<20 ng/ml had signs of insulin resistance as estimated by significant increase of HOMA-IR, HbA1c, and fasting plasma glucose (FPG). In addition, we found that serum 25(OH)D was inversely associated with insulin resistance. Vitamin D deficiency is associated with insulin resistance in nondiabetics, which is independent of obesity. Furthermore, vitamin D deficiency is associated with reduced insulin production in type 2 diabetics, which was mainly observed in men. Accordingly, a gender disparity also exists in association of serum 25(OH)D with glycemic measurements.

  15. Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia.

    PubMed

    Yao, Xiaoming; Derugin, Nikita; Manley, Geoffrey T; Verkman, A S

    2015-01-01

    Aquaporin-4 (AQP4) is a water channel expressed in astrocyte end-feet lining the blood-brain barrier. AQP4 deletion in mice is associated with improved outcomes in global cerebral ischemia produced by transient carotid artery occlusion, and focal cerebral ischemia produced by permanent middle cerebral artery occlusion (MCAO). Here, we investigated the consequences of 1-h transient MCAO produced by intraluminal suture blockade followed by 23 h of reperfusion. In nine AQP4(+/+) and nine AQP4(-/-) mice, infarct volume was significantly reduced by an average of 39 ± 4% at 24h in AQP4(-/-) mice, cerebral hemispheric edema was reduced by 23 ± 3%, and Evans Blue extravasation was reduced by 31 ± 2% (mean ± SEM). Diffusion-weighted magnetic resonance imaging showed greatest reduction in apparent diffusion coefficient around the occlusion site after reperfusion, with remarkably lesser reduction in AQP4(-/-) mice. The reduced infarct volume in AQP4(-/-) mice following transient MCAO supports the potential utility of therapeutic AQP4 inhibition in stroke.

  16. Maternal thyroid hormone deficiency affects the fetal neocorticogenesis by reducing the proliferating pool, rate of neurogenesis and indirect neurogenesis.

    PubMed

    Mohan, Vishwa; Sinha, Rohit A; Pathak, Amrita; Rastogi, Leena; Kumar, Praveen; Pal, Amit; Godbole, Madan M

    2012-10-01

    Neuronal progenitor cell proliferation and their optimum number are indispensable for neurogenesis, which is determined by cell cycle length and cell cycle quitting rate of the dividing progenitors. These processes are tightly orchestrated by transcription factors like Tbr2, Pax6, and E2f-1. Radial glia and intermediate progenitor cells (IPC) through direct and indirect neurogenesis maintain surface area and neocortical thickness during development. Here we show that fetal neurogenesis is maternal thyroid hormone (MTH) dependent with differential effect on direct and indirect neurogenesis. MTH deficiency (MTHD) impairs direct neurogenesis through initial down-regulation of Pax6 and diminished progenitor pool with recovery even before the onset of fetal thyroid function (FTF). However, persistent decrease in Tbr2 positive IPCs, diminished NeuN positivity in layers I-III of neocortex, and reduced cortical thickness indicate a non-compensatory impairment in indirect neurogenesis. TH deficiency causes disrupted cell cycle kinetics and deranged neurogenesis. It specifically affects indirect neurogenesis governed by intermediate progenitor cells (IPCs). TH replacement in hypothyroid dams partially restored the rate of neurogenesis in the fetal neocortex. Taken together we describe a novel role of maternal TH in promoting IPCs derived neuronal differentiation in developing neo-cortex. We have also shown for the first time that ventricular zone progenitors are TH responsive as they express its receptor, TR alpha-1, transporters (MCT8) and deiodinases. This study highlights the importance of maternal thyroid hormone (TH) even before the start of the fetal thyroid function.

  17. 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

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

    PubMed

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

    1997-05-01

    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.

  19. 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.

  20. 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.

  1. 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.

  2. Lamin A/C deficiency reduces circulating tumor cell resistance to fluid shear stress

    PubMed Central

    Denais, Celine; Chan, Maxine F.; Wang, Zhexiao; Lammerding, Jan

    2015-01-01

    Metastasis contributes to over 90% of cancer-related deaths and is initiated when cancer cells detach from the primary tumor, invade the basement membrane, and enter the circulation as circulating tumor cells (CTCs). While metastasis is viewed as an inefficient process with most CTCs dying within the bloodstream, it is evident that some CTCs are capable of resisting hemodynamic shear forces to form secondary tumors in distant tissues. We hypothesized that nuclear lamins A and C (A/C) act as key structural components within CTCs necessary to resist destruction from elevated shear forces of the bloodstream. Herein, we show that, compared with nonmalignant epithelial cells, tumor cells are resistant to elevated fluid shear forces in vitro that mimic those within the bloodstream, as evidenced by significant decreases in cellular apoptosis and necrosis. Knockdown of lamin A/C significantly reduced tumor cell resistance to fluid shear stress, with significantly increased cell death compared with parental tumor cell and nontargeting controls. Interestingly, lamin A/C knockdown increased shear stress-induced tumor cell apoptosis, but did not significantly affect cellular necrosis. These data demonstrate that lamin A/C is an important structural component that enables tumor cell resistance to fluid shear stress-mediated death in the bloodstream, and may thus facilitate survival and hematogenous metastasis of CTCs. PMID:26447202

  3. 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.

  4. Depleted iron stores and iron deficiency anemia associated with reduced ferritin and hepcidin and elevated soluble transferrin receptors in a multiethnic group of preschool-age children.

    PubMed

    Weiler, Hope A; Jean-Philippe, Sonia; Cohen, Tamara R; Vanstone, Catherine A; Agellon, Sherry

    2015-09-01

    Iron deficiency anemia is prevalent in subgroups of the Canadian population. The objective of this study was to examine iron status and anemia in preschool-age children. Healthy children (n = 430, 2-5 years old, Montreal, Quebec, Canada) were sampled from randomly selected daycares. Anthropometry, demographics, and diet were assessed. Biochemistry included hemoglobin, ferritin, soluble transferrin receptors (sTfR), ferritin index, markers of inflammation (C-reactive protein, interleukin 6 (IL-6), and tumour necrosis factor alpha (TNFα)), and hepcidin. Iron deficiency and anemia cutoffs conformed to the World Health Organization criteria. Differences among categories were tested using mixed-model ANOVA or χ(2) tests. Children were 3.8 ± 1.0 years of age, with a body mass index z score of 0.48 ± 0.97, and 51% were white. Adjusted intakes of iron indicated <1% were at risk for deficiency. Hemoglobin was higher in white children, whereas ferritin was higher with greater age and female sex. Inflammatory markers and hepcidin did not vary with any demographic variable. The prevalence of iron deficiency was 16.5% (95% confidence interval (CI), 13.0-20.0). Three percent (95% CI, 1.4-4.6) of children had iron deficiency anemia and 12.8% (95% CI, 9.6-16.0) had unexplained anemia. Children with iron deficiency, with and without anemia, had lower plasma ferritin and hepcidin but higher sTfR, ferritin index, and IL-6, whereas those with unexplained anemia had elevated TNFα. We conclude that iron deficiency anemia is not very common in young children in Montreal. While iron deficiency without anemia is more common than iron deficiency with anemia, the correspondingly reduced circulating hepcidin would have enabled heightened absorption of dietary iron in support of erythropoiesis.

  5. Zileuton prevents the activation of the leukotriene pathway and reduces sebaceous lipogenesis.

    PubMed

    Zouboulis, Christos C; Seltmann, Holger; Alestas, Theodosios

    2010-02-01

    Arachidonic acid (AA) activates the 5-lipoxygenase, induces leukotriene-B(4) (LTB(4)) synthesis, enhances interleukin-6 (IL-6) release and increases intracellular neutral lipids in human sebocytes. Moreover, the enzymes of LTB(4) biosynthesis are activated in acne-involved sebaceous glands. Zileuton a 5-lipoxygenase inhibitor, reduces the number of inflammatory acne lesions and lipogenesis in patients with acne. In this study, we investigated the activity of zileuton on LTB(4) generation, lipid content and IL-6 and -8 release from human SZ95 sebocytes in vitro. Pretreatment with zileuton partially prevented the AA-induced LTB(4) and IL-6 release and increased neutral lipid content. IL-6 release and neutral lipid content were also reduced under long-term zileuton treatment. In conclusion, zileuton prevents the activation of the leukotriene pathway and enhancement of lipogenesis by AA in human sebocytes in vitro.

  6. Elevated serum levels of T3 without metabolic effect in nutritionally deficient rats, attributable to reduced cellular uptake of T3

    SciTech Connect

    Okamura, K.; Taurog, A.; DiStefano, J.J.

    1981-08-01

    Rats receiving a nutritionally deficient diet displayed markedly elevated serum free T3 levels but showed no increase in oxygen consumption. This was associated with greatly reduced ratios of hepatic cellular and nuclear /sub 125/I-T3 to serum /sub 125/I-T3. Kinetic data supported the conclusion that cellular uptake of T3 was decreased in the nutritionally deficient rats. The lack of metabolic effect, despite the elevated serum T3 levels, is attributable to reduced availability of serum T3 to tissue nuclear receptor sites.

  7. The endogenous estradiol metabolite 2-methoxyestradiol reduces atherosclerotic lesion formation in female apolipoprotein E-deficient mice.

    PubMed

    Bourghardt, Johan; Bergström, Göran; Krettek, Alexandra; Sjöberg, Sara; Borén, Jan; Tivesten, Asa

    2007-09-01

    Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17beta-estradiol (6 microg/d), or 2-methoxyestradiol [6.66 microg/d (low-dose) or 66.6 microg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.

  8. 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

  9. Reducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with α7 nicotinic acetylcholine receptor agonists.

    PubMed

    Minami, S Sakura; Shen, Vivian; Le, David; Krabbe, Grietje; Asgarov, Rustam; Perez-Celajes, Liberty; Lee, Chih-Hung; Li, Jinhe; Donnelly-Roberts, Diana; Gan, Li

    2015-10-15

    Mutations in the progranulin gene cause frontotemporal dementia (FTD), a debilitating neurodegenerative disease that involves atrophy of the frontal and temporal lobes and affects personality, behavior, and language. Progranulin-deficient mouse models of FTD exhibit deficits in compulsive and social behaviors reminiscent of patients with FTD, and develop excessive microgliosis and increased release of inflammatory cytokines. Activation of nicotinic acetylcholine receptors (nAChRs) by nicotine or specific α7 nAChR agonists reduces neuroinflammation. Here, we investigated whether activation of nAChRs by nicotine or α7 agonists improved the excessive inflammatory and behavioral phenotypes of a progranulin-deficient FTD mouse model. We found that treatment with selective α7 agonists, PHA-568487 or ABT-107, strongly suppressed the activation of NF-κB in progranulin-deficient cells. Treatment with ABT-107 also reduced microgliosis, decreased TNFα levels, and reduced compulsive behavior in progranulin-deficient mice. Collectively, these data suggest that targeting activation of the α7 nAChR pathway may be beneficial in decreasing neuroinflammation and reversing some of the behavioral deficits observed in progranulin-deficient FTD.

  10. Hyperglycemia reduces integrin subunits alpha v and alpha 5 on the surface of dermal fibroblasts contributing to deficient migration.

    PubMed

    Almeida, Maira Estanislau S; Monteiro, Kelly S; Kato, Ellen E; Sampaio, Sandra C; Braga, Tarcio T; Câmara, Niels O S; Lamers, Marcelo L; Santos, Marinilce F

    2016-10-01

    Deficient wound healing is a common multifactorial complication in diabetic patients, but the cellular and molecular mechanisms involved are poorly defined. In the present study, we analyzed the effects of hyperglycemia on integrins expression in rat dermal fibroblasts and addressed its role in cell adhesion and migration. Diabetes Mellitus was induced in rats by streptozotocin injection and maintained for 30 days. Primary cultures of dermal fibroblasts from control and diabetic rats were maintained under low glucose (5 mM D-glucose) or high glucose (30 mM D-glucose) for 7 days. Cell adhesion and migration were studied by kymography, transwell, and time-lapse assays, and the expressions of integrin subunits αv and α5 were studied by immunocytochemistry and western blotting. Fibroblasts derived from diabetic rats confirmed a reduced migration speed and delayed spreading compared to fibroblasts derived from control rats. The membrane fraction of diabetic-derived fibroblasts showed a decrease of integrin subunits α5 and αv, which was confirmed by immunocytochemistry assays. A reduction in the pericellular fibronectin matrix was also observed. The exposure of diabetic-derived cells to a higher concentration of exogenous fibronectin improved migration velocity and the expression of αv but did not completely restore their migration capacity. In conclusion, the mechanisms involved in the deleterious effects of Diabetes Mellitus on wound healing include the ability of fibroblasts to secrete and to adhere to fibronectin.

  11. Reduced cathepsins B and D cause impaired autophagic degradation that can be almost completely restored by overexpression of these two proteases in Sap C-deficient fibroblasts.

    PubMed

    Tatti, Massimo; Motta, Marialetizia; Di Bartolomeo, Sabrina; Scarpa, Susanna; Cianfanelli, Valentina; Cecconi, Francesco; Salvioli, Rosa

    2012-12-01

    Saposin (Sap) C deficiency, a rare variant form of Gaucher disease, is due to mutations in the Sap C coding region of the prosaposin (PSAP) gene. Sap C is required as an activator of the lysosomal enzyme glucosylceramidase (GCase), which catalyzes glucosylceramide (GC) degradation. Deficit of either GCase or Sap C leads to the accumulation of undegraded GC and other lipids in lysosomes of monocyte/macrophage lineage. Recently, we reported that Sap C mutations affecting a cysteine residue result in increased autophagy. Here, we characterized the basis for the autophagic dysfunction. We analyzed Sap C-deficient and GCase-deficient fibroblasts and observed that autophagic disturbance was only associated with lack of Sap C. By a combined fluorescence microscopy and biochemical studies, we demonstrated that the accumulation of autophagosomes in Sap C-deficient fibroblasts is not due to enhanced autophagosome formation but to delayed degradation of autolysosomes caused, in part, to decreased amount and reduced enzymatic activity of cathepsins B and D. On the contrary, in GCase-deficient fibroblasts, the protein level and enzymatic activity of cathepsin D were comparable with control fibroblasts, whereas those of cathepsin B were almost doubled. Moreover, the enhanced expression of both these lysosomal proteases in Sap C-deficient fibroblasts resulted in close to functional autophagic degradation. Our data provide a novel example of altered autophagy as secondary event resulting from insufficient lysosomal function.

  12. Implementation of an intervention to reduce population-based screening for vitamin D deficiency: a cross-sectional study

    PubMed Central

    Naugler, Christopher; Hemmelgarn, Brenda; Quan, Hude; Clement, Fiona; Sajobi, Tolulope; Thomas, Roger; Turin, Tanvir C.; Hnydyk, William; Chin, Alex; Wesenberg, James

    2017-01-01

    Background: We describe the implementation of an intervention in Alberta in support of the Choosing Wisely Canada recommendation against population screening for vitamin D deficiency (as determined by serum total 25-hydroxyvitamin D testing). We hypothesized that the introduction of a specialized requisition for vitamin D testing would reduce the annual number of vitamin D tests performed. Methods: We performed a cross-sectional observational study that included all vitamin D tests ordered in Alberta between Apr. 1, 2015, and Mar. 31, 2016. There were no exclusion criteria. A special requisition for ordering vitamin D tests in Alberta was introduced on Apr. 1, 2015. Using an interrupted time series model, we compared predicted versus observed vitamin D test volumes for the 12-month period following the introduction of the new requisition. The sole outcome measure was the monthly change in volume of vitamin D testing. In addition, we calculated any cost savings as a result of reduced testing. Results: Over the first 12 months of the intervention, there was a reduction in the number of tests ordered from a predicted 342 477 tests to 29 525 tests (91.4% reduction). This decrease represented a direct spending decrease of Can$938 856-$1 564 760 per year in Alberta. Interpretation: A provincially led implementation of a Choosing Wisely Canada recommendation resulted in a large and sustained reduction in serum total 25-hydroxyvitamin D testing in Alberta. This study shows that provincially led interventions based on Choosing Wisely Canada recommendations can result in substantial reductions in laboratory tests.

  13. Low plasma renin and reduced renin secretory responses to acute stimuli in conscious COX-2-deficient mice.

    PubMed

    Kim, Soo Mi; Chen, Limeng; Mizel, Diane; Huang, Yuning G; Briggs, Josie P; Schnermann, Jurgen

    2007-01-01

    In the current experiments, we determined the response of plasma renin concentration (PRC) to acute intraperitoneal administration of furosemide (40 mg/kg), hydralazine (2 mg/kg), isoproterenol (10 mg/kg), candesartan (50 microg), or quinaprilate (50 microg) in conscious wild-type (WT) and cyclooxygenase (COX)-2-/- mice on three different genetic backgrounds (mixed, C57BL/6, 129J). PRC was measured in plasma obtained by tail vein puncture. Basal PRC was significantly lower in COX-2-/- than WT mice independent of genetic background (51, 10, and 17% of WT in mixed, 129J, and C57BL/6). All five acute interventions caused significant increases of PRC in both COX-2+/+ and -/- mice, but the response was consistently less in COX-2-deficient mice (e.g., DeltaPRC in ng ANG I x ml(-1) x h(-1) caused by furosemide, isoproterenol, hydralazine, quinaprilate, or candesartan 4,699 +/- 544, 3,534 +/- 957, 2,522 +/- 369, 9,453 +/- 1,705, 66,455 +/- 21,938 in 129J WT, and 201 +/- 78, 869 +/- 275, 140 +/- 71, 902 +/- 304, 2,660 +/- 954 in 129J COX-2-/-). A low-NaCl diet and enalapril for 1 wk caused a 14-fold elevation of PRC in COX-2-/- mice and was associated with a greatly increased PRC response to acute furosemide (DeltaPRC 201 +/- 78 before and 15,984 +/- 2,397 after low Na/enalapril). As measured by radiotelemetry, blood pressure and heart rate responses to furosemide, hydralazine, isoproterenol, candesartan, or quinaprilate were not different between COX-2 genotypes. In conclusion, chronic absence of COX-2 reduces renin expression, release, and PRC and is associated with a reduced ability to alter PRC during acute stimulation regardless of the nature of the stimulus. COX-2 activity does not appear to be a mandatory and specific requirement for furosemide-stimulated renin secretion.

  14. 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.

  15. Cathepsin G deficiency reduces peri-aortic calcium chloride injury-induced abdominal aortic aneurysms in mice

    PubMed Central

    Wang, Jing; Sukhova, Galina K.; Liu, Jian; Ozaki, Keith; Lesner, Adam; Libby, Peter; Kovanen, Petri T.; Shi, Guo-Ping

    2014-01-01

    Objective Cathepsin G (CatG) is a serine protease that mediates angiotensin-I (Ang-I) to angiotensin-II (Ang-II) conversion and is highly expressed in human abdominal aortic aneurysms (AAAs). However, it remains untested whether this protease participates in the pathogenesis of AAA. Methods and Results Immunofluorescent double staining demonstrated the expression of CatG in smooth-muscle cells (SMCs), macrophages, and endothelial cells (ECs) in human AAA lesions (n=12), but not in AAA-free aortas (n=10). While inflammatory cytokines induced CatG expression, high glucose increased CatG activity in producing Ang-II and angiotensin-converting enzyme (ACE) in SMCs, which could be fully blocked by a CatG-selective inhibitor or its siRNA. To test whether CatG contributes to AAA development, we generated CatG and low-density lipoprotein receptor (LDLr) double deficient (Ldlr−/−Ctsg−/−) mice and their littermate controls (Ldlr−/−Ctsg+/+). Absence of CatG did not affect Ang-II infusion-induced AAAs. In contrast, in Ang-II-independent AAAs induced by peri-aortic CaCl2 injury (n=12 per group), CatG deficiency significantly reduced aortic diameter increase (58.33%±6.83% vs. 31.67%±5.75%, P=0.007), aortic lesion area (0.35±0.04 mm2 vs. 0.21±0.02 mm2, P=0.005), and aortic wall elastin fragmentation grade (2.75±0.18 vs. 1.58±0.17, P=0.002) along with reduced lesion collagen content grade (2.80±0.17 vs. 2.12±0.17, P=0.009) without affecting indices of lesion inflammation, angiogenesis, cell proliferation, or apoptosis. In vitro elastin degradation assays demonstrated that CaCl2-induced AAA lesions from Ldlr−/−Ctsg−/− mice contained much lower elastinolytic activity than in those from littermate control mice. Gelatin gel zymogram assay suggested that absence of CatG in CaCl2-induced AAA lesions also reduced the activity of elastinolytic matrix metalloproteinase (MMP)-2 and MMP-9. Conclusion CatG may contribute to CaCl2-induced experimental AAAs directly

  16. 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

  17. CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer’s Disease Mouse Models

    PubMed Central

    Lee, Sungho; Varvel, Nicholas H.; Konerth, Megan E.; Xu, Guixiang; Cardona, Astrid E.; Ransohoff, Richard M.; Lamb, Bruce T.

    2010-01-01

    Microglia, the primary immune effector cells in the brain, continually monitor the tissue parenchyma for pathological alterations and become activated in Alzheimer’s disease. Loss of signaling between neurons and microglia via deletion of the microglial receptor, CX3CR1, worsens phenotypes in various models of neurodegenerative diseases. In contrast, CX3CR1 deficiency ameliorates pathology in murine stroke models. To examine the role of CX3CR1 in Alzheimer’s disease–related β-amyloid pathology, we generated APPPS1 and R1.40 transgenic mouse models of Alzheimer’s disease deficient for CX3CR1. Surprisingly, CX3CR1 deficiency resulted in a gene dose-dependent reduction in β-amyloid deposition in both the APPPS1 and R1.40 mouse models of AD. Immunohistochemical analysis revealed reduced staining for CD68, a marker of microglial activation. Furthermore, quantitative immunohistochemical analysis revealed reduced numbers of microglia surrounding β-amyloid deposits in the CX3CR1-deficient APPPS1 animals. The reduced β-amyloid pathology correlated with reduced levels of TNFα and CCL2 mRNAs, but elevated IL1β mRNA levels, suggesting an altered neuroinflammatory milieu. Finally, to account for these seemingly disparate results, both in vitro and in vivo studies provided evidence that CX3CL1/CX3CR1 signaling alters the phagocytic capacity of microglia, including the uptake of Aβ fibrils. Taken together, these results demonstrate that loss of neuron-microglial fractalkine signaling leads to reduced β-amyloid deposition in mouse models of AD that is potentially mediated by altered activation and phagocytic capability of CX3CR1-deficient microglia. PMID:20864679

  18. 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.

  19. Age-Related Vitamin D Deficiency Is Associated with Reduced Macular Ganglion Cell Complex: A Cross-Sectional High-Definition Optical Coherence Tomography Study

    PubMed Central

    Uro, Mathieu; Beauchet, Olivier; Cherif, Mehdi; Graffe, Alix; Milea, Dan; Annweiler, Cedric

    2015-01-01

    Background Vitamin D deficiency is associated with smaller volume of optic chiasm in older adults, indicating a possible loss of the visual axons and their cellular bodies. Our objective was to determine whether vitamin D deficiency in older adults is associated with reduced thickness of the ganglion cell complex(GCC) and of the retinal nerve fibre layer(RNFL), as measured with high-definition optical coherence tomography(HD-OCT). Methods Eighty-five French older community-dwellers without open-angle glaucoma and patent age-related macular degeneration(mean, 71.1±4.7years; 45.9%female) from the GAIT study were separated into 2 groups according to serum 25OHD level(i.e., deficient≤25nmol/L or sufficient>25nmol/L). Measurements of GCC and RNFL thickness were performed using HD-OCT. Age, gender, body mass index, number of comorbidities, dementia, functional autonomy, intracranial volume, visual acuity, serum calcium concentration and season of testing were considered as potential confounders. Results Mean serum 25OHD concentration was 58.4±26.8nmol/L. Mean logMAR visual acuity was 0.03±0.06. Mean visual field mean deviation was -1.25±2.29dB. Patients with vitamin D deficiency(n=11) had a reduced mean GCC thickness compared to those without vitamin D deficiency(72.1±7.4μm versus 77.5±7.5μm, P=0.028). There was no difference of the mean RNFL thickness in these two groups(P=0.133). After adjustment for potential confounders, vitamin D deficiency was associated with reduced GCC thickness(ß=-5.12, P=0.048) but not RNFL thickness(ß=-9.98, P=0.061). Specifically, vitamin D deficiency correlated with the superior medial GCC area(P=0.017) and superior temporal GCC area(P=0.010). Conclusions Vitamin D deficiency in older patients is associated with reduced mean GCC thickness, which can represent an early stage of optic nerve damage, prior to RNFL loss. PMID:26090872

  20. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E.

    PubMed

    Michelsen, Kathrin S; Wong, Michelle H; Shah, Prediman K; Zhang, Wenxuan; Yano, Juliana; Doherty, Terence M; Akira, Shizuo; Rajavashisth, Tripathi B; Arditi, Moshe

    2004-07-20

    Toll-like receptors (TLRs) and the downstream adaptor molecule myeloid differentiation factor 88 (MyD88) play an essential role in the innate immune responses. Here, we demonstrate that genetic deficiency of TLR4 or MyD88 is associated with a significant reduction of aortic plaque areas in atherosclerosis-prone apolipoprotein E-deficient mice, despite persistent hypercholesterolemia, implying an important role for the innate immune system in atherogenesis. Apolipoprotein E-deficient mice that also lacked TLR4 or MyD88 demonstrated reduced aortic atherosclerosis that was associated with reductions in circulating levels of proinflammatory cytokines IL-12 or monocyte chemoattractant protein 1, plaque lipid content, numbers of macrophage, and cyclooxygenase 2 immunoreactivity in their plaques. Endothelial-leukocyte adhesion in response to minimally modified low-density lipoprotein was reduced in aortic endothelial cells derived from MyD88-deficient mice. Taken together, our results suggest an important role for TLR4 and MyD88 signaling in atherosclerosis in a hypercholesterolemic mouse model, providing a pathophysiologic link between innate immunity, inflammation, and atherogenesis.

  1. 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.

  2. 17beta-estradiol deficiency reduces potassium excretion in an angiotensin type 1 receptor-dependent manner.

    PubMed

    Ji, Hong; Zheng, Wei; Falconetti, Celine; Roesch, Darren M; Mulroney, Susan E; Sandberg, Kathryn

    2007-07-01

    This study examined the effects of ovariectomy (OVX) and 17beta-estradiol (E(2)) replacement (OVX + E(2)) on renal function in Sprague-Dawley rats. OVX caused a 40% decrease in the fractional excretion of potassium (FE(K(+))) that was prevented by E(2) replacement [Sham, 24.2 +/- 2.9%; OVX, 14.5 +/- 2.1% (P < 0.05 vs. OVX + E(2)); and OVX + E(2), 26.2 +/- 2.7%; n = 7-11] and that corresponded to significant increases in plasma potassium [(in mmol/l): Sham, 3.15 +/- 0.087; OVX, 3.42 +/- 0.048 (P < 0.05 vs. OVX + E(2)); and OVX + E(2), 3.19 +/- 0.11; n = 7-11]. No effects of OVX were detected on plasma levels of sodium and aldosterone. Angiotensin II type 1 receptor (AT(1)R) densities in ovariectomized rats were 1.4-fold and 1.3-fold higher in glomerular [maximum binding capacity (B(max); in fmol/mg protein): Sham, 482 +/- 21; OVX, 666 +/- 20 (P < 0.05 vs. OVX + E(2)); and OVX + E(2), 504 +/- 26; n = 7-11] and proximal tubular [B(max) (in fmol/mg protein): Sham, 721 +/- 16; OVX, 741 +/- 24 (P < 0.05 vs. OVX + E(2)); and OVX + E(2), 569 +/- 23; n = 7-11] membranes compared with E(2) replete animals, respectively. Both the angiotensin-converting enzyme inhibitor captopril and the AT(1)R antagonist losartan prevented the OVX-induced decrease in the FE(K(+)) and the increase in renal AT(1)R densities, suggesting that E(2) deficiency reduces potassium excretion in an ANG II/AT(1)R-dependent manner. These findings may have implications for renal function in postmenopausal women as well as contribute to the reasons underlying the age-induced increase in susceptibility to hypertension-associated disease in women.

  3. Vitamin D Receptor Ablation and Vitamin D Deficiency Result in Reduced Grip Strength, Altered Muscle Fibers, and Increased Myostatin in Mice.

    PubMed

    Girgis, Christian M; Cha, Kuan Minn; Houweling, Peter J; Rao, Renuka; Mokbel, Nancy; Lin, Mike; Clifton-Bligh, Roderick J; Gunton, Jenny E

    2015-12-01

    Vitamin D deficiency is associated with muscle weakness, pain, and atrophy. Serum vitamin D predicts muscle strength and age-related muscle changes. However, precise mechanisms by which vitamin D affects skeletal muscle are unclear. To address this question, this study characterizes the muscle phenotype and gene expression of mice with deletion of vitamin D receptor (VDRKO) or diet-induced vitamin D deficiency. VDRKO and vitamin D-deficient mice had significantly weaker grip strength than their controls. Weakness progressed with age and duration of vitamin D deficiency, respectively. Histological assessment showed that VDRKO mice had muscle fibers that were significantly smaller in size and displayed hyper-nuclearity. Real-time PCR also indicated muscle developmental changes in VDRKO mice with dysregulation of myogenic regulatory factors (MRFs) and increased myostatin in quadriceps muscle (>2-fold). Vitamin D-deficient mice also showed increases in myostatin and the atrophy marker E3-ubiqutin ligase MuRF1. As a potential explanation for grip strength weakness, both groups of mice had down-regulation of genes encoding calcium-handling and sarco-endoplasmic reticulum calcium transport ATPase (Serca) channels. This is the first report of reduced strength, morphological, and gene expression changes in VDRKO and vitamin D-deficient mice where confounding by calcium, magnesium, and phosphate have been excluded by direct testing. Although suggested in earlier in vitro work, this study is the first to report an in vivo association between vitamin D, myostatin, and the regulation of muscle mass. These findings support a direct role for vitamin D in muscle function and corroborate earlier work on the presence of VDR in this tissue.

  4. 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...

  5. 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

  6. Mct8-Deficient Mice Have Increased Energy Expenditure and Reduced Fat Mass That Is Abrogated by Normalization of Serum T3 Levels

    PubMed Central

    Di Cosmo, Caterina; Liao, Xiao-Hui; Ye, Honggang; Ferrara, Alfonso Massimiliano; Weiss, Roy E.; Refetoff, Samuel

    2013-01-01

    Children with monocarboxylate transporter 8 (MCT8) deficiency lose weight, even when adequately nourished. Changes in serum markers of thyroid hormone (TH) action compatible with thyrotoxicosis suggested that this might be due to T3 excess in peripheral tissues. Mct8-deficient mice (Mct8KO) replicate the human thyroid phenotype and are thus suitable for metabolic studies so far unavailable in humans. In the current work, compared with wild-type (Wt) mice, Mct8KO mice were leaner due to reduced fat mass. They tended to use more carbohydrates and fewer lipids during the dark phase. Mct8KO mice had increased total energy expenditure (TEE) and food and water intake, with normal total activity, indicating hypermetabolism. To determine whether this is due to the high serum T3, we studied mice deficient in both Mct8 and deiodinase 1 (Mct8D1KO) with serum T3 similar to Wt mice and Wt mice given L-T3 to raise their serum T3 to the level of Mct8KO mice. Contrary to Mct8KO, Mct8D1KO mice had similar fat mass, TEE, and food intake as their D1KO littermates, whereas T3-treated Wt mice showed increased food intake and TEE, similar to Mct8KO mice. In skeletal muscle, Mct8KO mice had increased T3 content and TH action and increased glucose metabolism, which improved in Mct8D1KO mice. These studies indicate that the high serum T3 in MCT8 deficiency increases the TEE and fails to maintain weight despite adequate calorie intake. This is mediated by tissues that are not predominantly MCT8 dependent for TH transport, including skeletal muscle. Normalizing serum T3 level by deleting deiodinase 1 corrects body composition and the metabolic alterations caused by the MCT8 deficiency. PMID:24029243

  7. Mct8-deficient mice have increased energy expenditure and reduced fat mass that is abrogated by normalization of serum T3 levels.

    PubMed

    Di Cosmo, Caterina; Liao, Xiao-Hui; Ye, Honggang; Ferrara, Alfonso Massimiliano; Weiss, Roy E; Refetoff, Samuel; Dumitrescu, Alexandra M

    2013-12-01

    Children with monocarboxylate transporter 8 (MCT8) deficiency lose weight, even when adequately nourished. Changes in serum markers of thyroid hormone (TH) action compatible with thyrotoxicosis suggested that this might be due to T3 excess in peripheral tissues. Mct8-deficient mice (Mct8KO) replicate the human thyroid phenotype and are thus suitable for metabolic studies so far unavailable in humans. In the current work, compared with wild-type (Wt) mice, Mct8KO mice were leaner due to reduced fat mass. They tended to use more carbohydrates and fewer lipids during the dark phase. Mct8KO mice had increased total energy expenditure (TEE) and food and water intake, with normal total activity, indicating hypermetabolism. To determine whether this is due to the high serum T3, we studied mice deficient in both Mct8 and deiodinase 1 (Mct8D1KO) with serum T3 similar to Wt mice and Wt mice given L-T3 to raise their serum T3 to the level of Mct8KO mice. Contrary to Mct8KO, Mct8D1KO mice had similar fat mass, TEE, and food intake as their D1KO littermates, whereas T3-treated Wt mice showed increased food intake and TEE, similar to Mct8KO mice. In skeletal muscle, Mct8KO mice had increased T3 content and TH action and increased glucose metabolism, which improved in Mct8D1KO mice. These studies indicate that the high serum T3 in MCT8 deficiency increases the TEE and fails to maintain weight despite adequate calorie intake. This is mediated by tissues that are not predominantly MCT8 dependent for TH transport, including skeletal muscle. Normalizing serum T3 level by deleting deiodinase 1 corrects body composition and the metabolic alterations caused by the MCT8 deficiency.

  8. VPAC2 (vasoactive intestinal peptide receptor type 2) receptor deficient mice develop exacerbated experimental autoimmune encephalomyelitis with increased Th1/Th17 and reduced Th2/Treg responses.

    PubMed

    Tan, Yossan-Var; Abad, Catalina; Wang, Yuqi; Lopez, Robert; Waschek, James A

    2015-02-01

    Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating polypeptide (PACAP) are two structurally-related neuropeptides with widespread expression in the central and peripheral nervous systems. Although these peptides have been repeatedly shown to exert potent anti-inflammatory actions when administered in animal models of inflammatory disease, mice deficient in VIP and PACAP were recently shown to exhibit different phenotypes (ameliorated and exacerbated, respectively) in response to experimental autoimmune encephalomyelitis (EAE). Therefore, elucidating what are the specific immunoregulatory roles played by each of their receptor subtypes (VPAC1, VPAC2, and PAC1) is critical. In this study, we found that mice with a genetic deletion of VIPR2, encoding the VPAC2 receptor, exhibited exacerbated (MOG35-55)-induced EAE compared to wild type mice, characterized by enhanced clinical and histopathological features, increased proinflammatory cytokines (TNF-α, IL-6, IFN-γ (Th1), and IL-17 (Th17)) and reduced anti-inflammatory cytokines (IL-10, TGFβ, and IL-4 (Th2)) in the CNS and lymph nodes. Moreover, the abundance and proliferative index of lymph node, thymus and CNS CD4(+)CD25(+)FoxP3(+) Tregs were strikingly reduced in VPAC2-deficient mice with EAE. Finally, the in vitro suppressive activity of lymph node and splenic Tregs from VPAC2-deficient mice was impaired. Overall, our results demonstrate critical protective roles for PACAP and the VPAC2 receptor against autoimmunity, promoting the expansion and maintenance of the Treg pool.

  9. 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

  10. Matrix metalloproteinase-2 ablation in dystrophin-deficient mdx muscles reduces angiogenesis resulting in impaired growth of regenerated muscle fibers.

    PubMed

    Miyazaki, Daigo; Nakamura, Akinori; Fukushima, Kazuhiro; Yoshida, Kunihiro; Takeda, Shin'ichi; Ikeda, Shu-ichi

    2011-05-01

    Matrix metalloproteases (MMPs) are a family of endopeptidases classified into subgroups based on substrate preference in normal physiological processes such as embryonic development and tissue remodeling, as well as in various disease processes via degradation of extracellular matrix components. Among the MMPs, MMP-9 and MMP-2 have been reported to be up-regulated in skeletal muscles in the lethal X-linked muscle disorder Duchenne muscular dystrophy (DMD), which is caused by loss of dystrophin. A recent study showed that deletion of the MMP9 gene in mdx, a mouse model for DMD, improved skeletal muscle pathology and function; however, the role of MMP-2 in the dystrophin-deficient muscle is not well known. In this study, we aimed at verifying the role of MMP-2 in the dystrophin-deficient muscle by using mdx mice with genetic ablation of MMP-2 (mdx/MMP-2(-/-)). We found impairment of regenerated muscle fiber growth with reduction of angiogenesis in mdx/MMP-2(-/-) mice at 3 months of age. Expression of vascular endothelial growth factor-A (VEGF-A), an important angiogenesis-related factor, decreased in mdx/MMP-2(-/-) mice at 3 months of age. MMP-2 had not a critical role in the degradation of dystrophin-glycoprotein complex (DGC) components such as β-dystroglycan and β-sarcoglycan in the regeneration process of the dystrophic muscle. Accordingly, MMP-2 may be essential for growth of regenerated muscle fibers through VEGF-associated angiogenesis in the dystrophin-deficient skeletal muscle.

  11. Early methyl donor deficiency may induce persistent brain defects by reducing Stat3 signaling targeted by miR-124

    PubMed Central

    Kerek, R; Geoffroy, A; Bison, A; Martin, N; Akchiche, N; Pourié, G; Helle, D; Guéant, J-L; Bossenmeyer-Pourié, C; Daval, J-L

    2013-01-01

    The methyl donors folate (vitamin B9) and vitamin B12 are centrepieces of the one-carbon metabolism that has a key role in transmethylation reactions, and thus in epigenetic and epigenomic regulations. Low dietary intakes of folate and vitamin B12 are frequent, especially in pregnant women and in the elderly, and deficiency constitutes a risk factor for various diseases, including neurological and developmental disorders. In this respect, both vitamins are essential for normal brain development, and have a role in neuroplasticity and in the maintenance of neuronal integrity. The consequences of a methyl donor deficiency (MDD) were studied both in vivo in rats exposed in utero, and in vitro in hippocampal progenitors (H19-7 cell line). Deficiency was associated with growth retardation at embryonic day 20 (E20) and postnatally with long-term brain defects in selective areas. mRNA and protein levels of the transcription factor Stat3 were found to be decreased in the brains of deprived fetuses and in differentiating progenitors (62 and 48% for total Stat3 protein, respectively), along with a strong reduction in its phosphorylation at both Tyr705 and Ser727 residues. Vitamin shortage also affected upstream kinases of Stat3 signaling pathway (phospho-Erk1/2, phospho-Src, phospho-JNK, and phospho-p38) as well as downstream target gene products (Bcl-2 and Bcl-xL), thus promoting apoptosis. Conversely, the expression of the Stat3 regulator miR-124 was upregulated in deficiency conditions (≥65%), and its silencing by using siRNA partly restored Stat3 signaling in hippocampal neurons by increasing specifically the phosphorylation of Erk1/2 and Src kinases. Furthermore, miR-124 siRNA improved the phenotype of deprived cells, with enhanced neurite outgrowth. Taken together, our data suggest that downregulation of Stat3 signaling by miR-124 would be a key factor in the deleterious effects of MDD on brain development. PMID:23928694

  12. Reduced autophagy in livers of fasted, fat-depleted, ghrelin-deficient mice: Reversal by growth hormone

    PubMed Central

    Zhang, Yuanyuan; Fang, Fei; Goldstein, Joseph L.; Brown, Michael S.; Zhao, Tong-Jin

    2015-01-01

    Plasma growth hormone (GH) and hepatic autophagy each have been reported to protect against hypoglycemia in the fasted state, but previous data have not linked the two. Here we demonstrate a connection using a mouse model of fasting in a fat-depleted state. Mice were subjected to 1 wk of 60% calorie restriction, causing them to lose nearly all body fat. They were then fasted for 23 h. During fasting, WT mice developed massive increases in plasma GH and a concomitant increase in hepatic autophagy, allowing them to maintain viable levels of blood glucose. In contrast, lethal hypoglycemia occurred in mice deficient in the GH secretagogue ghrelin as a result of knockout of the gene encoding ghrelin O-acyltransferase (GOAT), which catalyzes a required acylation of the peptide. Fasting fat-depleted Goat−/− mice showed a blunted increase in GH and a marked decrease in hepatic autophagy. Restoration of GH by infusion during the week of calorie restriction maintained autophagy in the Goat−/− mice and prevented lethal hypoglycemia. Acute injections of GH after 7 d of calorie restriction also restored hepatic autophagy, but failed to increase blood glucose, perhaps owing to ATP deficiency in the liver. These data indicate that GH stimulation of autophagy is necessary over the long term, but not sufficient over the short term to maintain blood glucose levels in fasted, fat-depleted mice. PMID:25583513

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

    PubMed Central

    Shoemaker, Robin; Yiannikouris, Frederique; Thatcher, Sean

    2015-01-01

    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

  14. Laminin-111 Protein Therapy Reduces Muscle Pathology and Improves Viability of a Mouse Model of Merosin-Deficient Congenital Muscular Dystrophy

    PubMed Central

    Rooney, Jachinta E.; Knapp, Jolie R.; Hodges, Bradley L.; Wuebbles, Ryan D.; Burkin, Dean J.

    2012-01-01

    Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a lethal muscle-wasting disease that is caused by mutations in the LAMA2 gene, resulting in the loss of laminin-α2 protein. MDC1A patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance, and have reduced life expectancy. There are currently no effective treatments or cures for MDC1A. Laminin-α2 is required for the formation of heterotrimeric laminin-211 (ie, α2, β1, and γ1) and laminin-221 (ie, α2, β2, and γ1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (ie, α1, β1, and γ1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-α2–deficient muscle but is absent from adult skeletal muscle. In this study, we determined whether treatment with Engelbreth-Holm-Swarm–derived mouse laminin-111 protein could rescue MDC1A in the dyW−/− mouse model. We demonstrate that laminin-111 protein systemically delivered to the muscles of laminin-α2–deficient mice prevents muscle pathology, improves muscle strength, and dramatically increases life expectancy. Laminin-111 also prevented apoptosis in laminin-α2–deficient mouse muscle and primary human MDC1A myogenic cells, which indicates a conserved mechanism of action and cross-reactivity between species. Our results demonstrate that laminin-111 can serve as an effective protein substitution therapy for the treatment of muscular dystrophy in the dyW−/− mouse model and establish the potential for its use in the treatment of MDC1A. PMID:22322301

  15. Laminin-111 protein therapy reduces muscle pathology and improves viability of a mouse model of merosin-deficient congenital muscular dystrophy.

    PubMed

    Rooney, Jachinta E; Knapp, Jolie R; Hodges, Bradley L; Wuebbles, Ryan D; Burkin, Dean J

    2012-04-01

    Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a lethal muscle-wasting disease that is caused by mutations in the LAMA2 gene, resulting in the loss of laminin-α2 protein. MDC1A patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance, and have reduced life expectancy. There are currently no effective treatments or cures for MDC1A. Laminin-α2 is required for the formation of heterotrimeric laminin-211 (ie, α2, β1, and γ1) and laminin-221 (ie, α2, β2, and γ1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (ie, α1, β1, and γ1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-α2-deficient muscle but is absent from adult skeletal muscle. In this study, we determined whether treatment with Engelbreth-Holm-Swarm-derived mouse laminin-111 protein could rescue MDC1A in the dy(W-/-) mouse model. We demonstrate that laminin-111 protein systemically delivered to the muscles of laminin-α2-deficient mice prevents muscle pathology, improves muscle strength, and dramatically increases life expectancy. Laminin-111 also prevented apoptosis in laminin-α2-deficient mouse muscle and primary human MDC1A myogenic cells, which indicates a conserved mechanism of action and cross-reactivity between species. Our results demonstrate that laminin-111 can serve as an effective protein substitution therapy for the treatment of muscular dystrophy in the dy(W-/-) mouse model and establish the potential for its use in the treatment of MDC1A.

  16. Addition of chlorine during water purification reduces iodine content of drinking water and contributes to iodine deficiency.

    PubMed

    Samson, L; Czegeny, I; Mezosi, E; Erdei, A; Bodor, M; Cseke, B; Burman, K D; Nagy, E V

    2012-01-01

    Drinking water is the major natural source of iodine in many European countries. In the present study, we examined possible sites of iodine loss during the usual water purification process.Water samples from 6 sites during the technological process were taken and analyzed for iodine content. Under laboratory circumstances, prepared iodine in water solution has been used as a model to test the effect of the presence of chlorine. Samples from the purification sites revealed that in the presence of chlorine there is a progressive loss of iodine from the water. In the chlorine concentrations employed in the purification process, 24-h chlorine exposure eliminated more than 50% of iodine when the initial iodine concentration was 250 μg/l or less. Iodine was completely eliminated if the starting concentration was 16 μg/l.We conclude that chlorine used during water purification may be a major contributor to iodine deficiency in European communities.

  17. 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

  18. 5-Lipoxygenase-activating protein (FLAP) inhibitors. Part 4: development of 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (AM803), a potent, oral, once daily FLAP inhibitor.

    PubMed

    Stock, Nicholas S; Bain, Gretchen; Zunic, Jasmine; Li, Yiwei; Ziff, Jeannie; Roppe, Jeffrey; Santini, Angelina; Darlington, Janice; Prodanovich, Pat; King, Christopher D; Baccei, Christopher; Lee, Catherine; Rong, Haojing; Chapman, Charles; Broadhead, Alex; Lorrain, Dan; Correa, Lucia; Hutchinson, John H; Evans, Jilly F; Prasit, Peppi

    2011-12-08

    The potent 5-lipoxygenase-activating protein (FLAP) inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid 11cc is described (AM803, now GSK2190915). Building upon AM103 (1) (Hutchinson et al. J. Med Chem.2009, 52, 5803-5815; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 213-217; Stock et al. Bioorg. Med. Chem. Lett.2010, 20, 4598-4601), SAR studies centering around the pyridine moiety led to the discovery of compounds that exhibit significantly increased potency in a human whole blood assay measuring LTB(4) inhibition with longer drug preincubation times (15 min vs 5 h). Further studies identified 11cc with a potency of 2.9 nM in FLAP binding, an IC(50) of 76 nM for inhibition of LTB(4) in human blood (5 h incubation) and excellent preclinical toxicology and pharmacokinetics in rat and dog. 11cc also demonstrated an extended pharmacodynamic effect in a rodent bronchoalveolar lavage (BAL) model. This compound has successfully completed phase 1 clinical studies in healthy volunteers and is currently undergoing phase 2 trials in asthmatic patients.

  19. Reduced hepatic injury in Toll-like receptor 4-deficient mice following D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure.

    PubMed

    Ben Ari, Ziv; Avlas, Orna; Pappo, Orit; Zilbermints, Veacheslav; Cheporko, Yelena; Bachmetov, Larissa; Zemel, Romy; Shainberg, Asher; Sharon, Eran; Grief, Franklin; Hochhauser, Edith

    2012-01-01

    Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), D-galactosamine (GalN)-induced FHF is a well established model of liver injury in mice. Toll-Like Receptor 4 (TLR4) has been identified as a receptor for LPS. The aim of this study was to investigate the role of TLR4 in FHF induced by D-GalN/LPS administration in mice. Wild type (WT) and TLR4 deficient (TLR4ko) mice were studied in vivo in a fulminant model induced by GalN/LPS. Hepatic TLR4 expression, serum liver enzymes, hepatic and serum TNF-α and interleukin-1β levels were determined. Apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor-kappaβ (NF-κ β) and phosphorylated c-Jun hepatic expression were studied using Western blot analysis. All WT mice died within 24 hours after administration of GalN/LPS while all TLR4ko mice survived. Serum liver enzymes, interleukin-1β, TNF-α level, TLR4 mRNA expression, hepatic injury and hepatocyte apoptosis all significantly decreased in TLR4ko mice compared with WT mice. A significant decrease in hepatic c-Jun and IκB signaling pathway was noted in TLR4ko mice compared with WT mice. In conclusion, following induction of FHF, the inflammatory response and the liver injury in TLR4ko mice was significantly attenuated through decreased hepatic c-Jun and NF-κB expression and thus decreased TNF-α level. Down-regulation of TLR4 expression plays a pivotal role in GalN/LPS induced FHF. These findings might have important implications for the use of the anti TLR4 protein signaling as a potential target for therapeutic intervention in FHF.

  20. Vitamin D deficiency and reduced bone mineral density in multiple sclerosis: effect of ambulatory status and functional capacity.

    PubMed

    Ozgocmen, Salih; Bulut, Serpil; Ilhan, Nevin; Gulkesen, Arif; Ardicoglu, Ozge; Ozkan, Yusuf

    2005-01-01

    Multiple sclerosis (MS) is a chronic disease and a major cause of disability in young adults. The aims of this study were to assess bone mass in patients with MS in comparison to healthy age- and sex-matched controls, and to evaluate factors influencing bone mineral density (BMD), and the relationship of the pain threshold at peripheral and axial sites with BMD in MS. Thirty-one patients with MS and 30 matched healthy controls participated in the study. The Kurtzke expanded disability status scale (EDSS) and the functional independence measure (FIM) were used to scale disability, mobility, and functional status. Serum 25(OH) vitamin D levels were measured. BMD was measured using dual X-ray absorptiometry (DXA). MS patients had significantly lower BMD at the lumbar spine (L2-L4) and femur trochanter compared to the matched controls. BMD of the lumbar spine was nearly 1 SD lower in MS patients compared with the healthy reference population (Z scores). MS patients had significantly lower vitamin D levels (17.3 ng/ml vs 43.1 ng/ml; P < 0.001) compared to controls, and 19 patients (61%) had a serum level of vitamin D that was less than 20 ng/ml. EDSS scores in the patients were inversely correlated with proximal femur BMD but not with spinal BMD. There was a negative correlation with the cumulative steroid dose and BMD only for femur trochanter BMD. Total myalgia scores for paravertebral muscles correlated significantly with spinal BMD. In conclusion, BMD is significantly lower in MS patients than in healthy controls, vitamin D deficiency is prevalent in MS, and ambulatory status is a determinative factor for osteoporosis in MS. Patients should be encouraged to have adequate sunlight exposure and to increase their mobility. Specific strengthening exercises for hip and back muscles in MS patients would have a substantial impact on bone density, osteoporosis, fracture risk, and mobility.

  1. Reduced TORC1 signaling abolishes mitochondrial dysfunctions and shortened chronological lifespan of Isc1p-deficient cells

    PubMed Central

    Teixeira, Vitor; Medeiros, Tânia C.; Vilaça, Rita; Moradas-Ferreira, Pedro; Costa, Vítor

    2014-01-01

    The target of rapamycin (TOR) is an important signaling pathway on a hierarchical network of interacting pathways regulating central biological processes, such as cell growth, stress response and aging. Several lines of evidence suggest a functional link between TOR signaling and sphingolipid metabolism. Here, we report that the TORC1-Sch9p pathway is activated in cells lacking Isc1p, the yeast orthologue of mammalian neutral sphingomyelinase 2. The deletion of TOR1 or SCH9 abolishes the premature aging, oxidative stress sensitivity and mitochondrial dysfunctions displayed by isc1Δ cells and this is correlated with the suppression of the autophagic flux defect exhibited by the mutant strain. The protective effect of TOR1 deletion, as opposed to that of SCH9 deletion, is not associated with the attenuation of Hog1p hyperphosphorylation, which was previously implicated in isc1Δ phenotypes. Our data support a model in which Isc1p regulates mitochondrial function and chronological lifespan in yeast through the TORC1-Sch9p pathway although Isc1p and TORC1 also seem to act through independent pathways, as isc1Δtor1Δ phenotypes are intermediate to those displayed by isc1Δ and tor1Δ cells. We also provide evidence that TORC1 downstream effectors, the type 2A protein phosphatase Sit4p and the AGC protein kinase Sch9p, integrate nutrient and stress signals from TORC1 with ceramide signaling derived from Isc1p to regulate mitochondrial function and lifespan in yeast. Overall, our results show that TORC1-Sch9p axis is deregulated in Isc1p-deficient cells, contributing to mitochondrial dysfunction, enhanced oxidative stress sensitivity and premature aging of isc1Δ cells. PMID:28357207

  2. G-protein coupled receptor 6 deficiency alters striatal dopamine and cAMP concentrations and reduces dyskinesia in a mouse model of Parkinson's disease.

    PubMed

    Oeckl, Patrick; Hengerer, Bastian; Ferger, Boris

    2014-07-01

    The orphan G-protein coupled receptor 6 (GPR6) is a constitutively active receptor which is positively coupled to the formation of cyclic adenosine-3',5'-monophosphate (cAMP). GPR6 is predominantly expressed in striatopallidal neurons. Here, we investigated neurochemical and behavioural effects of Gpr6 deficiency in mice. Gpr6 depletion decreased in vivo cAMP tissue concentrations (20%) in the striatum. An increase of striatal tissue dopamine concentrations (10%) was found in Gpr6(-/-) mice, whereas basal extracellular dopamine levels were not changed compared with Gpr6(+/+) mice, as shown by in vivo microdialysis. Western blot analyses revealed no alteration in the expression and subcellular localisation of the dopamine D2 receptor in the striatum of Gpr6(-/-) mice, and the number of tyrosine hydroxylase positive neurons in the substantia nigra was unchanged. DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32kDa) expression in the striatum of Gpr6(-/-) mice was not altered, however, a twofold increase in the phosphorylation of DARPP-32 at Thr34 was detected in Gpr6(-/-) compared with Gpr6(+/+) mice. Gpr6(-/-) mice showed higher locomotor activity in the open field, which persisted after treatment with the dopamine D2 receptor antagonist haloperidol. They also displayed reduced abnormal involuntary movements after apomorphine and quinpirole treatment in the mouse dyskinesia model of Parkinson's disease. In conclusion, the depletion of Gpr6 reduces cAMP concentrations in the striatum and alters the striatal dopaminergic system. Gpr6 deficiency causes an interesting behavioural phenotype in the form of enhanced motor activity combined with reduced abnormal involuntary movements. These findings could offer an opportunity for the treatment of Parkinson's disease beyond dopamine replacement.

  3. 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.

  4. 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.

  5. IL1RAPL1 knockout mice show spine density decrease, learning deficiency, hyperactivity and reduced anxiety-like behaviours.

    PubMed

    Yasumura, Misato; Yoshida, Tomoyuki; Yamazaki, Maya; Abe, Manabu; Natsume, Rie; Kanno, Kouta; Uemura, Takeshi; Takao, Keizo; Sakimura, Kenji; Kikusui, Takefumi; Miyakawa, Tsuyoshi; Mishina, Masayoshi

    2014-10-14

    IL-1 receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic intellectual disability and is associated with autism. IL1RAPL1 mediates excitatory synapse formation through trans-synaptic interaction with PTPδ. Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice. The spatial reference and working memories and remote fear memory were mildly impaired in IL1RAPL1 knockout mice. Furthermore, the behavioural flexibility was slightly reduced in the T-maze test. Interestingly, the performance of IL1RAPL1 knockout mice in the rotarod test was significantly better than that of wild-type mice. Moreover, IL1RAPL1 knockout mice consistently exhibited high locomotor activity in all the tasks examined. In addition, open-space and height anxiety-like behaviours were decreased in IL1RAPL1 knockout mice. These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety.

  6. IL1RAPL1 knockout mice show spine density decrease, learning deficiency, hyperactivity and reduced anxiety-like behaviours

    PubMed Central

    Yasumura, Misato; Yoshida, Tomoyuki; Yamazaki, Maya; Abe, Manabu; Natsume, Rie; Kanno, Kouta; Uemura, Takeshi; Takao, Keizo; Sakimura, Kenji; Kikusui, Takefumi; Miyakawa, Tsuyoshi; Mishina, Masayoshi

    2014-01-01

    IL-1 receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic intellectual disability and is associated with autism. IL1RAPL1 mediates excitatory synapse formation through trans-synaptic interaction with PTPδ. Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice. The spatial reference and working memories and remote fear memory were mildly impaired in IL1RAPL1 knockout mice. Furthermore, the behavioural flexibility was slightly reduced in the T-maze test. Interestingly, the performance of IL1RAPL1 knockout mice in the rotarod test was significantly better than that of wild-type mice. Moreover, IL1RAPL1 knockout mice consistently exhibited high locomotor activity in all the tasks examined. In addition, open-space and height anxiety-like behaviours were decreased in IL1RAPL1 knockout mice. These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety. PMID:25312502

  7. The addition of a Buttiauxella sp. phytase to lactating sow diets deficient in phosphorus and calcium reduces weight loss and improves nutrient digestibility.

    PubMed

    Wealleans, A L; Bold, R M; Dersjant-Li, Y; Awati, A

    2015-11-01

    Improving the efficiency of P use by pigs is especially important for lactating sows, whose metabolic requirements for P and Ca are high. The effect of a sp. phytase on lactating sow performance and nutrient digestibility was investigated using the combined data set for 6 studies. Treatments included a nutritionally adequate positive control diet (PC), a negative control diet (NC; with an average reduction of 0.16% available phosphorous and 0.15% Ca vs. PC), and NC supplemented with a sp. phytase at 250, 500, 1,000 or 2,000 phytase unit (FTU)/kg, respectively. Phosphorus and Ca deficiency in the NC resulted in significantly higher BW loss compared with the PC. All phytase treatments maintained BW loss at the same level as the PC. Increasing doses of phytase significantly ( < 0.05) reduced sow BW loss and increased energy intake, with improvements most apparent in sows older than parity 5. The positive effects on BW and energy intake were not observed in first-parity sows. This may be a consequence of fewer first parity sows in the data set. The apparent total tract digestibility of DM, OM, and CP were not affected by phytase supplementation. Digestible P and Ca were significantly improved (linear, < 0.0001; quadratic, < 0.0001) by increasing the dose of phytase supplementation. Significantly lower apparent total tract digestibility of energy, Ca, and P was found in the NC treatment vs. the PC treatment, whereas no significant differences were found between phytase treatment and the PC treatment. In conclusion, phytase supplementation at a level of 250 FTU/kg can replace 0.16% available phosphorous and 0.15% Ca; however, increasing the phytase dose can further reduce BW loss in sows fed P- and Ca- deficient diets.

  8. Rac1 GTPase-deficient HeLa cells present reduced DNA repair, proliferation, and survival under UV or gamma irradiation.

    PubMed

    Espinha, Gisele; Osaki, Juliana H; Magalhaes, Yuli T; Forti, Fabio Luis

    2015-06-01

    Rac1 GTPase controls essential cellular functions related to the cytoskeleton, such as motility and adhesion. Rac1 is overexpressed in many tumor cells, including breast cancers, where it is also involved in the proliferation and checkpoint control necessary for the cell's recovery after exposure to ionizing radiation. However, its role in DNA damage and repair remains obscure in other tumor cells and under different genotoxic conditions. Here, we compare HeLa cells with mutants exogenously expressing a dominant-negative Rac1 (HeLa-Rac1-N17) by their responses to DNA damage induced by gamma or UV radiation. In HeLa cells, these treatments led to increased levels of active Rac1 (Rac1-GTP) and of stress fibers, with a diminished ability to migrate compared to untreated cells. However, the reduction of Rac1-GTP in Rac1-N17-deficient clones resulted in much higher levels of polymerized stress fibers accompanied by a strong impairment of cell migration, even after both radiation treatments. With regard to proliferation and genomic stability, dominant-negative Rac1 cells were more sensitive to gamma and UV radiation, exhibiting reduced proliferation and survival consistent with increased DNA damage and delayed or reduced DNA repair observed in this Rac1-deficient clone. The DNA damage response, as indicated by pH2AX and pChk1 levels, was increased in HeLa cells but was not effectively triggered in the Rac1-N17 clone after radiation treatment, which is likely the main cause of DNA damage accumulation. These data suggest that Rac1 GTPase plays an important role in signaling and contributes to the sensitivity of cervical cancer cells under UV or gamma radiation treatments.

  9. Selective cognitive deficits and reduced hippocampal brain-derived neurotrophic factor mRNA expression in small-conductance calcium-activated K+ channel deficient mice.

    PubMed

    Jacobsen, J P R; Redrobe, J P; Hansen, H H; Petersen, S; Bond, C T; Adelman, J P; Mikkelsen, J D; Mirza, N R

    2009-09-29

    Small-conductance calcium-activated K(+) channels 1-3 (SK1-3) are important for neuronal firing regulation and are considered putative CNS drug targets. For instance non-selective SK blockers improve performance in animal models of cognition. The SK subtype(s) involved herein awaits identification and the question is difficult to address pharmacologically due to the lack of subtype-selective SK-channel modulators. In this study, we used doxycycline-induced conditional SK3-deficient (T/T) mice to address the cognitive consequences of selective SK3 deficiency. In T/T mice SK3 protein is near-eliminated from the brain following doxycycline treatment. We tested T/T and wild type (WT) littermate mice in five distinct learning and memory paradigms. In Y-maze spontaneous alternations and five-trial inhibitory avoidance the performance of T/T mice was markedly inferior to WT mice. In contrast, T/T and WT mice performed equally well in passive avoidance, object recognition and the Morris water maze. Thus, some aspects of working/short-term memory are disrupted in T/T mice. Using in situ hybridization, we further found the cognitive deficits in T/T mice to be paralleled by reduced brain-derived neurotrophic factor (BDNF) mRNA expression in the dentate gyrus and CA3 of the hippocampus. BDNF mRNA levels in the frontal cortex were not affected. BDNF has been crucially implicated in many cognitive processes. Hence, the biological substrate for the cognitive impairments in T/T mice could conceivably entail reduced trophic support of the hippocampus.

  10. B‐cell very late antigen‐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.

    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, and recruitment of Th17 cells and macrophages, and reduces susceptibility to experimental autoimmune encephalomyelitis. These results underscore the importance of B‐cell VLA‐4 expression in the 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. Ann Neurol 2015;77:902–908 PMID:25712734

  11. 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

  12. Sodium Butyrate Reduces Colitogenic Immunoglobulin A-Coated Bacteria and Modifies the Composition of Microbiota in IL-10 Deficient Mice

    PubMed Central

    Zhang, Tenghui; Ding, Chao; Zhao, Mingli; Dai, Xujie; Yang, Jianbo; Li, Yi; Gu, Lili; Wei, Yao; Gong, Jianfeng; Zhu, Weiming; Li, Ning; Li, Jieshou

    2016-01-01

    High levels of immunoglobulin A (IgA)-coated bacteria may have a role in driving inflammatory bowel disease (IBD). We therefore investigated the effect of sodium butyrate on microbiota in IBD prone interleukin (IL)-10−/− mice. At 8 weeks of age, mice were allocated into three groups (n = 4/group): normal (C57BL/6), IL-10−/−, and IL-10−/− treated with sodium butyrate (100 mM). Severity of colitis, inflammatory cytokine and short-chain fatty acid (SCFA) concentration in proximal colon contents, the percentage of IgA-coated bacteria and microbiota composition by 16S ribosomal RNA assessment of stool were measured after 4 weeks of treatment. Sodium butyrate ameliorated histological colitis and decreased levels of tumor necrosis factor (TNF)-α and IL-6 in IL-10−/− mice compared with those without treatment. At the phylum level, a reduction in Bacteroidetes and an increase in Firmicutes in IL-10−/− mice treated with sodium butyrate were observed. Additionally, Prevotellaceae species were reduced in IL-10−/− mice treated with sodium butyrate as compared with those without treatment. The level of biodiversity was slightly increased and the amount of IgA-coated bacteria decreased in IL-10−/− mice treated with sodium butyrate compared with those without treatment. Our results indicate that sodium butyrate protects against colitis, possibly through modifying the gut microbiota, enriching biodiversity and reducing the amount of colitogenic IgA-coated bacteria in IL-10−/− mice. PMID:27886121

  13. 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.

  14. Striatal damage and oxidative stress induced by the mitochondrial toxin malonate are reduced in clorgyline-treated rats and MAO-A deficient mice.

    PubMed

    Maragos, William F; Young, Kristie L; Altman, Chris S; Pocernich, Chava B; Drake, Jennifer; Butterfield, D Allan; Seif, Isabelle; Holschneider, Daniel P; Chen, Kevin; Shih, Jean C

    2004-04-01

    Intrastriatal administration of the succinate dehydrogenase (SDH) inhibitor malonate produces neuronal injury by a "secondary excitotoxic" mechanism involving the generation of reactive oxygen species (ROS). Recent evidence indicates dopamine may contribute to malonate-induced striatal neurodegeneration; infusion of malonate causes a pronounced increase in extracellular dopamine and dopamine deafferentation attenuates malonate toxicity. Inhibition of the catabolic enzyme monoamine oxidase (MAO) also attenuates striatal lesions induced by malonate. In addition to forming 3,4-dihydroxyphenylacetic acid, metabolism of dopamine by MAO generates H2O2, suggesting that dopamine metabolism may be a source of ROS in malonate toxicity. There are two isoforms of MAO, MAO-A and MAO-B. In this study, we have investigated the role of each isozyme in malonate-induced striatal injury using both pharmacological and genetic approaches. In rats treated with either of the specific MAO-A or -B inhibitors, clorgyline or deprenyl, respectively, malonate lesion volumes were reduced by 30% compared to controls. In knock-out mice lacking the MAO-A isoform, malonate-induced lesions were reduced by 50% and protein carbonyls, an index ROS formation, were reduced by 11%, compared to wild-type animals. In contrast, mice deficient in MAO-B showed highly variable susceptibility to malonate toxicity precluding us from determining the precise role of MAO-B in this form of brain damage. These findings indicate that normal levels of MAO-A participate in expression of malonate toxicity by a mechanism involving oxidative stress.

  15. Ceruloplasmin Deficiency Reduces Levels of Iron and BDNF in the Cortex and Striatum of Young Mice and Increases Their Vulnerability to Stroke

    PubMed Central

    Texel, Sarah J.; Zhang, Jian; Camandola, Simonetta; Unger, Erica L.; Taub, Dennis D.; Koehler, Raymond C.; Harris, Z. Leah; Mattson, Mark P.

    2011-01-01

    Ceruloplasmin (Cp) is an essential ferroxidase that plays important roles in cellular iron trafficking. Previous findings suggest that the proper regulation and subcellular localization of iron are very important in brain cell function and viability. Brain iron dyshomeostasis is observed during normal aging, as well as in several neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, coincident with areas more susceptible to insults. Because of their high metabolic demand and electrical excitability, neurons are particularly vulnerable to ischemic injury and death. We therefore set out to look for abnormalities in the brain of young adult mice that lack Cp. We found that iron levels in the striatum and cerebral cortex of these young animals are significantly lower than wild-type (WT) controls. Also mRNA levels of the neurotrophin brain derived neurotrophic factor (BDNF), known for its role in maintenance of cell viability, were decreased in these brain areas. Chelator-mediated depletion of iron in cultured neural cells resulted in reduced BDNF expression by a posttranscriptional mechanism, suggesting a causal link between low brain iron levels and reduced BDNF expression. When the mice were subjected to middle cerebral artery occlusion, a model of focal ischemic stroke, we found increased brain damage in Cp-deficient mice compared to WT controls. Our data indicate that lack of Cp increases neuronal susceptibility to ischemic injury by a mechanism that may involve reduced levels of iron and BDNF. PMID:21949858

  16. Protease-activated receptor-2 deficient mice have reduced house dust mite-evoked allergic lung inflammation.

    PubMed

    de Boer, J Daan; Van't Veer, Cornelis; Stroo, Ingrid; van der Meer, Anne J; de Vos, Alex F; van der Zee, Jaring S; Roelofs, Joris J T H; van der Poll, Tom

    2014-08-01

    Protease-activated receptor-2 (PAR2) is abundantly expressed in the pulmonary compartment. House dust mite (HDM) is a common cause of allergic asthma and contains multiple PAR2 agonistic proteases. The aim of this study was to determine the role of PAR2 in HDM-induced allergic lung inflammation. For this, the extent of allergic lung inflammation was studied in wild type (Wt) and PAR2 knockout (KO) mice after repeated airway exposure to HDM. HDM exposure of Wt mice resulted in a profound influx of eosinophils in bronchoalveolar lavage fluid (BALF) and accumulation of eosinophils in lung tissue, which both were strongly reduced in PAR2 KO mice. PAR2 KO mice demonstrated attenuated lung pathology and protein leak in the bronchoalveolar space, accompanied by lower BALF levels of the anaphylatoxins C3a and C5a. This study reveals, for the first time, an important role for PAR2 in allergic lung inflammation induced by the clinically relevant allergens contained in HDM.

  17. Reduced operant ethanol self-administration and in vivo mesolimbic dopamine responses to ethanol in PKCepsilon-deficient mice.

    PubMed

    Olive, M F; Mehmert, K K; Messing, R O; Hodge, C W

    2000-11-01

    There is increasing evidence that individual protein kinase C (PKC) isozymes mediate specific effects of ethanol on the nervous system. In addition, multiple lines of evidence suggest that the mesoaccumbens dopamine reward system is critically involved in the rewarding and reinforcing effects of ethanol. Yet little is known about the role of individual PKC isozymes in ethanol reinforcement processes or in regulation of mesolimbic systems. In this study, we report that mice lacking the epsilon isoform of PKC (PKCepsilon) show reduced operant ethanol self-administration and an absence of ethanol-induced increase in extracellular dopamine levels in the nucleus accumbens. PKCepsilon null mice exhibited a 53% decrease in alcohol-reinforced operant responses under basal conditions, as well as following ethanol deprivation. Behavioural analysis revealed that while both genotypes had the same number of drinking bouts following deprivation, PKCepsilon null mice demonstrated a 61% reduction in number of ethanol reinforcers per bout and a 57% reduction in ethanol-reinforced response rate. In vivo microdialysis experiments showed that, in contrast to wild-type mice, PKCepsilon null mice exhibited no change in extracellular levels of dopamine in the nucleus accumbens following acute administration of ethanol (1 and 2 g/kg i.p.), while mesolimbic dopamine responses to cocaine (20 mg/kg i.p.) or high potassium (100 mM) in these mice were comparable with that of wild-types. These data provide further evidence that increases in extracellular mesolimbic dopamine levels contribute to the reinforcing effects of ethanol, and indicate that pharmacological agents inhibiting PKCepsilon may be useful in the treatment of alcohol dependence.

  18. Attenuation of cardiac contractility in Na,K-ATPase alpha1 isoform-deficient hearts under reduced calcium conditions.

    PubMed

    Moseley, Amy E; Cougnon, Marc H; Grupp, Ingrid L; El Schultz, Jo; Lingrel, Jerry B

    2004-11-01

    We have previously reported that genetic reduction of the Na,K-ATPase alpha1 isoform (alpha1(+/-)) results in a hypocontractile cardiac phenotype. This observation was surprising and unexpected. In order to determine if calcium overload contributes to the depressed phenotype, cardiac performance was examined by perfusing the hearts with buffer containing 2 or 1.5 mM calcium. At 2 mM calcium, +dP/dt for the alpha1(+/-) hearts (1374 +/- 180) was significantly less than that of wild-type (2656 +/- 75, P < 0.05). At 1.5 mM calcium, a larger decrease in +dP/dt occurred (vs. 2 mM calcium) for the alpha1(+/-) hearts (517 +/- 92) compared to wild-type (2238 +/- 157). At 2 mM calcium, -dP/dt was 50% lower in alpha1(+/-) hearts (-1903 +/- 141) than wild-type (-982 +/- 143). At 1.5 mM calcium relaxation was further reduced in alpha1(+/-) compared to wild-type (-443 +/- 56 vs. - 1691 +/- 109). We also tested whether the compensatory upregulation of the Na,K-ATPase alpha2 isoform in the alpha1(+/-) hearts contributes to the hypocontractile phenotype. At 8 x 10(-6) M ouabain, that would completely inhibit the alpha2 isoform, a 30% increase in contractility was obtained in alpha1(+/-) hearts compared to no ouabain treatment, while a 63% faster time-to-peak (TTP) and 67% faster half-time-to-relaxation (RT(1/2)) were observed in alpha1(+/-) hearts treated with ouabain. These results suggest that upregulation of the alpha2 isoform may play a role in slower TTP and RT(1/2) in the alpha1(+/-) hearts. Furthermore, lowering extracellular calcium in the perfusate did not alleviate the depressed contractile phenotype in the alpha1(+/-) hearts and resulted in further depressed cardiac contractility suggesting that these hearts are not calcium overloaded.

  19. 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.

  20. Angiotensin-converting enzyme inhibition reduces food intake and weight gain and improves glucose tolerance in melanocortin-4 receptor deficient female rats.

    PubMed

    Mul, Joram D; Seeley, Randy J; Woods, Stephen C; Begg, Denovan P

    2013-09-10

    Functional loss of melanocortin-4 receptor (MC4R) activity leads to hyperphagia and an obese, glucose intolerant phenotype. We have previously established that inhibition of angiotensin-converting enzyme (ACE) reduces food intake, body weight and glucose homeostasis in diet-induced obesity. The current study assessed the effect of ACE inhibitor treatment in MC4R-deficient female rats on body weight, adiposity and glucose tolerance. Rats homozygous (HOM) for a loss of function Mc4r mutation had an obese phenotype relative to their wildtype (WT) littermates. Inhibition of ACE for 8weeks produced reductions in body weight gain in both HOM and WT rats; however, food intake was only reduced in HOM rats. Weight loss following ACE inhibitor treatment was specific to fat mass while lean mass was unaffected. HOM rats were severely glucose intolerant and insensitive to exogenous insulin injection, and treatment with an ACE inhibitor improved both glucose tolerance and insulin sensitivity in HOM rats although not fully to that of the level of WT rats. The current study indicates that HOM rats are sensitive to the anorectic effects of ACE inhibition, unlike their WT littermates. This resulted in a more rapid reduction in body weight gain and a more substantial loss of adipose mass in HOM animals, relative to WT animals, treated with an ACE inhibitor. Overall, these data demonstrate that MC4R signaling is not required for weight loss following treatment with an ACE inhibitor.

  1. Reduced expression of brain-derived neurotrophic factor in mice deficient for pituitary adenylate cyclase activating polypeptide type-I-receptor.

    PubMed

    Zink, Mathias; Otto, Christiane; Zörner, Björn; Zacher, Christiane; Schütz, Günther; Henn, Fritz A; Gass, Peter

    2004-04-22

    In vitro pituitary adenylate cyclase activating polypeptide (PACAP) induces the expression of brain-derived neurotrophic factor (BDNF) via its specific receptor PAC1. Since BDNF has been implicated in learning paradigms and mice lacking functional PAC1 have deficits in hippocampus-dependent associative learning, we investigated whether PAC1 mutants show alterations in hippocampal expression of BDNF and its receptor TrkB. Semi-quantitative in situ-hybridization using exon-specific BDNF-probes revealed significantly reduced expression of the exon-III and exon-V-specific transcripts within the hippocampal CA3 region in PAC1-deficient mice. A similar trend was observed for the exon-I-specific transcript. The expression of the exon-III-specific transcript was also reduced within the dentate gyrus, while Trk B-expression did not differ between genotypes. Our data demonstrate that even in vivo PAC1-mediated signaling seems to play a pivotal role for the transcriptional regulation of BDNF.

  2. The role of reduced glutathione during the course of acute haemolysis in glucose-6-phosphate dehydrogenase deficient patients: clinical and pharmacodynamic aspects.

    PubMed

    Corbucci, G G

    1990-01-01

    Tissue hypoperfusion leads to cellular oxidative and peroxidative damage due to biochemical disorders in the oxygen and substrate metabolism. The metabolic turnover of glutathione (GSH) represents one the main cytoprotective systems against the peroxide attack and the depletion or defect in resynthesis of this compound is accompanied by pathological consequences. In the present study the clinical effects of glutathione depletion were investigated in conditions of acute tissue hypoxia due to marked haemolysis in glucose-6-phosphate dehydrogenase deficient patients (favism syndrome). In these subjects a significant marker of the tissue oxidative damage was represented by the uric acid blood levels, presumably linked to xanthine-hypoxanthine altered metabolism. To antagonize the effects of oxyradical pathology, reduced glutathione was administered to a group of patients and the results confirmed the cytoprotective role played by the GSH supplementation. The GSH action was evident on the tissue metabolism and this supports the opinion that reduced glutathione could represent a new and interesting therapeutic approach in marked and acute hypoxic conditions.

  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. Deficiency of CX3CR1 delays burn wound healing and is associated with reduced myeloid cell recruitment and decreased sub-dermal angiogenesis.

    PubMed

    Clover, Anthony J P; Kumar, Arun H S; Caplice, Noel M

    2011-12-01

    The development of a good blood supply is a key step in burn wound healing and appears to be regulated in part by myeloid cells. CX3CR1 positive cells have recently been identified as myeloid cells with a potential role in angiogenesis. The role of functional CX3CR1 system in burn wound healing is not previously investigated. A 2% contact burn was induced in CX3CR1(+/gfp) and CX3CR1(gfp/gfp) mice. These transgenic mice facilitate the tracking of CX3CR1 cells (CX3CR1(+/gfp)) and allow evaluation of the consequence of CX3CR1 functional knockout (CX3CR1(gfp/gfp)) on burn wound healing. The progression of wound healing was monitored before tissue was harvested and analyzed at day 6 and day 12 for migration of CX3CR1 cells into burn wound. Deficiency of a functional CX3CR1 system resulted in decreased recruitment of CX3CR1 positive cells into the burn wound associated with decreased myeloid cell recruitment (p<0.001) and reduced maintenance of new vessels (p<0.001). Burn wound healing was prolonged (p<0.05). Our study is the first to establish a role for CX3CR1 in burn wound healing which is associated with sub-dermal angiogenesis. This chemokine receptor pathway may be attractive for therapeutic manipulation as it could increase sub dermal angiogenesis and thereby improve time to healing.

  5. 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

  6. 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

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

    PubMed Central

    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

    2016-01-01

    ABSTRACT 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. Haploinsufficiency of E-selectin ligand-1 is associated with reduced atherosclerotic plaque macrophage content while complete deficiency leads to early embryonic lethality in mice.

    PubMed

    Luo, Wei; Wang, Hui; Guo, Chiao; Wang, Jintao; Kwak, Jeffrey; Bahrou, Kristina L; Eitzman, Daniel T

    2012-10-01

    E-selectin-1 (ESL-1), also known as golgi complex-localized glycoprotein-1 (GLG1), homocysteine-rich fibroblast growth factor receptor (CGR-1), and latent transforming growth factor-β complex protein 1 (LTCP-1), is a multifunctional protein with widespread tissue distribution. To determine the functional consequences of ESL-1 deficiency, mice were generated carrying an ESL-1 gene trap. After backcrossing to C57BL6/J for 6 generations, mice heterozygous for the gene trap (ESL-1(+/-)) were intercrossed to produce ESL-1(-/-) mice, however ESL-1(-/-) mice were not viable, even at embryonic day E10.5. To determine the effect of heterozygous ESL-1 deficiency on atherosclerosis, apolipoprotein E deficient (ApoE(-/-)), ESL-1(+/-) mice were generated and fed western diet. Compared to ApoE(-/-), ESL-1(+)(/)(+) mice, atherosclerotic lesions from ApoE(-/-), ESL-1(+/-) contained more collagen and fewer macrophages, suggesting increased plaque stability. In conclusion, heterozygous deficiency of ESL-1 is associated with features of increased atherosclerotic plaque stability while complete deficiency of ESL-1 leads to embryonic lethality.

  9. Disaccharidase deficiency.

    PubMed

    Bayless, T M; Christopher, N L

    1969-02-01

    This review of the literature and current knowledge concerning a nutritional disorder of disaccharidase deficiency discusses the following topics: 1) a description of disorders of disaccharide digestion; 2) some historical perspective on the laboratory and bedside advances in the past 10 years that have helped define a group of these digestive disorders; 3) a classification of conditions causing disaccharide intolerance; and 4) a discussion of some of the specific clinical syndromes emphasizing nutritional consequences of these syndromes. The syndromes described include congenital lactase deficiency, acquired lactase deficiency in teenagers and adults, acquired generalized disaccharidase deficiency secondary to diffuse mucosal damage, acquired lactose intolerance secondary to alterations in the intestinal transit, sucrase-isomaltase deficiencies, and other disease associations connected with lactase deficiency such as colitis.

  10. 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 ...

  11. Mineral profiling of local pig-feeds and pigs reared under resource driven production system to reduce porcine mineral deficiency in subtropical hill ecosystem of Northeastern India.

    PubMed

    Kumaresan, A; Bujarbaruah, K M; Pathak, K A; Das, Anubrata; Ramesh, T

    2009-04-01

    The present study assessed the mineral status of pigs fed with local feed resources. The commonly used plants for feeding pigs and blood serum samples from Hampshire, Large White Yorkshire and indigenous pigs were analyzed for total protein, albumin and cholesterol levels. Processed plant and serum samples were also analyzed for calcium, phosphorus, magnesium, sodium, potassium, copper, cobalt, manganese, iron and zinc. The incidence and extent of mineral deficiency in pigs was quantified. No significant difference was observed in total protein and albumin levels between any two breed/types of pigs, however the Indigenous pigs showed significantly (P < 0.05) higher cholesterol level compared to other two breeds. Among different plants, Spilanthus sp had majority of macro and micro nutrients in high levels. Regarding incidence of mineral deficiency in pigs, it was observed that 90, 67.1, 61.4, 48.6, 95.7% of the pigs were deficient in calcium, phosphorus, sodium, magnesium and potassium. An interesting finding was that all the pigs (100%) utilized in the study were deficient in zinc. From this study, it was inferred that there are good numbers of potential source of mineral that might be used more economically to improve the mineral availability to pigs.

  12. Restoration of insulin secretion in pancreatic islets of protein-deficient rats by reduced expression of insulin receptor substrate (IRS)-1 and IRS-2.

    PubMed

    Araujo, E P; Amaral, M E C; Filiputti, E; De Souza, C T; Laurito, T L; Augusto, V D; Saad, M J A; Boschero, A C; Velloso, L A; Carneiro, E M

    2004-04-01

    Autocrine and paracrine insulin signaling may participate in the fine control of insulin secretion. In the present study, tissue distribution and protein amounts of the insulin receptor and its major substrates, insulin receptor substrate (IRS)-1 and IRS-2, were evaluated in a model of impaired glucose-induced insulin secretion, the protein-deficient rat. Immunoblot and RT-PCR studies showed that the insulin receptor and IRS-2 expression are increased, whilst IRS-1 protein and mRNA contents are decreased in pancreatic islets of protein-deficient rats. Immunohistochemical studies revealed that the insulin receptor and IRS-1 and -2 are present in the great majority of islet cells; however, the greatest staining was localized at the periphery, suggesting a co-localization with non-insulin-secreting cells. Exogenous insulin stimulation of isolated islets promoted higher insulin receptor and IRS-1 and -2 tyrosine phosphorylation in islets from protein-deficient rats, as compared with controls. Moreover, insulin-induced IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase activity are increased in islets of protein-deficient rats. The reduction of IRS-1 and IRS-2 protein expression in islets isolated from protein-deficient rats by the use of antisense IRS-1 or IRS-2 phosphorthioate-modified oligonucleotides partially restored glucose-induced insulin secretion. Thus, the impairment of insulin cell signaling through members of the IRS family of proteins in isolated rat pancreatic islets improves glucose-induced insulin secretion. The present data reinforced the role of insulin paracrine and autocrine signaling in the control of its own secretion.

  13. Protonated nanostructured aluminosilicate (NSAS) reduces plasma cholesterol concentrations and atherosclerotic lesions in Apolipoprotein E deficient mice fed a high cholesterol and high fat diet

    PubMed Central

    Sivak, Olena; Darlington, Jerry; Gershkovich, Pavel; Constantinides, Panayiotis P; Wasan, Kishor M

    2009-01-01

    The aim of this work was to assess the effect of chronic administration of protonated nanostructured aluminosilicate (NSAS) on the plasma cholesterol levels and development of atherosclerotic lesions in Apolipoprotein (ApoE) deficient mice fed a high cholesterol and high fat diet. Apolipoprotein E (ApoE) deficient mice were divided into the following treatment groups: protonated NSAS 1.4% (w/w), untreated control and 2% (w/w) stigmastanol mixed with high-cholesterol/high-fat diet. Animals were treated for 12 weeks, blood samples were withdrawn every 4 weeks for determination of plasma cholesterol and triglyceride levels. At the end of the study the aortic roots were harvested for assessment of atherosclerotic lesions. NSAS at 1.4% (w/w) and stigmastanol at 2% (w/w) treatment groups showed significant decreases in plasma cholesterol concentrations at all time points relative to the control animals. The lesion sum area in 1.4% (w/w) NSAS and 2% (w/w) stigmastanol groups were significantly less from the control animals. In conclusion, in this study, the effectiveness of chronic administration of protonated NSAS material in the reduction of plasma cholesterol levels and decrease in development of atherosclerotic lesions was demonstrated in Apo-E deficient mice model. PMID:19638223

  14. 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

    2015-05-21

    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.

  15. Reduced difference of α₂-plasmin inhibitor levels between plasma and serum in patients with severe factor XIII deficiency, including autoimmune hemorrhaphilia due to anti-factor XIII antibodies.

    PubMed

    Ichinose, Akitada; Souri, Masayoshi

    2012-01-01

    Coagulation factor XIII/13 (FXIII/13) stabilizes fibrin molecules by creating crosslinks with other fibrin molecules as well as with α₂-plasmin inhibitor (α₂-PI). "Hemorrhagic acquired FXIII/13 deficiency" was formerly considered rare, but has been increasing recently in Japan. During the 10 months of our nationwide campaign, we diagnosed five new patients with "acquired hemorrhaphilia due to anti-FXIII/13 autoantibodies," after examining 20 newly suspected cases of "hemorrhagic acquired FXIII/13 deficiency." When FXIII/13 activity was reduced to less than 50% of normal, it was proportional to the difference in α₂-PI levels between plasma and serum (plasma-serum α₂-PI), likely due to its cross-linking to fibrin by activated FXIII/13. Accordingly, decreased amounts of the plasma-serum α₂-PI ex vivo may reflect reduced FXIII/13 activity in vivo. The plasma-serum α₂-PI may thus also be a useful diagnostic marker for severe FXIII/13 deficiency.

  16. Deletion of Galgt2 (B4Galnt2) Reduces Muscle Growth in Response to Acute Injury and Increases Muscle Inflammation and Pathology in Dystrophin-Deficient Mice

    PubMed Central

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

    2016-01-01

    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. 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.

  18. 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

  19. 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.

  20. E2F transcription factor-1 deficiency reduces pathophysiology in the mouse model of Duchenne muscular dystrophy through increased muscle oxidative metabolism.

    PubMed

    Blanchet, Emilie; Annicotte, Jean-Sébastien; Pradelli, Ludivine A; Hugon, Gérald; Matecki, Stéfan; Mornet, Dominique; Rivier, François; Fajas, Lluis

    2012-09-01

    E2F1 deletion leads to increased mitochondrial number and function, increased body temperature in response to cold and increased resistance to fatigue with exercise. Since E2f1-/- mice show increased muscle performance, we examined the effect of E2f1 genetic inactivation in the mdx background, a mouse model of Duchenne muscular dystrophy (DMD). E2f1-/-;mdx mice demonstrated a strong reduction of physiopathological signs of DMD, including preservation of muscle structure, decreased inflammatory profile, increased utrophin expression, resulting in better endurance and muscle contractile parameters, comparable to normal mdx mice. E2f1 deficiency in the mdx genetic background increased the oxidative metabolic gene program, mitochondrial activity and improved muscle functions. Interestingly, we observed increased E2F1 protein levels in DMD patients, suggesting that E2F1 might represent a promising target for the treatment of DMD.

  1. Iron-deficiency anemia in young working women can be reduced by increasing the consumption of cereal-based fermented foods or gooseberry juice at the workplace.

    PubMed

    Gopaldas, Tara

    2002-03-01

    This efficacy for both employers and employees (young working women 18 to 23 years of age) was undertaken to determine whether culturally acceptable dietary changes in lunches in the workplace and at home could bring about a behavioral change and improvement in their iron-deficiency anemia status. Maximum weight was given to increasing consumption of iddli, a popular cereal-based-fermented food, or of gooseberry juice. Four small factories were selected in periurban Bangalore, with a sample of 302 women. The 180-day interventions were supervised at the workplace. In unit 1 (72 women), the intervention consisted of iddli four times a week plus information, education, and communication (IEC) related to iron-deficiency anemia. Unit 2 (80 women) received 20 ml of gooseberry juice (containing 40 mg of vitamin C) three times a week plus IEC once a month. Women in unit 3 (70 women), the positive control, received 400 mg albendazole once plus ferrous sulfate tablets (60 mg elemental iron) two times a week. No IEC was given. Unit 4 (70 women) served as the negative control and received no intervention. The pre-post impact measures were dietary and nutrient intake, knowledge and practice, and hemoglobin status. In units 1, 2, and 3, the hemoglobin status of the women improved significantly from 11.10 to 12.30 g/dl, 11.20 to 12.70 g/dl, and 11.50 to 13.00 g/dl, respectively. In unit 4 there was no change: the values were 10.90 g/dl before and after intervention. The results show that the type of workplace lunch was of greater significance than IEC. Knowledge gains were impressive, but behavioral change was not sustained. It was concluded that the hemoglobin levels of the workers can easily be improved by cost-effective workplace lunches that also lead to better employer-employee relations.

  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 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

  3. [Vitamin deficiencies and hypervitaminosis].

    PubMed

    Mino, M

    1999-10-01

    There have recently been very few deficiencies with respect to fat soluble and water soluble vitamins in Japan All-trans-retinoic acid as induction or maintenance treatment improves disease free and overall survival against acute promyelocytic leukemia. In the isolated vitamin E deficiencies gene mutation has been cleared for alpha-tocopherol transferprotein. Recently, a relation of nutritional vitamin K intake and senile osteoporosis in women was epidemiologically demonstrated on a prospective study. Thiamin was yet noticed as development of deficiency in alcoholism, while the importance of supplemental folic acid during pregnancy has become especially clear in light of studies showing that folic acid supplements reduce the risk of neural tube defects in the fetus. With respect to hypervitaminosis, the Council for Responsible Nutrition (CRN), USA, has established safe intakes by identifying the NOAEL (No Observed Adverse Effect Level) and LOAEL (Lowest Observed Adverse Effect Level). Summaries of NOAEL and LOAEL for individual vitamins were shown.

  4. [Recombinant Escherichia coli strains deficient in mixed acid fermentation pathways and capable of rapid aerobic growth on glucose with a reduced Crabtree effect].

    PubMed

    Morzhakova, A A; Skorokhodova, A Iu; Gulevich, A Iu; Debabov, V G

    2013-01-01

    In this study, we constructed and characterized Escherichia coli strains deficient for mixed acid fermentation pathways, which are capable of rapid aerobic growth on glucose without pronounced bacterial Crabtree effect. The main pathways of production of acetic and lactic acids and ethanol in these strains were inactivated by a deletion of the ackA, pta, poxB, IdhA, and adhEgenes. The phosphoenolpyruvate-dependent phosphotransferase system of glucose transport and phosphorylation was inactivated in the strains by a deletion of the ptsG gene. The possibility of alternative transport and phosphorylation of the carbohydrate substrate was ensured in recombinants by constitutive expression of the galP and glk genes, which encode the low-affinity H+-symporter of D-galactose and glucokinase, respectively. SGMI.0DeltaptsG PtacgalP and SG M1.0DeltaptsG PIglk PtacgalP strains were capable of rapid aerobic growth in a minimal medium containing 2.0 and 10.0 g/l of glucose and secreted only small amounts of acetic acid and trace amounts of pyruvic acid.

  5. 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.

  6. Reduced neurotrophic factor level is the early event before the functional neuronal deficiency in high-fat diet induced obese mice.

    PubMed

    Wang, Huanhuan; Wang, Bing; Yin, Hongping; Zhang, Guoqing; Yu, Liping; Kong, Xiangmin; Yuan, Haiying; Fang, Xingyue; Liu, Qibing; Liu, Cuiqing; Shi, Liyun

    2017-02-01

    Neurodegeneration is considered one of the possible complications of high fat diet (HFD) induced obesity. Much evidence has shown the close relationship between HFD and dementia at comparatively later stage of neuronal injury. It is so far not clear that the initial events of neuronal injury resulting from HFD and obesity. In the present research, obese mouse model achieved by 3-month HFD was applied for the investigation of the possible neuronal deficiency before the obvious cognitive decline. We found that 3-month HFD has already increased the average level of body weight of mice. But almost no obvious cognitive defect was observed. At such time point, we detected the cleavage of amyloid precursor protein (APP), including the expression and maturation level of α- and β-secretase and proteolytic fragment soluble APP. Results showed similar readout between HFD and normal diet (ND) mice. Besides, neuronal inflammation and brain-blood barrier permeability were also detected. No obvious changes could be observed between HFD and ND mice. Surprisingly, the first detectable neuronal changes was showed to be the downregulation of some neurotrpic factors, like neuronal growth factor β and brain derived neurotrophic factor, together with the activity of specific receptors, like Trk receptor phosphorylation. All the data piled up indicated that the early neuronal change in HFD induced obese mice was the downregulation of some neurotrophic factors. The results may provide the potential clue to therapeutic and preventive strategy for HFD induced cognitive decline.

  7. Concomitant deficits in working memory and fear extinction are functionally dissociated from reduced anxiety in metabotropic glutamate receptor 7-deficient mice.

    PubMed

    Callaerts-Vegh, Zsuzsanna; Beckers, Tom; Ball, Simon M; Baeyens, Frank; Callaerts, Patrick F; Cryan, John F; Molnar, Elek; D'Hooge, Rudi

    2006-06-14

    Metabotropic glutamate receptor 7 (mGluR7), a receptor with a distinct brain distribution and a putative role in anxiety, emotional responding, and spatial working memory, could be an interesting therapeutic target for fear and anxiety disorders. mGluR7-deficient (mGluR7-/-) mice showed essentially normal performance in tests for neuromotor and exploratory activity and passive avoidance learning but prominent anxiolytic behavior in two anxiety tests. They showed a delayed learning curve during the acquisition of the hidden-platform water maze, and three interspersed probe trials indicated that mGluR7-/- mice were slower to acquire spatial information. Working memory in the water maze task and the radial arm maze was impaired in mGluR7-/- mice compared with mGluR7+/+. mGluR7-/- mice also displayed a higher resistance to extinction of fear-elicited response suppression in a conditioned emotional response protocol. In a non-fear-based water maze protocol, mGluR7-/- mice displayed similar delayed extinction. These observed behavioral changes are probably not attributable to changes in AMPA or NMDA receptor function because expression levels of AMPA and NMDA receptors were unaltered. Extinction of conditioned fear is an active and context-dependent form of inhibitory learning and an experimental model for therapeutic fear reduction. It appears to depend on glutamatergic and higher-level brain functions similar to those involved in spatial working memory but functionally dissociated from those that mediate constitutional responses in anxiety tests.

  8. Linoleic acid-rich fats reduce atherosclerosis development beyond its oxidative and inflammatory stress-increasing effect in apolipoprotein E-deficient mice in comparison with saturated fatty acid-rich fats.

    PubMed

    Sato, Masao; Shibata, Kenichi; Nomura, Run; Kawamoto, Daisuke; Nagamine, Rika; Imaizumi, Katsumi

    2005-12-01

    The relative benefit of replacing saturated fatty acid with linoleic acids is still being debated because a linoleic acid-enriched diet increases oxidative and inflammatory stresses, although it is associated with a reduction in serum cholesterol levels. The present study was conducted to evaluate the effect of dietary supplementation of linoleic acid-rich (HL) fat, compared with a saturated fatty acid-rich (SF) fat on atherosclerotic lesion areas, serum and liver cholesterol levels, oxidative stress (urinary isoprostanes and serum malondialdehayde) and inflammatory stress (expression of aortic monocyte chemoattractant protein-1; MCP-1) in apo E-deficient mice. Male and female apo E-deficient mice (8 weeks old; seven to eight per group) were fed an AIN-76-based diet containing SF fat (50 g palm oil and 50 g lard/kg) or HL fat (100 g high-linoleic safflower-seed oil/kg) for 9 weeks. Compared with the SF diet, the HL diet lowered atherosclerosis (P<0.05). It reduced serum total cholesterol levels (P<0.05), increased HDL-cholesterol levels (P<0.05) and lowered liver esterified cholesterol levels (P<0.01). The HL diet-fed mice showed increased expression of MCP-1 mRNA (P<0.05), serum levels of malondialdehayde (P<0.05) and urinary excretion of 2,3-dinor-5,6-dihydro-8-iso-prostaglandin F2alpha; P<0.05). These results suggest that having biomarkers in vivo for oxidative stress and inflammatory status of endothelial cells does not necessarily indicate predisposition to an increased lesion area in the aortic root in apo E-deficient mice fed an HL or SF diet.

  9. Triple-fortified rice containing vitamin A reduced marginal vitamin A deficiency and increased vitamin A liver stores in school-aged Thai children.

    PubMed

    Pinkaew, Siwaporn; Wegmuller, Rita; Wasantwisut, Emorn; Winichagoon, Pattanee; Hurrell, Richard F; Tanumihardjo, Sherry A

    2014-04-01

    Vitamin A (VA)-fortified rice is a potential intervention strategy to prevent VA deficiency in at-risk populations. Hot-extruded, triple-fortified rice grains with added VA, zinc, and iron were produced by hot extrusion technology and their ability to improve VA status was tested in Thai schoolchildren. The fortification levels were 10 mg of iron, 9 mg of zinc, and 1.05 mg of VA/g extruded rice. A paired stable isotope dilution technique with labeled ¹³C₂-retinyl acetate (¹³C-RID) was used to quantify VA pool size at the beginning and end of the feeding period. Fifty healthy schoolchildren with a serum retinol (SR) concentration of >0.7 μmol/L were randomly assigned to 2 groups to receive either triple-fortified rice (n = 25) or natural rice (n = 25) for 2 mo as part of the daily school meal. The fortified grains, mixed 1:50 with regular rice, were estimated to provide an extra 890 μg of VA/d, 5 d/wk. ¹³C₂-retinyl acetate (1.0 μmol) was administered orally to each child before and at the end of the feeding period to estimate total body reserves (TBRs) of VA, which increased significantly (P < 0.05) in the intervention group from 153 ± 66 μmol retinol at baseline to 269 ± 148 μmol retinol after 2 mo of feeding. There was no change in the TBRs of VA in the control group (108 ± 67 vs. 124 ± 89 μmol retinol) (P = 0.22). Serum retinol remained unchanged in both groups. We conclude that VA-fortified, hot-extruded rice is an efficacious vehicle to provide additional VA to at-risk populations, and that the efficacy of VA-fortified foods can be usefully monitored by the ¹³C-RID measurement of TBRs of VA but not by changes in SR concentration.

  10. 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

  11. Deficient nitric oxide responsible for reduced nerve blood flow in diabetic rats: effects of L-NAME, L-arginine, sodium nitroprusside and evening primrose oil.

    PubMed Central

    Omawari, N.; Dewhurst, M.; Vo, P.; Mahmood, S.; Stevens, E.; Tomlinson, D. R.

    1996-01-01

    1. This study examined the potential role of impaired nitric oxide production and response in the development of endoneurial ischaemia in experimental diabetes. Rats were anaesthetized (Na pentobarbitone 45 mg kg-1, diazepam 2 mg kg-1) for measurement of sciatic nerve laser Doppler flux and systemic arterial pressure. Drugs were administered into the sciatic endoneurium via a microinjector attached to a glass micropipette. 2. In two separate studies comparing diabetic rats (streptozotocin-induced; 8-10 wk duration) with controls, nerve Doppler flux in diabetic rats (Study 1, 116.6 +/- 40.4 and Study 2, 90.1 +/- 34.7 (s.d.) in arbitrary units) was about half that measured in controls (219.6 +/- 52.4 and 212.8 +/- 95.5 respectively; P < 0.005 for both). There were no significant differences between the two in systemic arterial pressure. 3. Inhibition of nitric oxide production by microinjection of 1 nmol L-NAME into the endoneurium halved flux in controls (to 126.3 +/- 41.3 in Study 1 and 102.1 +/- 38.9 in Study 2; both P < 0.001), with no significant effect in diabetic rats, indicating markedly diminished tonic nitric oxide production in the latter. D-NAME was without effect on nerve Doppler flux. 4. L-Arginine (100 nmol), injected after L-NAME, markedly increased flux in controls (by 65.8% (P < 0.03) and 97.8% (P < 0.01) in the two studies) and by proportionally similar amounts in diabetic rats [75.8% (P < 0.001) and 60.2% (P < 0.02)]. The nitro-donor, sodium nitroprusside (SNP; 10 nmol) had similar effects to L-arginine in both groups (increases of 66.0% in controls and 77.5% in diabetics; both P < 0.002). 5. A second diabetic group, treated with evening primrose oil performed exactly like control rats in respect of responses to L-NAME, L-arginine and SNP. 6. These findings implicate deficient nitric oxide in nerve ischaemia of diabetes and suggest correction thereof as a mechanism of action of evening primrose oil. PMID:8733594

  12. Stabilization of Oxygen-deficient Structure for Conducting Li4Ti5O12-δ by Molybdenum Doping in a Reducing Atmosphere

    PubMed Central

    Song, Hannah; Jeong, Tae-Gyung; Moon, Young Hoon; Chun, Ho-Hwan; Chung, Kyung Yoon; Kim, Hyung Sun; Cho, Byung Won; Kim, Yong-Tae

    2014-01-01

    Li4Ti5O12 (LTO) is recognized as being one of the most promising anode materials for high power Li ion batteries; however, its insulating nature is a major drawback. In recent years, a simple thermal treatment carried out in a reducing atmosphere has been shown to generate oxygen vacancies (VO) for increasing the electronic conductivity of this material. Such structural defects, however, lead to re-oxidization over time, causing serious deterioration in anode performance. Herein, we report a unique approach to increasing the electronic conductivity with simultaneous improvement in structural stability. Doping of LTO with Mo in a reducing atmosphere resulted in extra charges at Ti sites caused by charge compensation by the homogeneously distributed Mo6+ ions, being delocalized over the entire lattice, with fewer oxygen vacancies (VO) generated. Using this simple method, a marked increase in electronic conductivity was achieved, in addition to an extremely high rate capability, with no performance deterioration over time. PMID:24618982

  13. ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice.

    PubMed

    Terasaka, Naoki; Miyazaki, Atsuhiro; Kasanuki, Naomi; Ito, Kayoko; Ubukata, Naoko; Koieyama, Tadashi; Kitayama, Ken; Tanimoto, Tatsuo; Maeda, Naoyuki; Inaba, Toshimori

    2007-02-01

    The objective of the present study was to determine whether a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, pactimibe sulfate (CS-505), could reduce atherosclerotic lesions beyond and independent of the reduction achieved by cholesterol lowering alone from two different types of lesions. (1) Early lesion model. Twelve-week-old apolipoprotein E (apoE)(-/-) mice were treated with 0.03 or 0.1% (w/w) CS-505, 0.1 or 0.3% avasimibe (CI-1011), or 3% cholestyramine for 12 weeks. Each treatment significantly reduced plasma cholesterol by a similar degree (43-48%). The antiatherosclerotic activity of 0.1% CS-505, however, was more efficacious than the effects of the other treatments (90% versus 40-50%). (2) Advanced lesion model. Twenty-four-week-old apoE(-/-) mice were treated with 0.03 or 0.1% CS-505 or 0.1% CI-1011 for 12 weeks. CS-505 at 0.1% revealed enhanced lesion reduction compared with 0.1% CI-1011 (77% versus 54%), whereas the plasma cholesterol-lowering effect of 0.1% CS-505 was almost the same as that of 0.1% CI-1011. Furthermore, immunohistochemical analysis demonstrated that CS-505 significantly reduced the number of macrophages and expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13. These data indicate that CS-505 can reduce and stabilize atherosclerotic lesions. This antiatherosclerotic activity is exerted via both cholesterol lowering and direct ACAT inhibition in plaque macrophages.

  14. SIZ1 deficiency causes reduced stomatal aperture and enhanced drought tolerance via controlling salicylic acid-induced accumulation of reactive oxygen species in Arabidopsis.

    PubMed

    Miura, Kenji; Okamoto, Hiroyuki; Okuma, Eiji; Shiba, Hayato; Kamada, Hiroshi; Hasegawa, Paul M; Murata, Yoshiyuki

    2013-01-01

    Transpiration and gas exchange occur through stomata. Thus, the control of stomatal aperture is important for the efficiency and regulation of water use, and for the response to drought. Here, we demonstrate that SIZ1-mediated endogenous salicylic acid (SA) accumulation plays an important role in stomatal closure and drought tolerance. siz1 reduced stomatal apertures. The reduced stomatal apertures of siz1 were inhibited by the application of peroxidase inhibitors, salicylhydroxamic acid and azide, which inhibits SA-dependent reactive oxygen species (ROS) production, but not by an NADPH oxidase inhibitor, diphenyl iodonium chloride, which inhibits ABA-dependent ROS production. Furthermore, the introduction of nahG into siz1, which reduces SA accumulation, restored stomatal opening. Stomatal closure is generally induced by water deficit. The siz1 mutation caused drought tolerance, whereas nahG siz1 suppressed the tolerant phenotype. Drought stresses also induced expression of SA-responsive genes, such as PR1 and PR2. Furthermore, other SA-accumulating mutants, cpr5 and acd6, exhibited stomatal closure and drought tolerance, and nahG suppressed the phenotype of cpr5 and acd6, as did siz1 and nahG siz1. Together, these results suggest that SIZ1 negatively affects stomatal closure and drought tolerance through the accumulation of SA.

  15. Plasminogen deficiency.

    PubMed

    Celkan, Tiraje

    2017-01-01

    Plasminogen plays an important role in fibrinolysis as well as wound healing, cell migration, tissue modeling and angiogenesis. Congenital plasminogen deficiency is a rare autosomal recessive disorder that leads to the development of thick, wood-like pseudomembranes on mucosal surfaces, mostly seen in conjunctivas named as ''ligneous conjunctivitis''. Local conjunctival use of fresh frozen plazma (FFP) in combination with other eye medications such as cyclosporin and artificial tear drops may relieve the symptoms. Topical treatment with plasminogen eye drops is the most promising treatment that is not yet available in Turkey.

  16. SBDS-Deficient Cells Have an Altered Homeostatic Equilibrium due to Translational Inefficiency Which Explains their Reduced Fitness and Provides a Logical Framework for Intervention

    PubMed Central

    Miluzio, Annarita; Russo, Arianna; Ricciardi, Sara; Khanim, Farhat; Cheroni, Cristina; Alfieri, Roberta; Mancino, Marilena; Gorrini, Chiara; Peluso, Ivana; Pagani, Massimiliano; Medina, Diego L.

    2017-01-01

    Ribosomopathies are a family of inherited disorders caused by mutations in genes necessary for ribosomal function. Shwachman-Diamond Bodian Syndrome (SDS) is an autosomal recessive disease caused, in most patients, by mutations of the SBDS gene. SBDS is a protein required for the maturation of 60S ribosomes. SDS patients present exocrine pancreatic insufficiency, neutropenia, chronic infections, and skeletal abnormalities. Later in life, patients are prone to myelodisplastic syndrome and acute myeloid leukemia (AML). It is unknown why patients develop AML and which cellular alterations are directly due to the loss of the SBDS protein. Here we derived mouse embryonic fibroblast lines from an SbdsR126T/R126T mouse model. After their immortalization, we reconstituted them by adding wild type Sbds. We then performed a comprehensive analysis of cellular functions including colony formation, translational and transcriptional RNA-seq, stress and drug sensitivity. We show that: 1. Mutant Sbds causes a reduction in cellular clonogenic capability and oncogene-induced transformation. 2. Mutant Sbds causes a marked increase in immature 60S subunits, limited impact on mRNA specific initiation of translation, but reduced global protein synthesis capability. 3. Chronic loss of SBDS activity leads to a rewiring of gene expression with reduced ribosomal capability, but increased lysosomal and catabolic activity. 4. Consistently with the gene signature, we found that SBDS loss causes a reduction in ATP and lactate levels, and increased susceptibility to DNA damage. Combining our data, we conclude that a cell-specific fragile phenotype occurs when SBDS protein drops below a threshold level, and propose a new interpretation of the disease. PMID:28056084

  17. SBDS-Deficient Cells Have an Altered Homeostatic Equilibrium due to Translational Inefficiency Which Explains their Reduced Fitness and Provides a Logical Framework for Intervention.

    PubMed

    Calamita, Piera; Miluzio, Annarita; Russo, Arianna; Pesce, Elisa; Ricciardi, Sara; Khanim, Farhat; Cheroni, Cristina; Alfieri, Roberta; Mancino, Marilena; Gorrini, Chiara; Rossetti, Grazisa; Peluso, Ivana; Pagani, Massimiliano; Medina, Diego L; Rommens, Johanna; Biffo, Stefano

    2017-01-01

    Ribosomopathies are a family of inherited disorders caused by mutations in genes necessary for ribosomal function. Shwachman-Diamond Bodian Syndrome (SDS) is an autosomal recessive disease caused, in most patients, by mutations of the SBDS gene. SBDS is a protein required for the maturation of 60S ribosomes. SDS patients present exocrine pancreatic insufficiency, neutropenia, chronic infections, and skeletal abnormalities. Later in life, patients are prone to myelodisplastic syndrome and acute myeloid leukemia (AML). It is unknown why patients develop AML and which cellular alterations are directly due to the loss of the SBDS protein. Here we derived mouse embryonic fibroblast lines from an SbdsR126T/R126T mouse model. After their immortalization, we reconstituted them by adding wild type Sbds. We then performed a comprehensive analysis of cellular functions including colony formation, translational and transcriptional RNA-seq, stress and drug sensitivity. We show that: 1. Mutant Sbds causes a reduction in cellular clonogenic capability and oncogene-induced transformation. 2. Mutant Sbds causes a marked increase in immature 60S subunits, limited impact on mRNA specific initiation of translation, but reduced global protein synthesis capability. 3. Chronic loss of SBDS activity leads to a rewiring of gene expression with reduced ribosomal capability, but increased lysosomal and catabolic activity. 4. Consistently with the gene signature, we found that SBDS loss causes a reduction in ATP and lactate levels, and increased susceptibility to DNA damage. Combining our data, we conclude that a cell-specific fragile phenotype occurs when SBDS protein drops below a threshold level, and propose a new interpretation of the disease.

  18. 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

  19. Nonclassical export pathway: overexpression of NCE102 reduces protein and DNA damage and prolongs lifespan in an SGS1 deficient Saccharomyces cerevisiae.

    PubMed

    Desmyter, Liesbeth; Verstraelen, Jan; Dewaele, Sylviane; Libert, Claude; Contreras, Roland; Chen, Cuiying

    2007-10-01

    In this study, we used our recently developed screening method, Bud-Scar-based Screening (BSS), to screen a yeast cDNA expression library in an SGS1 deletion BY4742 yeast strain. One gene involved in a nonclassical export pathway, NCE102, was found to extend the life span of Deltasgs1 yeast. Deletion of NCE102 in a wild type yeast strain increased its sensitivity to oxidative stress upon diethylmaleate (DEM) treatment but did not shorten its lifespan, indicating that this gene is not essential in determining yeast lifespan. Transformation of NCE102 into either Deltance102 or Deltasgs1 strains could rescue its tolerance to DEM stress, indicating that NCE102 is protective during oxidative stress. Moreover, overexpression of NCE102 in Deltasgs1 strain leads to reduced protein damage. However, overexpression of NCE102 in wild type yeast strain BY4742 neither protected against oxidative stress due to DEM nor extended yeast lifespan compared to its parental wild type strain, indicating that nonclassical export is redundant and DNA repair is fully sufficient in the wild type strain. We therefore demonstrate that a nonclassical export pathway functions as an alternative clearance/detoxification pathway to eliminate damaged material, when the basic repair pathway is not sufficient.

  20. GATA1-Deficient Dendritic Cells Display Impaired CCL21-Dependent Migration toward Lymph Nodes Due to Reduced Levels of Polysialic Acid.

    PubMed

    Scheenstra, Maaike R; De Cuyper, Iris M; Branco-Madeira, Filipe; de Bleser, Pieter; Kool, Mirjam; Meinders, Marjolein; Hoogenboezem, Mark; Mul, Erik; Wolkers, Monika C; Salerno, Fiamma; Nota, Benjamin; Saeys, Yvan; Klarenbeek, Sjoerd; van IJcken, Wilfred F J; Hammad, Hamida; Philipsen, Sjaak; van den Berg, Timo K; Kuijpers, Taco W; Lambrecht, Bart N; Gutiérrez, Laura

    2016-12-01

    Dendritic cells (DCs) play a pivotal role in the regulation of the immune response. DC development and activation is finely orchestrated through transcriptional programs. GATA1 transcription factor is required for murine DC development, and data suggest that it might be involved in the fine-tuning of the life span and function of activated DCs. We generated DC-specific Gata1 knockout mice (Gata1-KO(DC)), which presented a 20% reduction of splenic DCs, partially explained by enhanced apoptosis. RNA sequencing analysis revealed a number of deregulated genes involved in cell survival, migration, and function. DC migration toward peripheral lymph nodes was impaired in Gata1-KO(DC) mice. Migration assays performed in vitro showed that this defect was selective for CCL21, but not CCL19. Interestingly, we show that Gata1-KO(DC) DCs have reduced polysialic acid levels on their surface, which is a known determinant for the proper migration of DCs toward CCL21.

  1. 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 Central

    Myers, Kasiani C; Howell, Jonathan C.; Wallace, Gregory; Dandoy, Christopher; El-Bietar, Javier; Lane, Adam; Davies, Stella M.; Jodele, Sonata; Rose, Susan R.

    2016-01-01

    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. Analysis was grouped by age (<2y and ≥2y), and diagnosis (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), while older subjects had worsening (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 mean BMI Z-score of 1.20 vs. 0.64, p=0.02, likewise in 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 standard chemotherapy protocols. PMID:26974276

  2. IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients.

    PubMed

    Weller, Sandra; Bonnet, Mélanie; Delagreverie, Héloïse; Israel, Laura; Chrabieh, Maya; Maródi, László; Rodriguez-Gallego, Carlos; Garty, Ben-Zion; Roifman, Chaim; Issekutz, Andrew C; Zitnik, Simona Eva; Hoarau, Cyrille; Camcioglu, Yildiz; Vasconcelos, Júlia; Rodrigo, Carlos; Arkwright, Peter D; Cerutti, Andrea; Meffre, Eric; Zhang, Shen-Ying; Alcais, Alexandre; Puel, Anne; Casanova, Jean-Laurent; Picard, Capucine; Weill, Jean-Claude; Reynaud, Claude-Agnès

    2012-12-13

    We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor-associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM(+)IgD(+)CD27(+) but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM(+)IgD(+)CD27(+) B cells were not affected in these patients. In contrast, the numbers of IgM(+)IgD(+)CD27(+) B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B-dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM(+)IgD(+)CD27(+) compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM(+)IgD(+)CD27(+) B cells in humans.

  3. Vitamin Deficiency Anemia

    MedlinePlus

    Vitamin deficiency anemia Overview By Mayo Clinic Staff Vitamin deficiency anemia is a lack of healthy red blood ... normal amounts of certain vitamins. Vitamins linked to vitamin deficiency anemia include folate, vitamin B-12 and vitamin ...

  4. Alpha-1 Antitrypsin Deficiency

    MedlinePlus

    ... 1 antitrypsin (an-tee-TRIP-sin) deficiency, or AAT deficiency, is a condition that raises your risk ... and other diseases. Some people who have severe AAT deficiency develop emphysema (em-fi-SE-ma)—often ...

  5. 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

    2015-11-27

    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.

  6. 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

    2015-08-06

    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

  7. Sigma-1 (σ₁) receptor deficiency reduces β-amyloid(25-35)-induced hippocampal neuronal cell death and cognitive deficits through suppressing phosphorylation of the NMDA receptor NR2B.

    PubMed

    Yin, Jun; Sha, Sha; Chen, Tingting; Wang, Conghui; Hong, Juan; Jie, Pinghui; Zhou, Rong; Li, Lin; Sokabe, Masahiro; Chen, Ling

    2015-02-01

    In early Alzheimer's disease (AD) brain, reduction of sigma-1 receptors (σ1R) is detected. In this study, we employed male heterozygous σ1R knockout (σ1R(+/-)) mice showing normal cognitive performance to investigate association of σ1R deficiency with AD risk. Herein we report that a single injection (i.c.v.) of Aβ(25-35) impaired spatial memory with approximately 25% death of pyramidal cells in the hippocampal CA1 region of WT mice (Aβ(25-35)-WT mice), whereas it did not cause such impairments in σ1R(+/-) mice (Aβ(25-35)-σ1R(+/-) mice). Compared with WT mice, Aβ(25-35)-WT mice showed increased levels of NMDA-activated currents (INMDA) and NR2B phosphorylation (phospho-NR2B) in the hippocampal CA1 region at 48 h after Aβ25-35-injection (post-Aβ(25-35)) followed by approximately 40% decline at 72 h post-Aβ(25-35) of their respective control levels, which was inhibited by the σ1R antagonist NE100. In Aβ(25-35)-WT mice, the administration of NR2B inhibitor Ro25-6981 or NE100 on day 1-4 post-Aβ(25-35) attenuated the memory deficits and loss of pyramidal cells. By contrast, Aβ(25-35)-σ1R(+/-) mice showed a slight increase in the INMDA density and the phospho-NR2B at 48 h or 72 h post-Aβ25-35 compared to σ1R(+/-) mice. Treatment with σ1R agonist PRE084 in Aβ(25-35)-σ1R(+/-) mice caused the same changes in the INMDA density and the phospho-NR2B as those in Aβ(25-35)-WT mice. Furthermore, Aβ(25-35)-σ1R(+/-) mice treated with the NMDA receptor agonist NMDA or PRE084 on day 1-4 post-Aβ(25-35) showed a loss of neuronal cells and memory impairment. These results indicate that the σ1R deficiency can reduce Aβ(25-35)-induced neuronal cell death and cognitive deficits through suppressing Aβ(25-35)-enhanced NR2B phosphorylation.

  8. 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.

  9. Living with Alpha-1 Antitrypsin Deficiency

    MedlinePlus

    ... information about the benefits of physical activity. Reduce Stress Learning how to manage stress, relax, and cope with problems can improve your ... and muscle relaxation—can help you cope with stress. Emotional Issues and Support Living with AAT deficiency ...

  10. 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.

  11. Pyruvate kinase deficiency

    MedlinePlus

    ... the second most common cause, after glucose-6-phosphate dehydrogenase (G6PD) deficiency . PKD is found in people ... Read More Anemia Autosomal recessive Enzyme Glucose-6-phosphate dehydrogenase deficiency Hemolytic anemia Review Date 10/27/ ...

  12. Vitamin D Deficiency

    MedlinePlus

    Vitamin D Deficiency A Patient’s Guide Vitamin D helps the body absorb calcium. Along with calcium, it is vital ... for physicians about testing for, treating, and preventing vitamin D deficiency. These guidelines do not apply to people who ...

  13. 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) ...

  14. Epidemiology of iodine deficiency.

    PubMed

    Vanderpump, Mark P

    2017-04-01

    Iodine is an essential component of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) produced by the thyroid gland. Iodine deficiency impairs thyroid hormone production and has adverse effects throughout life, particularly early in life as it impairs cognition and growth. Iodine deficiency remains a significant problem despite major national and international efforts to increase iodine intake, primarily through the voluntary or mandatory iodization of salt. Recent epidemiological data suggest that iodine deficiency is an emerging issue in industrialized countries, previously thought of as iodine-sufficient. International efforts to control iodine deficiency are slowing, and reaching the third of the worldwide population that remains deficient poses major challenges.

  15. [Glucose-6-phosphate dehydrogenase deficiency in Japan].

    PubMed

    Kanno, Hitoshi; Ogura, Hiromi

    2015-07-01

    In the past 10 years, we have diagnosed congenital hemolytic anemia in 294 patients, approximately 33% of whom were found to have glucose-6-phosphate dehydrogenase (G6PD) deficiency. It is becoming more common for Japanese to marry people of other ethnic origins, such that G6PD deficiency is becoming more prevalent in Japan. Japanese G6PD deficiency tends to be diagnosed in the neonatal period due to severe jaundice, while G6PD-deficient patients with foreign ancestors tend to be diagnosed at the onset of an acute hemolytic crisis before the age of six. It is difficult to predict the clinical course of each patient by G6PD activity, reduced glutathione content, or the presence/absence of severe neonatal jaundice. We propose that both neonatal G6PD screening and systematic analyses of G6PD gene mutations may be useful for personalized management of patients with G6PD-deficient hemolytic anemia.

  16. Role of 5-lipoxygenase pathway in the regulation of RAW 264.7 macrophage proliferation.

    PubMed

    Nieves, Diana; Moreno, Juan José

    2006-10-16

    Arachidonic acid (AA) metabolites control cell proliferation, among other physiologic functions. RAW 264.7 macrophages can metabolise AA through the cyclooxygenase and lipoxygenase (LOX) pathways. We aimed to study the role of AA-metabolites derived from 5-LOX in the control of RAW 264.7 macrophage growth. Our results show that zileuton, a specific 5-LOX inhibitor, and nordihydroguaiaretic acid (NDGA), a non-specific LOX inhibitor, inhibit cell proliferation and [(3)H]-thymidine incorporation in a concentration-dependent fashion. Growth inhibition induced by NDGA can be explained by an apoptotic process, while zileuton does not seem to induce apoptosis. Moreover, these treatments delay the cell cycle, as analysed by flow cytometry. On the other hand, the leukotriene (LT) B(4) receptor antagonist U-75302, the LTD(4) receptor antagonists LY-171883 and MK-571, and the cysteinyl-LT receptor antagonist REV-5901 also inhibit cell proliferation and [(3)H]-thymidine incorporation in a concentration-dependent manner, and delay the RAW 264.7 cell cycle. However, these antagonists did not induce annexin V staining, caspase activation or DNA fragmentation. Furthermore, we demonstrated that exogenous addition of LTB(4) or LTD(4) revert the cell growth inhibition induced by zileuton or the leukotriene receptor antagonists mentioned above. Finally, we observed that LTB(4) and LTD(4), in the absence of growth factors, have pro-proliferative effects on macrophages, and we obtained preliminary evidences that this effect could be through mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. In conclusion, our results show that the interaction between LTB(4) and LTD(4) with its respective receptor is involved in the control of RAW 264.7 macrophage growth.

  17. Altered gravity modulates 5-lipoxygenase in human erythroleukemia K562 cells.

    PubMed

    Maccarrone, M; Putti, S; Finazzi Agro, A

    1998-07-01

    Mammalian lipoxygenases catalyse the first committed step in the so-called "arachidonate cascade", leading to the production of potent bioactive molecules, such as leukotrienes, lipoxins and hepoxilins. Leukotrienes interact with G protein-couple receptors involved in neuronal plasticity and T lymphocyte activation, lipoxins activate leukocytes, hepoxilines control the insulin release and stimulate the phospholipase C. Lipoxygenase (linoleate:oxygen oxidoreductase; E.C. 1.13.11.34; 5-LOX) are responsible for lymphocyte maturation and programmed death (apoptosis) of neuronal cells. Therefore, 5-LOX might be Space relevant, because among the most striking effects of Space enviroment are indeed those on T lymphocyte activation, neuronal cell growth and suspectedly apoptosis. In this study, the possible effects of the force of gravity on the activity and expression of 5-LOX have been investigated by subjecting human erythroleukemia K562 cells to simulated hypogravity or hypergravity.

  18. Discovery of a novel activator of 5-lipoxygenase from an anacardic acid derived compound collection

    PubMed Central

    Wisastra, Rosalina; Kok, Petra A.M; Eleftheriadis, Nikolaos; Baumgartner, Matthew P.; Camacho, Carlos J.; Haisma, Hidde J.; Dekker, Frank J.

    2013-01-01

    Lipoxygenases (LOXs) and cyclooxygenases (COXs) metabolize poly-unsaturated fatty acids into inflammatory signaling molecules. Modulation of the activity of these enzymes may provide new approaches for therapy of inflammatory diseases. In this study, we screened novel anacardic acid derivatives as modulators of human 5-LOX and COX-2 activity. Interestingly, a novel salicylate derivative 23a was identified as a surprisingly potent activator of human 5-LOX. This compound showed both non-competitive activation towards the human 5-LOX activator adenosine triphosphate (ATP) and non-essential mixed type activation against the substrate linoleic acid, while having no effect on the conversion of the substrate arachidonic acid. The kinetic analysis demonstrated a non-essential activation of the linoleic acid conversion with a KA of 8.65 μM, αKA of 0.38 μM and a β value of 1.76. It is also of interest that a comparable derivative 23d showed a mixed type inhibition for linoleic acid conversion. These observations indicate the presence of an allosteric binding site in human 5-LOX distinct from the ATP binding site. The activatory and inhibitory behavior of 23a and 23d on the conversion of linoleic compared to arachidonic acid are rationalized by docking studies, which suggest that the activator 23a stabilizes linoleic acid, whereas the larger inhibitor 23d blocks the enzyme active site. PMID:24231650

  19. 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

  20. Colour vision deficiency.

    PubMed

    Simunovic, M P

    2010-05-01

    Colour vision deficiency is one of the commonest disorders of vision and can be divided into congenital and acquired forms. Congenital colour vision deficiency affects as many as 8% of males and 0.5% of females--the difference in prevalence reflects the fact that the commonest forms of congenital colour vision deficiency are inherited in an X-linked recessive manner. Until relatively recently, our understanding of the pathophysiological basis of colour vision deficiency largely rested on behavioural data; however, modern molecular genetic techniques have helped to elucidate its mechanisms. The current management of congenital colour vision deficiency lies chiefly in appropriate counselling (including career counselling). Although visual aids may be of benefit to those with colour vision deficiency when performing certain tasks, the evidence suggests that they do not enable wearers to obtain normal colour discrimination. In the future, gene therapy remains a possibility, with animal models demonstrating amelioration following treatment.

  1. Acquired color vision deficiency.

    PubMed

    Simunovic, Matthew P

    2016-01-01

    Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations.

  2. 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

  3. Autism and Folate Deficiency

    DTIC Science & Technology

    2010-05-01

    W81XWH-09-1-0246 TITLE: Autism and Folate Deficiency PRINCIPAL INVESTIGATOR: Richard H. Finnell, Ph.D...5a. CONTRACT NUMBER W81XWH-09-1-0246 Autism and Folate Deficiency 5b. GRANT NUMBER AR080064-Concept Award 5c. PROGRAM ELEMENT NUMBER...risk factor for autism : alterations in m ethionine metabolism in autistic patients may be due to a functional folate deficiency, and folate receptor

  4. 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...

  5. 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…

  6. 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…

  7. 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.

  8. 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.

  9. Iodine deficiency: Clinical implications.

    PubMed

    Niwattisaiwong, Soamsiri; Burman, Kenneth D; Li-Ng, Melissa

    2017-03-01

    Iodine is crucial for thyroid hormone synthesis and fetal neurodevelopment. Major dietary sources of iodine in the United States are dairy products and iodized salt. Potential consequences of iodine deficiency are goiter, hypothyroidism, cretinism, and impaired cognitive development. Although iodine status in the United States is considered sufficient at the population level, intake varies widely across the population, and the percentage of women of childbearing age with iodine deficiency is increasing. Physicians should be aware of the risks of iodine deficiency and the indications for iodine supplementation, especially in women who are pregnant or lactating.

  10. Vitamin D deficiency and diabetes.

    PubMed

    Berridge, Michael J

    2017-03-24

    Vitamin D deficiency has been linked to the onset of diabetes. This review summarizes the role of Vitamin D in maintaining the normal release of insulin by the pancreatic beta cells (β-cells). Diabetes is initiated by the onset of insulin resistance. The β-cells can overcome this resistance by releasing more insulin, thus preventing hyperglycaemia. However, as this hyperactivity increases, the β-cells experience excessive Ca(2+) and reactive oxygen species (ROS) signalling that results in cell death and the onset of diabetes. Vitamin D deficiency contributes to both the initial insulin resistance and the subsequent onset of diabetes caused by β-cell death. Vitamin D acts to reduce inflammation, which is a major process in inducing insulin resistance. Vitamin D maintains the normal resting levels of both Ca(2+) and ROS that are elevated in the β-cells during diabetes. Vitamin D also has a very significant role in maintaining the epigenome. Epigenetic alterations are a feature of diabetes by which many diabetes-related genes are inactivated by hypermethylation. Vitamin D acts to prevent such hypermethylation by increasing the expression of the DNA demethylases that prevent hypermethylation of multiple gene promoter regions of many diabetes-related genes. What is remarkable is just how many cellular processes are maintained by Vitamin D. When Vitamin D is deficient, many of these processes begin to decline and this sets the stage for the onset of diseases such as diabetes.

  11. Iron deficiency anemia

    MedlinePlus

    ... GM. Disorders of iron homeostasis: iron deficiency and overload. In: Hoffman R, Benz EJ Jr, Silberstein LE, ... to achieve this important distinction for online health information and services. Learn more about A.D.A. ...

  12. [Selenium deficiency in pregnancy?].

    PubMed

    Lechner, W; Jenewein, I; Ritzberger, G; Sölder, E; Waitz-Penz, A; Schirmer, M; Abfalter, E

    1990-07-15

    Selenium content was investigated by atomic absorbtion spectroscopy in 32 normal pregnant women in the 38th-42, week of pregnancy. In congruence with other investigations from middle and northern Europe, selenium deficiency was stated in all of the patients.

  13. Adenine phosphoribosyltransferase deficiency.

    PubMed

    Bollée, Guillaume; Harambat, Jérôme; Bensman, Albert; Knebelmann, Bertrand; Daudon, Michel; Ceballos-Picot, Irène

    2012-09-01

    Complete adenine phosphoribosyltransferase (APRT) deficiency is a rare inherited metabolic disorder that leads to the formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine. The low solubility of DHA results in precipitation of this compound and the formation of urinary crystals and stones. The disease can present as recurrent urolithiasis or nephropathy secondary to crystal precipitation into renal parenchyma (DHA nephropathy). The diagnostic tools available-including stone analysis, crystalluria, and APRT activity measurement-make the diagnosis easy to confirm when APRT deficiency is suspected. However, the disease can present at any age, and the variability of symptoms can present a diagnostic challenge to many physicians. The early recognition and treatment of APRT deficiency are of crucial importance for preventing irreversible loss of renal function, which still occurs in a non-negligible proportion of cases. This review summarizes the genetic and metabolic mechanisms underlying stone formation and renal disease, along with the diagnosis and management of APRT deficiency.

  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. Factor VII deficiency

    MedlinePlus

    ... if one or more of these factors are missing or are not functioning like they should. Factor VII is one such coagulation factor. Factor VII deficiency runs in families (inherited) and is very rare. Both parents must ...

  16. Factor II deficiency

    MedlinePlus

    ... if one or more of these factors are missing or are not functioning like they should. Factor II is one such coagulation factor. Factor II deficiency runs in families (inherited) and is very rare. Both parents must ...

  17. Vitamin D deficiency

    PubMed Central

    Gani, Linsey Utami; How, Choon How

    2015-01-01

    Vitamin D deficiency is common and may contribute to osteopenia, osteoporosis and falls risk in the elderly. Screening for vitamin D deficiency is important in high-risk patients, especially for patients who suffered minimal trauma fractures. Vitamin D deficiency should be treated according to the severity of the deficiency. In high-risk adults, follow-up serum 25-hydroxyvitamin D concentration should be measured 3–4 months after initiating maintenance therapy to confirm that the target level has been achieved. All patients should maintain a calcium intake of at least 1,000 mg for women aged ≤ 50 years and men ≤ 70 years, and 1,300 mg for women > 50 years and men > 70 years. PMID:26311908

  18. Cerebral creatine deficiencies: a group of treatable intellectual developmental disorders.

    PubMed

    Stockler-Ipsiroglu, Sylvia; van Karnebeek, Clara D M

    2014-07-01

    Currently there are 91 treatable inborn errors of metabolism that cause intellectual developmental disorders. Cerebral creatine deficiencies (CDD) comprise three of these: arginine: glycine amidinotransferase [AGAT], guanidinoacetate methyltransferase [GAMT], and X-linked creatine transporter deficiency [SLC6A8]. Intellectual developmental disorder and cerebral creatine deficiency are the hallmarks of CDD. Additional clinical features include prominent speech delay, autism, epilepsy, extrapyramidal movement disorders, and signal changes in the globus pallidus. Patients with GAMT deficiency exhibit the most severe clinical spectrum. Myopathy is a distinct feature in AGAT deficiency. Guanidinoacetate (GAA) is the immediate product in the creatine biosynthetic pathway. Low GAA concentrations in urine, plasma, and cerebrospinal fluid are characteristic diagnostic markers for AGAT deficiency, while high GAA concentrations are characteristic markers for GAMT deficiency. An elevated ratio of urinary creatine /creatinine excretion serves as a diagnostic marker in males with SLC6A8 deficiency. Treatment strategies include oral supplementation of high-dose creatine-monohydrate for all three CDD. Guanidinoacetate-reducing strategies (high-dose ornithine, arginine-restricted diet) are additionally employed in GAMT deficiency. Supplementation of substrates for intracerebral creatine synthesis (arginine, glycine) has been used additionally to treat SLC6A8 deficiency. Early recognition and treatment improves outcomes. Normal outcomes in neonatally ascertained siblings from index families with AGAT and GAMT deficiency suggest a potential benefit of newborn screening for these disorders.

  19. Recognition and management of vitamin D deficiency.

    PubMed

    Bordelon, Paula; Ghetu, Maria V; Langan, Robert C

    2009-10-15

    Vitamin D deficiency affects persons of all ages. Common manifestations of vitamin D deficiency are symmetric low back pain, proximal muscle weakness, muscle aches, and throbbing bone pain elicited with pressure over the sternum or tibia. A 25-hydroxyvitamin D level should be obtained in patients with suspected vitamin D deficiency. Deficiency is defined as a serum 25-hydroxyvitamin D level of less than 20 ng per mL (50 nmol per L), and insufficiency is defined as a serum 25-hydroxyvitamin D level of 20 to 30 ng per mL (50 to 75 nmol per L). The goal of treatment is to normalize vitamin D levels to relieve symptoms and decrease the risk of fractures, falls, and other adverse health outcomes. To prevent vitamin D deficiency, the American Academy of Pediatrics recommends that infants and children receive at least 400 IU per day from diet and supplements. Evidence shows that vitamin D supplementation of at least 700 to 800 IU per day reduces fracture and fall rates in adults. In persons with vitamin D deficiency, treatment may include oral ergocalciferol (vitamin D2) at 50,000 IU per week for eight weeks. After vitamin D levels normalize, experts recommend maintenance dosages of cholecalciferol (vitamin D3) at 800 to 1,000 IU per day from dietary and supplemental sources.

  20. Congenital prothrombin deficiency.

    PubMed

    Lancellotti, Stefano; De Cristofaro, Raimondo

    2009-06-01

    Prothrombin deficiency is among the rarest inherited coagulation disorders, with a prevalence of approximately 1:2,000,000. Two main phenotypes can be distinguished: (1) hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of activity and antigen; and (2) dysprothrombinemia (type II deficiency), characterized by the normal or near-normal synthesis of a dysfunctional protein. In some cases, hypoprothrombinemia associated with dysprothrombinemia was also described in compound heterozygous defects. No living patient with undetectable plasma prothrombin has been reported to date. Prothrombin is encoded by a gene of approximately 21 kb located on chromosome 11 and containing 14 exons. Forty different mutations have been identified and characterized in prothrombin deficiency. Many of them surround the catalytic site, whereas another "hot spot" is localized in the recognition domain called anion binding exosite I, also called fibrinogen recognition site. Recently, mutations were identified also in the Na (+)-binding loop and in the light A-chain of thrombin. Most hypoprothrombinemia-associated mutations are missense, but there are also nonsense mutations leading to stop codons and one single nucleotide deletion. Finally, the main aspects of clinical manifestations and therapy of congenital prothrombin deficiency are presented and discussed.

  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.

  2. CoQ10 Deficiency Is Not a Common Finding in GLUT1 Deficiency Syndrome.

    PubMed

    Barca, Emanuele; Tang, Maoxue; Kleiner, Giulio; Engelstad, Kristin; DiMauro, Salvatore; Quinzii, Catarina M; De Vivo, Darryl C

    2016-01-01

    CoQ10 deficiency has been recently described in tissues of a patient with GLUT1 deficiency syndrome. Here, we investigated patients and mice with GLUT1 deficiency in order to determine whether low CoQ is a recurrent biochemical feature of this disorder, to justify CoQ10 supplementation as therapeutic option.CoQ10 levels were investigated in plasma, white blood cells, and skin fibroblasts of 16 patients and healthy controls and in the brain, cerebellum, liver, kidney, muscle, and plasma of 4-month-old GLUT1 mutant and control mice.CoQ10 levels in plasma did not show any difference compared with controls. Since most of the patients studied were on a ketogenic diet, which can alter CoQ10 content in plasma, we also analyzed white blood cells and cultured skin fibroblasts. Again, we found no differences. In mice, we found slightly reduced CoQ in the cerebellum, likely an epiphenomenon, and activity of the mitochondrial respiratory chain enzymes was normal.Our data from GLUT1 deficiency patients and from GLUT1 model mice fail to support CoQ10 deficiency as a common finding in GLUT1 deficiency, suggesting that CoQ deficiency is not a direct biochemical consequence of defective glucose transport caused by molecular defects in the SLC2A1 gene.

  3. 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

    Lopez, Adam M; Posey, Kenneth S; Turley, Stephen D

    2014-11-07

    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 1.9mg 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.

  4. 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

  5. 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.

  6. Natural killer cell deficiency.

    PubMed

    Orange, Jordan S

    2013-09-01

    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 persons 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 more than 40 presently known to impair NK cells. However, the abnormality of NK cells in certain cases represents the majority immunologic defect. In aggregate, these conditions are termed NK cell deficiency. Recent advances have added clarity to this diagnosis and identified defects in 3 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.

  7. Multiple sulfatase deficiency.

    PubMed

    Soong, B W; Casamassima, A C; Fink, J K; Constantopoulos, G; Horwitz, A L

    1988-08-01

    Multiple sulfatase deficiency is an inherited disorder characterized by a deficiency of several sulfatases and the accumulation of sulfatides, glycosaminoglycans, sphingolipids, and steroid sulfates in tissues and body fluids. The clinical manifestations represent the summation of two diseases: late infantile metachromatic leukodystrophy and mucopolysaccharidosis. We present a 9-year-old girl with a phenotype similar to a mucopolysaccharidosis: short stature, microcephaly, and mild facial dysmorphism, along with dysphagia, retinal degeneration, developmental arrest, and ataxia. We discuss the importance of measuring the sulfatase activities in the leukocytes, and the instability of sulfatases in the cultured skin fibroblasts.

  8. Experimental models of melatonin-deficient hypertension.

    PubMed

    Simko, Fedor; Reiter, Russel J; Pechanova, Olga; Paulis, Ludovit

    2013-01-01

    Melatonin secreted by the pineal gland plays an important role in the regulation of blood pressure (BP) and its administration reduces hypertension both in animals and humans. There are two experimental models of melatonin-deficient hypertension: one induced by pinealectomy and another by continuous 24 hour exposure to light. Both models cause melatonin deficiency and prevent darkness-mediated nocturnal melatonin secretion and are associated with increased BP and myocardial, vascular and renal dysfunction. These models also lead to neurohumoral activation of the renin-angiotensin system, sympathetic nervous system, adrenocorticotrophin-glucocorticoid axis and cause insulin resistance. Together, these alterations contribute to rise in blood pressure by vasoconstrictive or circulatory fluid volume overload. The light induced hypertension model mimics the melatonin deficiency in patients with insufficient nocturnal BP decline, in those who have night shift or who are exposed to environmental light pollution. For this reason, this model is useful in development of anti-hypertensive drugs.

  9. Diagnosing oceanic nutrient deficiency

    NASA Astrophysics Data System (ADS)

    Moore, C. Mark

    2016-11-01

    The supply of a range of nutrient elements to surface waters is an important driver of oceanic production and the subsequent linked cycling of the nutrients and carbon. Relative deficiencies of different nutrients with respect to biological requirements, within both surface and internal water masses, can be both a key indicator and driver of the potential for these nutrients to become limiting for the production of new organic material in the upper ocean. The availability of high-quality, full-depth and global-scale datasets on the concentrations of a wide range of both macro- and micro-nutrients produced through the international GEOTRACES programme provides the potential for estimation of multi-element deficiencies at unprecedented scales. Resultant coherent large-scale patterns in diagnosed deficiency can be linked to the interacting physical-chemical-biological processes which drive upper ocean nutrient biogeochemistry. Calculations of ranked deficiencies across multiple elements further highlight important remaining uncertainties in the stoichiometric plasticity of nutrient ratios within oceanic microbial systems and caveats with regards to linkages to upper ocean nutrient limitation. This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.

  10. 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.

  11. 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

  12. 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.

  13. Galactose Epimerase Deficiency: Expanding the Phenotype.

    PubMed

    Dias Costa, Filipa; Ferdinandusse, Sacha; Pinto, Carla; Dias, Andrea; Keldermans, Liesbeth; Quelhas, Dulce; Matthijs, Gert; Mooijer, Petra A; Diogo, Luísa; Jaeken, Jaak; Garcia, Paula

    2017-03-01

    Galactose epimerase deficiency is an inborn error of metabolism due to uridine diphosphate-galactose-4'-epimerase (GALE) deficiency. We report the clinical presentation, genetic and biochemical studies in two siblings with generalized GALE deficiency.Patient 1: The first child was born with a dysmorphic syndrome. Failure to thrive was noticed during the first year. Episodes of heart failure due to dilated cardiomyopathy, followed by liver failure, occurred between 12 and 42 months. The finding of a serum transferrin isoelectrofocusing (IEF) type 1 pattern led to the suspicion of a congenital disorder of glycosylation (CDG). Follow-up disclosed psychomotor disability, deafness, and nuclear cataracts.Patient 2: The sibling of patient 1 was born with short limbs and hip dysplasia. She is deceased in the neonatal period due to intraventricular hemorrhage in the context of liver failure. Investigation disclosed galactosuria and normal transferrin glycosylation.Next-generation sequence panel analysis for CDG syndrome revealed the previously reported c.280G>A (p.[V94M]) homozygous mutation in the GALE gene. Enzymatic studies in erythrocytes (patient 1) and fibroblasts (patients 1 and 2) revealed markedly reduced GALE activity confirming generalized GALE deficiency. This report describes the fourth family with generalized GALE deficiency, expanding the clinical spectrum of this disorder, since major cardiac involvement has not been reported before.

  14. Hearing Dysfunction in Xpa-Deficient Mice

    PubMed Central

    Shinomiya, Hitomi; Yamashita, Daisuke; Fujita, Takeshi; Nakano, Eiji; Inokuchi, Go; Hasegawa, Shingo; Otsuki, Naoki; Nishigori, Chikako; Nibu, Ken-ichi

    2017-01-01

    Xeroderma pigmentosum (XP) is a rare recessive heredity disease caused by DNA repair impairment characterized by photosensitivity and neurologic symptoms in half of the cases. There are eight subtypes of XP: XP-A–XP-G and XP variant. Among eight subtypes, XP complementation group A (XP-A) display the lowest DNA repair ability and the severest cutaneous and neurologic symptoms. While its pathogenesis of skin symptoms have been well-studied, that of neurological symptoms, including sensorineural hearing loss (SNHL) remains unknown. Basic studies have suggested that SNHL may be caused by inner ear damage, including damage to the spiral ganglion neurons and organ of Corti, and that the XP-A is associated with most severe form of SNHL in humans. Here, we report the occurrence of SNHL in Xpa-deficient mice. Xpa-deficient mice and wild-type mice underwent measurements for auditory brainstem response, and the results revealed that Xpa-deficient mice exhibited significantly greater (p < 0.01) ABR thresholds at 4, 8, and 16 kHz than the wild-type mice. Furthermore, the number of spiral ganglion neurons was reduced in Xpa-deficient mice compared with that in wild-type mice, indicating that hearing loss may be related to spiral ganglion neuron deficiency, consistent with the few reports published in human patients with XP. These results provide important insights into the pathogenesis of SNHL in patients with XP-A. PMID:28239347

  15. Genetics Home Reference: isolated growth hormone deficiency

    MedlinePlus

    ... Isolated growth hormone deficiency Educational Resources (10 links) Boston Children's Hospital CLIMB: Growth Hormone Deficiency Information Sheet (PDF) Disease InfoSearch: Isolated growth hormone deficiency ...

  16. Genetics Home Reference: proopiomelanocortin deficiency

    MedlinePlus

    ... Open All Close All Description Proopiomelanocortin (POMC) deficiency causes severe obesity that begins at an early age. In addition ... and severe obesity. POMC deficiency is a rare cause of obesity; POMC gene mutations are not frequently associated with ...

  17. Sanitary Surveys & Significant Deficiencies Presentation

    EPA Pesticide Factsheets

    The Sanitary Surveys & Significant Deficiencies Presentation highlights some of the things EPA looks for during drinking water system site visits, how to avoid significant deficiencies and what to do if you receive one.

  18. Genetics Home Reference: biotinidase deficiency

    MedlinePlus

    ... links) Children Living With Inherited Metabolic Diseases (CLIMB) (UK): Biotinidase Deficiency (PDF) Disease InfoSearch: Biotinidase Deficiency Illinois ... Group Children Living with Inherited Metabolic Diseases (CLIMB) (UK) National Organization for Rare Disorders (NORD) GeneReviews (1 ...

  19. Ichthyosis: the skin manifestation of multiple sulfatase deficiency.

    PubMed

    Castaño Suárez, E; Segurado Rodríguez, A; Guerra Tapia, A; Simón de las Heras, R; López-Ríos, F; Coll Rosell, M J

    1997-01-01

    Juvenile sulfatidosis (Austin type) or multiple sulfatase deficiency is an extremely rare autosomal recessive disorder affecting the activity of many sulfatases: arylsulfatase A, several mucopolysaccharide sulfatases, and steroid sulfatase. Certain aspects of the clinical phenotype can be attributed mainly to a deficiency of one specific sulfatase. Most patients develop metachromatic leukodystrophy caused by arylsulfatase A deficiency, dysostosis multiplex by mucopolysaccharide sulfatase deficiency, and ichthyotic skin by steroid sulfatase deficiency. We describe a 7-year-old boy with developmental delay from 7 months of age, progressive spastic quadriparesis, and coarse facial features. By 27 months of age, an ichthyotic rash had developed on the limbs, trunk, and scalp. A skin biopsy specimen revealed hyperkeratosis with a normal granular layer. The diagnosis of multiple sulfatase deficiency was demonstrated by measuring sulfatase activities in fresh leukocytes: there were large deficiencies of arylsulfatase A and B plus reduced arylsulfatase C. The ichthyosis associated with multiple sulfatase deficiency has an autosomal recessive inheritance, is caused by steroid sulfatase deficiency, and the scaling is sometimes milder than in X-linked recessive ichthyosis. This could reflect the residual activity of steroid sulfatase in some cases.

  20. 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 ...

  1. Language deficiency in children.

    PubMed

    Morehead, D M; Morehead, K E; Morehead, W A

    1980-01-01

    Research in cognition and language has provided useful constructs which suggests that specific deficits underlie language deficiencies in children. In addition, this research has provided procedures that the determine what a child knows about language at a particular level of development and has established a sequence of linguistic development that maps the specific content and structure of training programs. Two new areas of research offer additional approaches to assessment and remediation. One approach focuses on the actual principles and strategies that normal children use to learn language, making it possible to determine which methods are most efficient. The second research approach looks at the contextual conditions adults and children provide the first language learner. Preliminary work suggests that the natural conditions found universally in first language learning may be the best indicators of how to proceed with language-deficient children.

  2. Iron-Deficiency Anemia (For Parents)

    MedlinePlus

    ... Your 1- to 2-Year-Old 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 ...

  3. How Is Iron-Deficiency Anemia Treated?

    MedlinePlus

    ... the NHLBI on Twitter. How Is Iron-Deficiency Anemia Treated? Treatment for iron-deficiency anemia will depend ... may be advised. Treatments for Severe Iron-Deficiency Anemia Blood Transfusion If your iron-deficiency anemia is ...

  4. Phenylalanine hydroxylase deficiency.

    PubMed

    Mitchell, John J; Trakadis, Yannis J; Scriver, Charles R

    2011-08-01

    Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid phenylalanine. It occurs in approximately 1:15,000 individuals. Deficiency of this enzyme produces a spectrum of disorders including classic phenylketonuria, mild phenylketonuria, and mild hyperphenylalaninemia. Classic phenylketonuria is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity and without dietary restriction of phenylalanine most children will develop profound and irreversible intellectual disability. Mild phenylketonuria and mild hyperphenylalaninemia are associated with lower risk of impaired cognitive development in the absence of treatment. Phenylalanine hydroxylase deficiency can be diagnosed by newborn screening based on detection of the presence of hyperphenylalaninemia using the Guthrie microbial inhibition assay or other assays on a blood spot obtained from a heel prick. Since the introduction of newborn screening, the major neurologic consequences of hyperphenylalaninemia have been largely eradicated. Affected individuals can lead normal lives. However, recent data suggest that homeostasis is not fully restored with current therapy. Treated individuals have a higher incidence of neuropsychological problems. The mainstay of treatment for hyperphenylalaninemia involves a low-protein diet and use of a phenylalanine-free medical formula. This treatment must commence as soon as possible after birth and should continue for life. Regular monitoring of plasma phenylalanine and tyrosine concentrations is necessary. Targets of plasma phenylalanine of 120-360 μmol/L (2-6 mg/dL) in the first decade of life are essential for optimal outcome. Phenylalanine targets in adolescence and adulthood are less clear. A significant proportion of patients with phenylketonuria may benefit from adjuvant therapy with 6R-tetrahydrobiopterin stereoisomer. Special consideration must be

  5. 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.

  6. 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.

  7. 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 Central

    Lopez, Adam M.; Chuang, Jen-Chieh; Posey, Kenneth S.; Ohshiro, Taichi; Tomoda, Hiroshi; Rudel, Lawrence L.

    2015-01-01

    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

  8. 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...

  9. 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

  10. 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

  11. Placental steroid deficiency: association with arylsulfatase A deficiency.

    PubMed Central

    Vidgoff, J; Buxman, M M; Shapiro, L J; Dimond, R L; Wilson, T G; Hepburn, C A; Tabei, T; Heinrichs, W R

    1982-01-01

    A family with an obstetric history consistent with placental sulfatase deficiency has X-linked ichthyosis. Steroid sulfatase deficiency was confirmed in placenta, leukocytes, and cultured skin fibroblasts of affected males; arylsulfatase A diminution was also observed in these tissues of both affected males and 2 generations of related females. No symptoms of metachromatic leukodystrophy are present in any family members. In this family, placental sulfatase deficiency, and arylsulfatase A pseudodeficiency are nonallelic. PMID:6123259

  12. Prevention of Vitamin K Deficiency Bleeding.

    PubMed

    Phillippi, Julia C; Holley, Sharon L; Morad, Anna; Collins, Michelle R

    2016-07-07

    The risk that a newborn will develop vitamin K deficiency bleeding is 1700/100,000 (one out of 59) if vitamin K is not administered. When intramuscular vitamin K is administered, the risk of vitamin K deficiency bleeding is reduced to 1/100,000. While women may have misconceptions about vitamin K prophylaxis for their newborns, health care providers should be prepared with factual information. Prophylaxis is needed even for healthy newborns without risk factors for bleeding. Other forms of vitamin K supplementation, including oral administration of Food and Drug Administration-approved vitamin K preparations and maternal supplements during pregnancy or lactation, do not have the same effectiveness as the parenteral form. The formulations of vitamin K approved for use in the United States have not been associated with childhood leukemia or other childhood health problems. Care providers need to give accurate information to families regarding the risks and benefits of vitamin K prophylaxis. An interprofessional approach to education can be effective in increasing acceptance of vitamin K prophylaxis and decreasing the incidence of vitamin K deficiency bleeding. This article uses a case study approach to highlight common misconceptions about vitamin K prophylaxis and discuss a recent interprofessional collaboration to prevent vitamin K deficiency bleeding.

  13. Primary hyperparathyroidism and vitamin D deficiency.

    PubMed

    Vélayoudom-Céphise, Fritz-Line; Wémeau, Jean-Louis

    2015-05-01

    Primary hyperparathyroidism (PHPT) and vitamin D (VD) deficiency are frequent conditions due to the widespread application of assays for calcium and VD. PHPT presentation is dominated by diversity in its expression and the current predominance of asymptomatic forms. VD, which plays a major role in calcium and phosphate homeostasis, is also involved in many physiological processes in this disease, such as lipid and glucose metabolism, and in the signalling pathways and functioning of many cell types. The bone and cardiometabolic complications described in PHPT are exacerbated by vitamin D deficiency, the prevalence of which varies according to many parameters (environment, skin pigmentation, associated chronic diseases, liver and kidney function, assay kit used, etc.). In response to this observation, experts in field from medical societies validated the indication for systematic assay of VD occurring with PHPT and the need for replacement in case of deficiency. Several epidemiological studies have confirmed that replacement with natural vitamin D is well tolerated and safe in subjects with PHPT and VD deficiency. This supplementation reduces hyperparathormonemia, does not have symptomatic effects on calciuria, and especially improves the bone and functional condition of patients.

  14. by Cu Deficiencies

    NASA Astrophysics Data System (ADS)

    Wei, Tian-Ran; Li, Fu; Li, Jing-Feng

    2014-06-01

    This work revealed that the Cu-deficient ternary compounds Cu3- x SbSe4 free of Te and Pb exhibit enhanced thermoelectric performance. Cu3- x SbSe4 ( x = 0, 0.025, 0.050, 0.075) polycrystalline materials with high phase purity were fabricated by a facile method combining mechanical alloying and spark plasma sintering. Effects of Cu deficiencies on crystal structures, microstructures, element chemical states, and thermoelectric properties were systematically studied. High carrier concentration was obtained for the compositions Cu2.95SbSe4 and Cu2.925SbSe4 due to additional Cu vacancies, contributing to a remarkable increase in electrical conductivity. Together with a satisfactorily large Seebeck coefficient above 300 μV/K, a high power factor of about 890 μW/m-K2 at 523 K was achieved for Cu2.95SbSe4 and Cu2.925SbSe4, almost 60% larger than that of the stoichiometric sample with x = 0. The maximum ZT value was increased to 0.50 at 673 K in the Cu2.925SbSe4 sample sintered at a high temperature (703 K); this is the highest value reported so far for the undoped Cu3SbSe4 system.

  15. Familial apolipoprotein E deficiency.

    PubMed Central

    Schaefer, E J; Gregg, R E; Ghiselli, G; Forte, T M; Ordovas, J M; Zech, L A; Brewer, H B

    1986-01-01

    A unique kindred with premature cardiovascular disease, tubo-eruptive xanthomas, and type III hyperlipoproteinemia (HLP) associated with familial apolipoprotein (apo) E deficiency was examined. Homozygotes (n = 4) had marked increases in cholesterol-rich very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL), which could be effectively lowered with diet and medication (niacin, clofibrate). Homozygotes had only trace amounts of plasma apoE, and accumulations of apoB-48 and apoA-IV in VLDL, IDL, and low density lipoproteins. Radioiodinated VLDL apoB and apoE kinetic studies revealed that the homozygous proband had markedly retarded fractional catabolism of VLDL apoB-100, apoB-48 and plasma apoE, as well as an extremely low apoE synthesis rate as compared to normals. Obligate heterozygotes (n = 10) generally had normal plasma lipids and mean plasma apoE concentrations that were 42% of normal. The data indicate that homozygous familial apoE deficiency is a cause of type III HLP, is associated with markedly decreased apoE production, and that apoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. Images PMID:3771793

  16. 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

  17. [Iron deficiency and digestive disorders].

    PubMed

    Cozon, G J N

    2014-11-01

    Iron deficiency anemia still remains problematic worldwide. Iron deficiency without anemia is often undiagnosed. We reviewed, in this study, symptoms and syndromes associated with iron deficiency with or without anemia: fatigue, cognitive functions, restless legs syndrome, hair loss, and chronic heart failure. Iron is absorbed through the digestive tract. Hepcidin and ferroportin are the main proteins of iron regulation. Pathogenic micro-organisms or intestinal dysbiosis are suspected to influence iron absorption.

  18. Iron deficiency anemia in celiac disease.

    PubMed

    Freeman, Hugh James

    2015-08-21

    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.

  19. 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

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

    PubMed

    Kollée, L A A

    2006-03-04

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

  1. Hereditary galactokinase deficiency

    PubMed Central

    Cook, J. G. H.; Don, N. A.; Mann, Trevor P.

    1971-01-01

    A baby with galactokinase deficiency, a recessive inborn error of galactose metabolism, is described. The case is exceptional in that there was no evidence of gypsy blood in the family concerned. The investigation of neonatal hyperbilirubinaemia led to the discovery of galactosuria. As noted by others, the paucity of presenting features makes early diagnosis difficult, and detection by biochemical screening seems desirable. Cataract formation, of early onset, appears to be the only severe persisting complication and may be due to the biosynthesis and accumulation of galactitol in the lens. Ophthalmic surgeons need to be aware of this enzyme defect, because with early diagnosis and dietary treatment these lens changes should be reversible. PMID:5109408

  2. Peroxisomal bifunctional enzyme deficiency.

    PubMed Central

    Watkins, P A; Chen, W W; Harris, C J; Hoefler, G; Hoefler, S; Blake, D C; Balfe, A; Kelley, R I; Moser, A B; Beard, M E

    1989-01-01

    Peroxisomal function was evaluated in a male infant with clinical features of neonatal adrenoleukodystrophy. Very long chain fatty acid levels were elevated in both plasma and fibroblasts, and beta-oxidation of very long chain fatty acids in cultured fibroblasts was significantly impaired. Although the level of the bile acid intermediate trihydroxycoprostanoic acid was slightly elevated in plasma, phytanic acid and L-pipecolic acid levels were normal, as was plasmalogen synthesis in cultured fibroblasts. The latter three parameters distinguish this case from classical neonatal adrenoleukodystrophy. In addition, electron microscopy and catalase subcellular distribution studies revealed that, in contrast to neonatal adrenoleukodystrophy, peroxisomes were present in the patient's tissues. Immunoblot studies of peroxisomal beta-oxidation enzymes revealed that the bifunctional enzyme (enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase) was deficient in postmortem liver samples, whereas acyl-CoA oxidase and the mature form of beta-ketothiolase were present. Density gradient centrifugation of fibroblast homogenates confirmed that intact peroxisomes were present. Immunoblots of fibroblasts peroxisomal fractions showed that they contained acyl-CoA oxidase and beta-ketothiolase, but bifunctional enzyme was not detected. Northern analysis, however, revealed that mRNA coding for the bifunctional enzyme was present in the patient's fibroblasts. These results indicate that the primary biochemical defect in this patient is a deficiency of peroxisomal bifunctional enzyme. It is of interest that the phenotype of this patient resembled neonatal adrenoleukodystrophy and would not have been distinguished from this disorder by clinical study alone. Images PMID:2921319

  3. Iodine deficiency in Europe.

    PubMed

    Delange, F

    1995-01-18

    Iodine is a trace element present in the human body in minute amounts (15-20 mg in adults, i.e. 0.0285 x 10(-3)% of body weight). The only confirmed function of iodine is to constitute an essential substrate for the synthesis of thyroid hormones, tetraiodothyronine, thyroxine or T4 and triiodothyronine, T3 (1). In thyroxine, iodine is 60% by weight. Thyroid hormones, in turn, play a decisive role in the metabolism of all cells of the organism (2) and in the process of early growth and development of most organs, especially of the brain (3). Brain development in humans occurs from fetal life up to the third postnatal year (4). Consequently, a deficit in iodine and/or in thyroid hormones occurring during this critical period of life will result not only in the slowing down of the metabolic activities of all the cells of the organism but also in irreversible alterations in the development of the brain. The clinical consequence will be mental retardation (5). When the physiological requirements of iodine are not met in a given population, a series of functional and developmental abnormalities occur (Table 1), including thyroid function abnormalities and, when iodine deficiency is severe, endemic goiter and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death, and infant mortality. These complications, which constitute an hindrance to the development of the affected population, are grouped under the general heading of Iodine Deficiency Disorders, IDD (6). Broad geographic areas exist in which the population is affected by IDD.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. 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.

  5. Congenital deficiency of meibomian glands.

    PubMed Central

    Bron, A J; Mengher, L S

    1987-01-01

    A 16-year-old girl presented with contact lens intolerance. She was found to have a marked deficiency of meibomian glands in the upper lids and almost total absence in the lower lids. Evidence of tear film instability was found and attributed to deficient lid oil production. A daily wear soft contact lens was later fitted and tolerated. PMID:3580344

  6. Vitamin B12 deficiency anemia

    MedlinePlus

    ... body tissues. There are many types of anemia. Vitamin B12 deficiency anemia is a low red blood cell count ... anemia often do well with treatment. Long-term vitamin B12 deficiency can cause nerve damage. This may be permanent ...

  7. 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…

  8. 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

  9. Iron deficiency: definition and diagnosis.

    PubMed

    Cook, J D; Skikne, B S

    1989-11-01

    There has been a continuous refinement over the past several decades of methods to detect iron deficiency and assess its magnitude. The optimal combination of measurements differs for clinical and epidemiological assessment. Clinically, the major problem is to distinguish true iron deficiency from other causes of iron-deficient erythropoiesis, such as the anaemia of chronic disease. Epidemiologically, techniques that provide quantified estimates of body iron are preferable. For both purposes, the serum ferritin is the focal point of the laboratory detection of iron deficiency. Serum ferritin measurements provide a reliable index of body iron stores in healthy individuals, a cost-effective method of screening for iron deficiency, and a useful alternative to bone marrow examinations in the evaluation of anaemic patients. Preliminary studies indicate that measurement of the serum transferrin receptor may be the most reliable way to assess deficits in tissue iron supply.

  10. Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice.

    PubMed

    Li, Yanli; Gao, Rufei; Liu, Xueqing; Chen, Xuemei; Liao, Xinggui; Geng, Yanqing; Ding, Yubin; Wang, Yingxiong; He, Junlin

    2015-08-04

    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.

  11. 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

  12. 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.

  13. Genetics Home Reference: protein C deficiency

    MedlinePlus

    ... Management Genetic Testing (1 link) Genetic Testing Registry: Thrombophilia, hereditary, due to protein C deficiency, autosomal dominant ... my area? Other Names for This Condition hereditary thrombophilia due to protein C deficiency PROC deficiency Related ...

  14. Genetics Home Reference: glucose phosphate isomerase deficiency

    MedlinePlus

    ... Understand Genetics Home Health Conditions GPI deficiency glucose phosphate isomerase deficiency Enable Javascript to view the expand/ ... Download PDF Open All Close All Description Glucose phosphate isomerase (GPI) deficiency is an inherited disorder that ...

  15. Genetics Home Reference: dopamine transporter deficiency syndrome

    MedlinePlus

    ... Genetics Home Health Conditions dopamine transporter deficiency syndrome dopamine transporter deficiency syndrome Enable Javascript to view the ... boxes. Download PDF Open All Close All Description Dopamine transporter deficiency syndrome is a rare movement disorder. ...

  16. Facts about Vitamin K Deficiency Bleeding

    MedlinePlus

    ... Button Information For... Media Policy Makers Facts about Vitamin K Deficiency Bleeding Recommend on Facebook Tweet Share Compartir Vitamins ... serious bleeding problems if not supplemented. What is Vitamin K Deficiency Bleeding or VKDB? Vitamin K deficiency bleeding or ...

  17. What Causes Alpha-1 Antitrypsin Deficiency?

    MedlinePlus

    ... Causes Alpha-1 Antitrypsin Deficiency? Alpha-1 antitrypsin (AAT) deficiency is an inherited disease. "Inherited" means it's ... parents to children through genes. Children who have AAT deficiency inherit two faulty AAT genes, one from ...

  18. How Is Alpha-1 Antitrypsin Deficiency Treated?

    MedlinePlus

    ... Alpha-1 Antitrypsin Deficiency Treated? Alpha-1 antitrypsin (AAT) deficiency has no cure, but its related lung ... pulmonary disease). If you have symptoms related to AAT deficiency, your doctor may recommend: Medicines called inhaled ...

  19. Primary Immune Deficiency Disease Genetics & Inheritance

    MedlinePlus

    ... twitter share with linkedin Primary Immune Deficiency Disease Genetics & Inheritance Primary Immune Deficiency Diseases (PIDDs) Primary Immune Deficiency Diseases (PIDDs) Types of PIDDs Genetics & Inheritance Talking to Your Doctor Featured Research Credit: ...

  20. Genetics Home Reference: lysosomal acid lipase deficiency

    MedlinePlus

    ... Home Health Conditions lysosomal acid lipase deficiency lysosomal acid lipase deficiency Enable Javascript to view the expand/ ... Download PDF Open All Close All Description Lysosomal acid lipase deficiency is an inherited condition characterized by ...

  1. Does vitamin C deficiency affect cognitive development and function?

    PubMed

    Hansen, Stine Normann; Tveden-Nyborg, Pernille; Lykkesfeldt, Jens

    2014-09-19

    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.

  2. Iron deficiency and thrombocytosis.

    PubMed

    Holbro, A; Volken, T; Buser, A; Sigle, J P; Halter, J P; Passweg, J R; Tichelli, A; Infanti, L

    2017-01-01

    According to many textbooks, iron deficiency (ID) is associated with reactive thrombocytosis. In this study, we aimed to investigate the correlation between serum ferritin levels and platelet counts in a large cohort of healthy blood donors. We included all whole blood and apheresis donors aged 18 years or older with at least one ferritin measurement and one platelet count performed at the same visit between 1996 and 2014. A total of 130 345 blood counts and ferritin measurements obtained from 22 046 healthy donors were analysed. Overall, no correlation between serum ferritin and platelet count was observed (r = -0.03, ρ = 0.04 for males, and r = 0.01, ρ = -0.02 for females, respectively). Associations remained clinically negligible after adjusting for age, time since previous blood donation, number of donations and restricting the analysis to ferritin deciles. In this large, retrospective single-centre study, correlations between low ferritin and platelet count in a large and homogeneous cohort of healthy donors were negligible. Further studies in patients with more severe anaemia and patients with inflammation are warranted.

  3. 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

  4. Iron Deficiency Anemia in Pregnancy.

    PubMed

    Breymann, Christian

    2015-10-01

    Anemia is a common problem in obstetrics and perinatal care. Any hemoglobin below 10.5 g/dL can be regarded as true anemia regardless of gestational age. Reasons for anemia in pregnancy are mainly nutritional deficiencies, parasitic and bacterial diseases, and inborn red blood cell disorders such as thalassemias. The main cause of anemia in obstetrics is iron deficiency, which has a worldwide prevalence between estimated 20%-80% and consists of a primarily female population. Stages of iron deficiency are depletion of iron stores, iron-deficient erythropoiesis without anemia, and iron deficiency anemia, the most pronounced form of iron deficiency. Pregnancy anemia can be aggravated by various conditions such as uterine or placental bleedings, gastrointestinal bleedings, and peripartum blood loss. In addition to the general consequences of anemia, there are specific risks during pregnancy for the mother and the fetus such as intrauterine growth retardation, prematurity, feto-placental miss ratio, and higher risk for peripartum blood transfusion. Besides the importance of prophylaxis of iron deficiency, the main therapy options for the treatment of pregnancy anemia are oral iron and intravenous iron preparations.

  5. Iatrogenic limbal stem cell deficiency.

    PubMed Central

    Holland, E J; Schwartz, G S

    1997-01-01

    PURPOSE: To describe a group of patients with limbal stem cell (SC) deficiency without prior diagnosis of a specific disease entity known to be causative of SC deficiency. METHODS: We performed a retrospective review of the records of all patients with ocular surface disease presenting to the University of Minnesota between 1987 and 1996. Patients were categorized according to etiology of limbal deficiency. Patients who did not have a specific diagnosis previously described as being causative for limbal deficiency were analyzed. Risk factors, clinical findings and sequelae were evaluated. RESULTS: Eight eyes of six patients with stem cell deficiency not secondary to a known diagnosis were described. All eyes had prior ocular surgery involving the corneoscleral limbus. Six eyes had been on chronic topical medications and all eyes had concurrent external disease such as pterygium, keratoconjunctivitis sicca, rosacea or herpes simplex virus keratitis. All eyes had superior quadrants affected corresponding to areas of prior limbal surgery. Sequelae of disease included corneal scarring and neo-vascularization, and five eyes had with visual acuity of 20/200 or worse. CONCLUSIONS: Because the epitheliopathy started peripherally and extended centrally in all patients, we feel it represents a stem cell deficiency. The fact that all patients were affected superiorly, at sites of a prior limbal surgical incision, points to surgical trauma to the SC as the likely major etiologic factor for the deficiency. The surgical trauma to the limbal SC probably made these cells more susceptible to damage from other external disease influences and toxicity from chronic topical medications. Because the stem cell deficiency is secondary to prior ocular surgery and chronic topical medications, we propose the term "iatrogenic limbal stem cell deficiency". Images FIGURE 1 FIGURE 2A FIGURE 2B FIGURE 3A FIGURE 3B PMID:9440165

  6. Organophosphates and monocyte esterase deficiency.

    PubMed Central

    McClean, E; Mackey, H; Markey, G M; Morris, T C

    1995-01-01

    AIMS--To examine the possibility that monocyte esterase deficiency (MED) could be caused by exposure to organophosphates. METHODS--Pseudocholinesterase, paraoxonase and arylesterase activities were measured in the serum and acetylcholinesterase activity was measured in the red cells of a group of monocyte esterase deficient subjects and compared with the enzyme activities of a control group of monocyte esterase positive subjects. RESULTS--No significant difference was found between the enzyme activities of the monocyte esterase deficient group and the control group for any of the esterases investigated. CONCLUSION--Current or recent exposure to organophosphorus is not the cause of MED. PMID:7560207

  7. Genetics Home Reference: hereditary antithrombin deficiency

    MedlinePlus

    ... Merck Manual Home Edition for Patients and Caregivers: Thrombophilia National Blood Clot Alliance: Antithrombin Deficiency Orphanet: Hereditary thrombophilia due to congenital antithrombin deficiency Patient Support and ...

  8. 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.

  9. 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.

  10. 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

  11. Metabolic Remodeling in Iron-deficient Fungi

    PubMed Central

    Philpott, Caroline C.; Leidgens, Sebastien; Frey, Avery G.

    2012-01-01

    Eukaryotic cells contain dozens, perhaps hundreds, of iron-dependent proteins, which perform critical functions in nearly every major cellular process. Nutritional iron is frequently available to cells in only limited amounts; thus, unicellular and higher eukaryotes have evolved mechanisms to cope with iron scarcity. These mechanisms have been studied at the molecular level in the model eukaryotes Saccharomyces cerevisiae and Schizosaccharomyces pombe, as well as in some pathogenic fungi. Each of these fungal species exhibits metabolic adaptations to iron deficiency that serve to reduce the cell’s reliance on iron. However, the regulatory mechanisms that accomplish these adaptations differ greatly between fungal species. PMID:22306284

  12. Chromium deficiency during total parenteral nutrition.

    PubMed

    Freund, H; Atamian, S; Fischer, J E

    1979-02-02

    Chromium is required for maintenance of normal glucose tolerance. After complete bowel resection and five months of total parenteral nutrition, severe glucose intolerance, weight loss, and a metabolic encephalopathy-like confusional state developed in a patient. Serum chromium levels were at the lowest normal level. Supplementation of 150 microgram of chromium per day reversed the glucose intolerance, reduced insulin requirements, and resulted in weight gain and the disappearance of encephalopathy. The low levels of chromium and response to chromium supplementation suggest that chromium deficiency can arise in long-term total parenteral nutrition.

  13. Vitamin A deficiency modulates iron metabolism via ineffective erythropoiesis.

    PubMed

    da Cunha, Marcela S B; Siqueira, Egle M A; Trindade, Luciano S; Arruda, Sandra F

    2014-10-01

    Vitamin A modulates inflammatory status, iron metabolism and erythropoiesis. Given that these factors modulate the expression of the hormone hepcidin (Hamp), we investigated the effect of vitamin A deficiency on molecular biomarkers of iron metabolism, the inflammatory response and the erythropoietic system. Five groups of male Wistar rats were treated: control (AIN-93G), the vitamin A-deficient (VAD) diet, the iron-deficient (FeD) diet, the vitamin A- and iron-deficient (VAFeD) diet or the diet with 12 mg atRA/kg diet replacing all-trans-retinyl palmitate by all-trans retinoic acid (atRA). Vitamin A deficiency reduced serum iron and transferrin saturation levels, increased spleen iron concentrations, reduced hepatic Hamp and kidney erythropoietin messenger RNA (mRNA) levels and up-regulated hepatic and spleen heme oxygenase-1 gene expression while reducing the liver HO-1 specific activity compared with the control. The FeD and VAFeD rats exhibited lower levels of serum iron and transferrin saturation, lower iron concentrations in tissues and lower hepatic Hamp mRNA levels compared with the control. The treatment with atRA resulted in lower serum iron and transferrin concentrations, an increased iron concentration in the liver, a decreased iron concentration in the spleen and in the gut, and decreased hepatic Hamp mRNA levels. In summary, these findings suggest that vitamin A deficiency leads to ineffective erythropoiesis by the down-regulation of renal erythropoietin expression in the kidney, resulting in erythrocyte malformation and the consequent accumulation of the heme group in the spleen. Vitamin A deficiency indirectly modulates systemic iron homeostasis by enhancing erythrophagocytosis of undifferentiated erythrocytes.

  14. 1,25-Vitamin D3 Deficiency Induces Albuminuria.

    PubMed

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

    2016-04-01

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

  15. [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.

  16. Genetics Home Reference: transcobalamin deficiency

    MedlinePlus

    ... Version: Failure to Thrive Merck Manual Consumer Version: Vitamin Deficiency Anemia Merck Manual Professional Version: Vitamin B12 Orphanet: ... Neutropenia Washington University, St. Louis: Neuromuscular Disease Center: Vitamin B12 (Cobalamin) ... Patient Support and Advocacy Resources (3 links) American ...

  17. Genetics Home Reference: tetrahydrobiopterin deficiency

    MedlinePlus

    ... named? Additional Information & Resources MedlinePlus (3 links) Encyclopedia: Serum Phenylalanine Screening Health Topic: Newborn Screening Health Topic: Phenylketonuria Genetic and Rare Diseases Information Center (1 link) Tetrahydrobiopterin deficiency Educational Resources ( ...

  18. 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

  19. Increased hippocampal DNA oxidation in serotonin transporter deficient mice.

    PubMed

    Mössner, R; Dringen, R; Persico, A M; Janetzky, B; Okladnova, O; Albert, D; Götz, M; Benninghoff, J; Schmitt, A; Gerlach, M; Riederer, P; Lesch, K P

    2002-05-01

    The serotonin transporter (5HTT) is the molecule responsible for the high-affinity reuptake of 5HT from the synaptic cleft. Mice lacking the 5HTT exhibit highly elevated extracellular concentrations of 5HT. We assessed whether the glutathione detoxification system is altered in 5HTT-deficient mice. While levels of reduced and oxidized glutathione were unchanged, glutathione metabolising enzymes showed a differential pattern of modulation. Glutathione peroxidase was reduced in frontal cortex, brainstem, and cerebellum of 5HTT-deficient mice, though not to a statistically significant extent, while a putative isoform of the detoxifying enzyme glutathione-S-transferase pi was decreased in a number of brain regions, especially in brainstem. At the level of the DNA, we found an increase of oxidative DNA adducts in the hippocampus of 5HTT-deficient mice. Given the importance of the hippocampus in learning and memory, this may be the most important neurochemical consequence of the absence of the 5HTT.

  20. 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.

  1. 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.

  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.

  3. 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.

  4. Glucagon deficiency and hyperaminoacidemia after total pancreatectomy.

    PubMed Central

    Boden, G; Master, R W; Rezvani, I; Palmer, J P; Lobe, T E; Owen, O E

    1980-01-01

    The first goal of this study was to investigate whether totally pancreatectomized patients are glucagon deficient and if so, to what degree. Immunoreactive glucagon (IRG) concentrations in peripheral plasma of nine pancreatectomized patients were not significantly different from those of 10 normal controls as measured by two antisera (30-K and RCS-5) both detecting the COOH-terminal portion of the molecule and one (RCS-5) postulated to be specific for pancreatic glucagon. Plasma from six of nine pancreatectomized patients were fractionated over Sephadex G-50 and IRG was measured with both antisera in the column eluates. Using 30-K, 80.8 +/- 9% of the IRG eluted within the void volume. This material was rechromatographed on Sephadex G-200 and found to have an apparent mol wt of approximately 200,000. Only 18.3 +/- 9% eluted in the IRG3500 region. IRG3500 was significantly reduced in pancreatectomized patients as compared to normal controls (49 +/- 9 vs. 18 +/- 9 pg/ml, P less than 0.05). Using RCS-5, all IRG (corresponding to 20 +/- 6 pg/ml of plasma) eluted in the IRG3500 region. The second goal of this study was to investigate the effects of chronic glucagon deficiency on plasma amino acids. In the nine pancreatectomized patients studied, postabsorptive plasma concentrations of serine, alanine, arginine, glycine, threonine, citrulline, alpha-aminobutyrate, and tryosine were significantly elevated compared to values obtained from 20 normal controls. Physiological glucagon increments produced in two pancreatectomized patients by infusion of glucagon (6.25 and 8.0 microgram/h, respectively) resulted in normalization of the hyperaminoacidemia within 22 h. We conclude (a) that pancreatectomized patients are partially glucagon deficient because of diminished basal as well as diminished stimulated glucagon secretion; (b) that fasting concentrations of certain glucogenic amino acids are elevated in pancreatectomized patients probably as result of reduce; hepatic

  5. Mechanisms of thiamin deficiency in chronic alcoholism.

    PubMed

    Hoyumpa, A M

    1980-12-01

    In the United States and other developed countries thiamin deficiency is often related to chronic alcoholism. A number of mechanisms may be involved in the pathogenesis of thiamin deficiency in the alcoholic population. An important cause is inadequate intake of thiamin. Moreover, there may be decreased converstion of thiamin to the active coenzyme, reduced hepatic storage of the vitamin in patients with fatty metamorphosis, ethanol inhibition of intestinal thiamin transport, and impaired thiamin absorption secondary to other states of nutritional deficiency. The present discussion focuses on the mechanism of ethanol-related thiamin malabsorption. Under normal conditions thiamin transport in animals and humans is biphasic. At low or physiological thiamin concentrations, transport is a saturable, carrier-mediated, active process; but at higher concentrations, the transport of thiamin is predominantly passive. Ethanol reduces the rate of intestinal absorption and the net transmural flux of thiamin. Furthermore, ethanol inhibits only the active and not the passive component of thiamin transport by impeding the cellular exit of thiamin across the basolateral or serosal membrane. The impairment of thiamin movement out of the enterocyte correlates with a fall in the activity of Na-K ATPase. Bound to the basolateral membrane, Na-K ATPase is believed to be involved in the kinetics of active transport. Ethanol also increases the fluidity of enterocyte brush border and basolateral membranes. Since ethanol increases membrane fluidity it is possible that tahe impairment of thiamin transport and the diminution of Na-K ATPase activity may be related, at least partly, to a physical perturbation of the enterocyte membrane.

  6. Vitamin D deficiency and supplementation and relation to cardiovascular health.

    PubMed

    Vacek, James L; Vanga, Subba Reddy; Good, Mathew; Lai, Sue Min; Lakkireddy, Dhanunjaya; Howard, Patricia A

    2012-02-01

    Recent evidence supports an association between vitamin D deficiency and hypertension, peripheral vascular disease, diabetes mellitus, metabolic syndrome, coronary artery disease, and heart failure. The effect of vitamin D supplementation, however, has not been well studied. We examined the associations between vitamin D deficiency, vitamin D supplementation, and patient outcomes in a large cohort. Serum vitamin D measurements for 5 years and 8 months from a large academic institution were matched to patient demographic, physiologic, and disease variables. The vitamin D levels were analyzed as a continuous variable and as normal (≥30 ng/ml) or deficient (<30 ng/ml). Descriptive statistics, univariate analysis, multivariate analysis, survival analysis, and Cox proportional hazard modeling were performed. Of 10,899 patients, the mean age was 58 ± 15 years, 71% were women (n = 7,758), and the average body mass index was 30 ± 8 kg/m(2). The mean serum vitamin D level was 24.1 ± 13.6 ng/ml. Of the 10,899 patients, 3,294 (29.7%) were in the normal vitamin D range and 7,665 (70.3%) were deficient. Vitamin D deficiency was associated with several cardiovascular-related diseases, including hypertension, coronary artery disease, cardiomyopathy, and diabetes (all p <0.05). Vitamin D deficiency was a strong independent predictor of all-cause death (odds ratios 2.64, 95% confidence interval 1.901 to 3.662, p <0.0001) after adjusting for multiple clinical variables. Vitamin D supplementation conferred substantial survival benefit (odds ratio for death 0.39, 95% confidence interval 0.277 to 0.534, p <0.0001). In conclusion, vitamin D deficiency was associated with a significant risk of cardiovascular disease and reduced survival. Vitamin D supplementation was significantly associated with better survival, specifically in patients with documented deficiency.

  7. Partial pyruvate kinase deficiency aggravates the phenotypic expression of band 3 deficiency in a family with hereditary spherocytosis.

    PubMed

    van Zwieten, Rob; van Oirschot, Brigitte A; Veldthuis, Martijn; Dobbe, Johannes G; Streekstra, Geert J; van Solinge, Wouter W; Schutgens, Roger E G; van Wijk, Richard

    2015-03-01

    In a family with mild dominant spherocytosis, affected members showed partial band 3 deficiency. The index patient showed more severe clinical symptoms than his relatives, and his red blood cells displayed concomitant low pyruvate kinase activity. We investigated the contribution of partial PK deficiency to the phenotypic expression of mutant band 3 in this family. Pyruvate kinase deficiency and band 3 deficiency were characterized by DNA analysis. Results of red cell osmotic fragility testing, the results of cell deformability obtained by the Automated Rheoscope and Cell Analyzer and the results obtained by Osmotic Gradient Ektacytometry, which is a combination of these tests, were related to the red cell ATP content. Spherocytosis in this family was due to a novel heterozygous mutation in SLC4A1, the gene for band 3. Reduced PK activity of the index patient was attributed to a novel mutation in PKLR inherited from his mother, who was without clinical symptoms. Partial PK deficiency was associated with decreased red cell ATP content and markedly increased osmotic fragility. This suggests an aggravating effect of low ATP levels on the phenotypic expression of band 3 deficiency.

  8. Vitamin D Deficiency in Human and Murine Sepsis*

    PubMed Central

    Parekh, Dhruv; Patel, Jaimin M.; Scott, Aaron; Lax, Sian; Dancer, Rachel C. A.; D’Souza, Vijay; Greenwood, Hannah; Fraser, William D.; Gao, Fang; Sapey, Elizabeth; Perkins, Gavin D.

    2017-01-01

    Objectives: Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and ICU mortality but causality of these associations has not been demonstrated. To determine whether sepsis and severe sepsis are associated with vitamin D deficiency and to determine whether vitamin D deficiency influences the severity of sepsis. Design, Setting, and Patients: Sixty-one patients with sepsis and severe sepsis from two large U.K. hospitals and 20 healthy controls were recruited. Murine models of cecal ligation and puncture and intratracheal lipopolysaccharide were undertaken in normal and vitamin D deficient mice to address the issue of causality. Measurements and Main Results: Patients with severe sepsis had significantly lower concentrations of 25-hydroxyvitamin D3 than patients with either mild sepsis or age-matched healthy controls (15.7 vs 49.5 vs 66.5 nmol/L; p = 0.0001). 25-hydroxyvitamin D3 concentrations were significantly lower in patients who had positive microbiologic culture than those who were culture negative (p = 0.0023) as well as those who died within 30 days of hospital admission (p = 0.025). Vitamin D deficiency in murine sepsis was associated with increased peritoneal (p = 0.037), systemic (p = 0.019), and bronchoalveolar lavage (p = 0.011) quantitative bacterial culture. This was associated with reduced local expression of the cathelicidin-related antimicrobial peptide as well as evidence of defective macrophage phagocytosis (p = 0.029). In the intratracheal lipopolysaccharide model, 1,500 IU of intraperitoneal cholecalciferol treatment 6 hours postinjury reduced alveolar inflammation, cellular damage, and hypoxia. Conclusions: Vitamin D deficiency is common in severe sepsis. This appears to contribute to the development of the condition in clinically relevant murine models and approaches to correct vitamin D deficiency in patients with sepsis should be developed. PMID:27632669

  9. Alpha-1 antitrypsin (AAT) deficiency - what are the treatment options?

    PubMed

    Modrykamien, Ariel; Stoller, James K

    2009-11-01

    Alpha-1 antitrypsin (AAT) deficiency is an under-recognized genetic condition that predisposes to liver disease and early-onset emphysema. Although AAT is mainly produced in the liver, its main function is to protect the lung against proteolytic damage from neutrophil elastase. The most common mutation responsible for severe AAT deficiency, the so-called Z variant, reduces serum levels by promoting polymerization of the molecule within the hepatocyte, thereby reducing secretion. Serum levels below the putative protective threshold level of 11 micromolar (mumol/L) increase the risk of emphysema. In addition to the usual treatments for emphysema, infusion of purified AAT from pooled human plasma represents a specific therapy for AAT deficiency and raises serum and epithelial lining fluid levels above the protective threshold. Substantial evidence supports the biochemical efficacy of this approach, particularly for the weekly infusion regimen. Definitive evidence of clinical efficacy is still needed, as the two available randomized controlled trials showed non-significant trends towards slowing rates of loss of lung density on lung computerized axial tomography. However, concordant results of prospective cohort studies suggest that augmentation therapy has efficacy in slowing the rate of decline of lung function in patients with moderate airflow obstruction and severe deficiency of AAT. Overall, augmentation therapy is well-tolerated and, despite its failure to satisfy criteria for cost-effectiveness, is recommended because it is the only currently available specific therapy for AAT deficiency.

  10. Pitfalls in the diagnosis of multiple sulfatase deficiency.

    PubMed

    Mancini, G M; van Diggelen, O P; Huijmans, J G; Stroink, H; de Coo, R F

    2001-02-01

    Multiple sulfatase deficiency (MSD, OMIM 272200) is an autosomal recessive leukodystrophy associated with the deficiency of several, in total seven, sulfatases. The disorder is clinically and biochemically variable. The clinical picture combines features of mucopolysaccharidosis and metachromatic leukodystrophy (MLD, OMIM 250100) in a variable spectrum. Here we report a 3-year old Iranian girl with an MLD-like presentation of MSD. Arylsulfatase A deficiency and sulfatide excretion were found. Differently from what was previously reported in the literature, this girl never showed abnormal mucopolysaccharide excretion in the urine. There were no additional visceral or skeletal signs. She was originally diagnosed as having MLD. Only when she developed ichthyosis were seven additional sulfatases measured. In leukocytes, arylsulfatase A, steroid sulfatase and N-acetylglucosamine-6 sulfatase were profoundly deficient, while iduronate-2 sulfatase and arylsulfatase B were moderately reduced. In fibroblasts, N-acetylglucosamine-6 sulfatase was deficient, while arylsulfatase A was moderately reduced. This case illustrates the possible pitfalls in the clinical and laboratory diagnosis of MSD.

  11. Iron Deficiency and Bariatric Surgery

    PubMed Central

    Jáuregui-Lobera, Ignacio

    2013-01-01

    It is estimated that the prevalence of anaemia in patients scheduled for bariatric surgery is higher than in the general population and the prevalence of iron deficiencies (with or without anaemia) may be higher as well. After surgery, iron deficiencies and anaemia may occur in a higher percentage of patients, mainly as a consequence of nutrient deficiencies. In addition, perioperative anaemia has been related with increased postoperative morbidity and mortality and poorer quality of life after bariatric surgery. The treatment of perioperative anaemia and nutrient deficiencies has been shown to improve patients’ outcomes and quality of life. All patients should undergo an appropriate nutritional evaluation, including selective micronutrient measurements (e.g., iron), before any bariatric surgical procedure. In comparison with purely restrictive procedures, more extensive perioperative nutritional evaluations are required for malabsorptive procedures due to their nutritional consequences. The aim of this study was to review the current knowledge of nutritional deficits in obese patients and those that commonly appear after bariatric surgery, specifically iron deficiencies and their consequences. As a result, some recommendations for screening and supplementation are presented. PMID:23676549

  12. 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

  13. Melatonin deficiencies in women.

    PubMed

    Rohr, Uwe D; Herold, Jens

    2002-04-15

    The pineal hormone melatonin is the mediator of external light to physiologic adaptation to day and night rhythms, it regulates reproduction in animals but attempts to utilize melatonin in women for contraception have failed. Melatonin seems to be the natural hormone to facilitate sleep in insomniac patients and causes no hang over. When applied together with benzodiazepine it allows reduction of benzodiazepine without withdrawal effects. It should be applied 2 h before sleeping time in doses between 3 and 5 mg. Melatonin acts via the gamma-aminobutyric acid- and benzodiazepine receptor explaining its success in treatment of seizures in children and in adults. Constant application of benzodiazepine reduced the production of natural melatonin in rats, supporting the evidence that long-term application of benzodiazepine in humans does not restore sleeping habits but reduces natural sleeping habits even more. Low melatonin levels were seen in bulimia or neuralgia and in women with fibromyalgia; replacement reduced pain, sleeping disorders, and depression in fibromyalgia and bulimia. Melatonin profiles are a diagnostic tool to distinguish between several forms of depression, like major depression, winter depression (SAD), unipolar depression, delayed sleep phase syndrome (DSPS). In patients with a major depression success with antidepressants correlated with an increase in their melatonin profiles but only patients suffering from DSPS can be successfully treated with melatonin. In perimenopausal women melatonin administration did produce a change in LH, FSH and thyroid hormones. Some oncostatic properties are supported by cell culture work and studies in animals. In Nordic countries indigenous people suffer less from breast and prostate cancer, winter darkness seems to protect. The supposedly increased melatonin levels created the 'melatonin hypothesis'. Epidemiological studies did show that blind people indeed have half the rate of breast cancers, supporting the

  14. What factors contribute to successful appeals of nursing homes’ deficiencies in the informal dispute resolution process?

    PubMed Central

    Li, Yue; Weimer, David L.; Spector, William D.; Bailey, Lauren; Harrington, Charlene

    2012-01-01

    Objectives To determine what factors contribute to successful appeals of nursing home deficiencies in the Informal Dispute Resolution (IDR) process. Design We merged CMS data about IDRs with OSCAR data about nursing home characteristics. We performed multivariate statistical analyses to predict successful appeals as a function of characteristics of the deficiency being appealed, the survey that triggered the deficiency, characteristics of the nursing home, and the state. Setting All nursing homes nationally in the period 2005–2008. Measurements Successful appeals were defined as those in which the deficiency was removed or its severity or scope reduced. Independent variables included the CMS measures of severity and scope of deficiency, abuse and neglect, substandard care, total number of deficiencies in the survey, whether the IDR was triggered by a survey or complaint, facility ownership and reputation, and state stringency of regulation. Results 26% of submitted IDRs were successful in 2005–2008. Success was more likely for less severe deficiencies, when deficiencies were triggered by a survey rather than a complaint, and when fewer deficiencies were included in the appeal. Facility ownership and state stringency of regulation were not significantly associated with the IDR success. Conclusions Overall, 2.6% of deficiencies issued were overturned through the IDR process. Further study is required to determine the appropriateness of these overturned cases and the opportunities they offer to improve the survey process. PMID:23141210

  15. Effects of manganese deficiency and added cerium on nitrogen metabolism of maize.

    PubMed

    Gong, Xiaolan; Qu, Chunxiang; Liu, Chao; Hong, Mengmeng; Wang, Ling; Hong, Fashui

    2011-12-01

    Manganese is one of the essential microelements for plant growth, and cerium is a beneficial element for plant growth. However, whether manganese deficiency affects nitrogen metabolism of plants and cerium improves the nitrogen metabolism of plants by exposure to manganese-deficient media are still unclear. The main aim of the study was to determine the effects of manganese deficiency in nitrogen metabolism and the roles of cerium in the improvement of manganese-deficient effects in maize seedlings. Maize seedlings were cultivated in manganese present Meider's nutrient solution. They were subjected to manganese deficiency and to cerium chloride administered in the manganese-present and manganese-deficient media. Maize seedlings grown in the various media were measured for key enzyme activities involved in nitrogen metabolism, such as nitrate reductase, glutamate dehydrogenase, glutamine synthetase, and glutamic-oxaloace transaminase. We found that manganese deficiency restricted uptake and transport of NO(3)(-), inhibited activities of nitrogen-metabolism-related enzymes, such as nitrate reductase, glutamine synthetase, and glutamic-oxaloace transaminase, thus decreasing the synthesis of chlorophyll and soluble protein, and inhibited the growth of maize seedlings. Manganese deficiency promoted the activity of glutamate dehydrogenase and reduced the toxicity of excess ammonia to the plant, while added cerium relieved the damage to nitrogen metabolism caused by manganese deficiency in maize seedlings. However, cerium addition exerted positively to relieve the damage of nitrogen metabolism process in maize seedlings caused by exposure to manganese-deficient media.

  16. 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.

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

    PubMed

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

    2016-11-01

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

  19. Impact of micronutrient deficiencies on obesity.

    PubMed

    García, Olga P; Long, Kurt Z; Rosado, Jorge L

    2009-10-01

    Micronutrient deficiencies have been found in obese individuals across age groups worldwide. While the effects of micronutrient deficiencies on human functions have been studied widely in different populations, there is limited information on how these micronutrient deficiencies affect obese populations. An examination of the available literature suggests associations exist between micronutrient deficiencies and obesity in different populations. These associations and possible mechanisms of the deficiencies' metabolic effects, such as their influence on leptin and insulin metabolism, are discussed here. Further studies are needed to clarify the roles of the different micronutrient deficiencies with respect to obesity and its comorbid conditions.

  20. Parental vitamin deficiency affects the embryonic gene expression of immune-, lipid transport- and apolipoprotein genes

    PubMed Central

    Skjærven, Kaja H.; Jakt, Lars Martin; Dahl, John Arne; Espe, Marit; Aanes, Håvard; Hamre, Kristin; Fernandes, Jorge M. O.

    2016-01-01

    World Health Organization is concerned for parental vitamin deficiency and its effect on offspring health. This study examines the effect of a marginally dietary-induced parental one carbon (1-C) micronutrient deficiency on embryonic gene expression using zebrafish. Metabolic profiling revealed a reduced 1-C cycle efficiency in F0 generation. Parental deficiency reduced the fecundity and a total of 364 genes were differentially expressed in the F1 embryos. The upregulated genes (53%) in the deficient group were enriched in biological processes such as immune response and blood coagulation. Several genes encoding enzymes essential for the 1-C cycle and for lipid transport (especially apolipoproteins) were aberrantly expressed. We show that a parental diet deficient in micronutrients disturbs the expression in descendant embryos of genes associated with overall health, and result in inherited aberrations in the 1-C cycle and lipid metabolism. This emphasises the importance of parental micronutrient status for the health of the offspring. PMID:27731423

  1. Parental vitamin deficiency affects the embryonic gene expression of immune-, lipid transport- and apolipoprotein genes

    NASA Astrophysics Data System (ADS)

    Skjærven, Kaja H.; Jakt, Lars Martin; Dahl, John Arne; Espe, Marit; Aanes, Håvard; Hamre, Kristin; Fernandes, Jorge M. O.

    2016-10-01

    World Health Organization is concerned for parental vitamin deficiency and its effect on offspring health. This study examines the effect of a marginally dietary-induced parental one carbon (1-C) micronutrient deficiency on embryonic gene expression using zebrafish. Metabolic profiling revealed a reduced 1-C cycle efficiency in F0 generation. Parental deficiency reduced the fecundity and a total of 364 genes were differentially expressed in the F1 embryos. The upregulated genes (53%) in the deficient group were enriched in biological processes such as immune response and blood coagulation. Several genes encoding enzymes essential for the 1-C cycle and for lipid transport (especially apolipoproteins) were aberrantly expressed. We show that a parental diet deficient in micronutrients disturbs the expression in descendant embryos of genes associated with overall health, and result in inherited aberrations in the 1-C cycle and lipid metabolism. This emphasises the importance of parental micronutrient status for the health of the offspring.

  2. 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

  3. 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.

  4. Association between celiac disease and primary lactase deficiency.

    PubMed

    Basso, M S; Luciano, R; Ferretti, F; Muraca, M; Panetta, F; Bracci, F; Ottino, S; Diamanti, A

    2012-12-01

    Primary lactase deficiency (PLD) is a common inherited condition caused by a reduced activity of lactase. Two single-nucleotide polymorphisms C/T(-13910) and G/A(-22018) upstream of the lactase gene are associated with lactase nonpersistence. In celiac disease (CD) patients, lactose intolerance could be due to secondary lactase deficiency and to PLD. The aim of this study were to evaluate the association of PLD and CD using genetic test, and to define the prevalence of PLD in celiac subjects compared with a control population. A total of 188 controls and 92 biopsy-proven CD patients were included in the study. More than 70% of all subjects were found homozygous for the polymorphisms. Differences in the prevalence of PLD were not found between CD patients and controls.In conclusions, the hereditary lactase deficiency is frequent in Italian CD children as in control population.

  5. Gestational magnesium deficiency is deleterious to fetal outcome.

    PubMed

    Almonte, R A; Heath, D L; Whitehall, J; Russell, M J; Patole, S; Vink, R

    1999-07-01

    A number of recent epidemiological findings have implicated magnesium as being essential to fetal well-being. Few studies, however, have examined the relationship between maternal requirements for dietary magnesium and subsequent mortality and morbidity in offspring. The present study uses a rodent model of dietary-induced hypomagnesemia to investigate the effects of magnesium deficiency prior to and during gestation on neonatal morbidity and mortality. Magnesium deficiency during gestation significantly increased neonatal mortality and morbidity. Such increases were associated with a reduced free magnesium concentration in both maternal and offspring blood and an increased incidence of periventricular hemorrhage and edema in newborn pups as observed by magnetic resonance imaging and histology. Animals fed a magnesium-deficient diet before mating but given magnesium supplementation during gestation did not demonstrate a significant change in neonatal mortality and morbidity when compared to control animals. The significant improvement in fetal outcome with dietary magnesium supports the concept of magnesium supplementation during pregnancy.

  6. 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.

  7. Nutritional deficiencies after bariatric surgery.

    PubMed

    Davies, D J; Baxter, J M; Baxter, J N

    2007-09-01

    A current review of nutritional complications following bariatric procedures is presented, focusing on the most common and clinically important deficiencies. A brief outline of nutritional supplementation protocol is presented, highlighting the need for a standardized, national or international set of guidelines for pre- and postoperative nutritional screening and appropriate supplementation.

  8. 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…

  9. 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…

  10. Case report: pyruvate kinase deficiency.

    PubMed

    Rothman, J M

    1995-09-01

    Pyruvate kinase deficiency is a rare cause of congenital hemolytic anemia. Despite a paucity of reports, splenectomy resulted in successful outcomes for two siblings with this disorder. The sisters were diagnosed at birth with profound jaundice and congenital nonspherocytic hemolytic anemia.

  11. Genetics Home Reference: arginase deficiency

    MedlinePlus

    ... of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, ... enzyme controls the final step of the urea cycle, which produces urea by removing nitrogen from arginine. In people with arginase deficiency , arginase ...

  12. 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 ...

  13. Impaired energy metabolism of the taurine‑deficient heart.

    PubMed

    Schaffer, Stephen W; Shimada-Takaura, Kayoko; Jong, Chian Ju; Ito, Takashi; Takahashi, Kyoko

    2016-02-01

    Taurine is a β-amino acid found in high concentrations in excitable tissues, including the heart. A significant reduction in myocardial taurine content leads to the development of a unique dilated, atrophic cardiomyopathy. One of the major functions of taurine in the heart is the regulation of the respiratory chain. Hence, we tested the hypothesis that taurine deficiency-mediated defects in respiratory chain function lead to impaired energy metabolism and reduced ATP generation. We found that while the rate of glycolysis was significantly enhanced in the taurine-deficient heart, glucose oxidation was diminished. The major site of reduced glucose oxidation was pyruvate dehydrogenase, an enzyme whose activity is reduced by the increase in the NADH/NAD+ ratio and by decreased availability of pyruvate for oxidation to acetyl CoA and changes in [Mg2+]i. Also diminished in the taurine-deficient heart was the oxidation of two other precursors of acetyl CoA, endogenous fatty acids and exogenous acetate. In the taurine-deficient heart, impaired citric acid cycle activity decreased both acetate oxidation and endogenous fatty acid oxidation, but reductions in the activity of the mitochondrial transporter, carnitine palmitoyl transferase, appeared to also contribute to the reduction in fatty acid oxidation. These changes diminished the rate of ATP production, causing a decline in the phosphocreatine/ATP ratio, a sign of reduced energy status. The findings support the hypothesis that the taurine-deficient heart is energy starved primarily because of impaired respiratory chain function, an increase in the NADH/NAD+ ratio and diminished long chain fatty acid uptake by the mitochondria. The results suggest that improved energy metabolism contributes to the beneficial effect of taurine therapy in patients suffering from heart failure.

  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. 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

  16. Vitamin D deficiency in chronic idiopathic urticaria.

    PubMed

    Movahedi, Masoud; Tavakol, Marzieh; Hirbod-Mobarakeh, Armin; Gharagozlou, Mohammad; Aghamohammadi, Asghar; Tavakol, Zahra; Momenzadeh, Kaveh; Nabavi, Mohammad; Dabbaghzade, Abbas; Mosallanejad, Asieh; Rezaei, Nima

    2015-04-01

    Chronic urticaria is the most common skin diseases, characterized by chronic cutaneous lesions which severely debilitates patients in several aspects of their everyday life. Vitamin D is known to exert several actions in the immune system and to influence function and differentiation of mast cells, central role players in the pathogenesis of chronic idiopathic urticaria. This study was performed to evaluate the relationship between vitamin D levels and susceptibility to chronic idiopathic urticaria. One hundred and fourteen patients with chronic idiopathic urticaria were recruited in this study along with one hundred and eighty seven sex-matched and age-matched healthy volunteers as the control group. For each patient, urticaria activity score was calculated and autologous serum skin test was done. Vitamin D metabolic statue was measured in serum as 25 hydroxyvitamin D using enzyme immunoassay method. Patients with chronic idiopathic urticaria significantly showed lower levels of vitamin D. Vitamin D deficiency was significantly associated with increased susceptibility to chronic idiopathic urticaria. There was a significant positive correlation between vitamin D levels and urticaria activity score. This study showed that patients with chronic idiopathic urticaria had reduced levels of vitamin D, while vitamin D deficiency could increase susceptibility to chronic idiopathic urticaria.

  17. Adult neurogenesis in serotonin transporter deficient mice.

    PubMed

    Schmitt, A; Benninghoff, J; Moessner, R; Rizzi, M; Paizanis, E; Doenitz, C; Gross, S; Hermann, M; Gritti, A; Lanfumey, L; Fritzen, S; Reif, A; Hamon, M; Murphy, D L; Vescovi, A; Lesch, K-P

    2007-09-01

    Serotonin (5-HT) is a regulator of morphogenetic activities during early brain development and neurogenesis, including cell proliferation, migration, differentiation, and synaptogenesis. The 5-HT transporter (5-HTT, SLC6A4) mediates high-affinity reuptake of 5-HT into presynaptic terminals and thereby fine-tunes serotonergic neurotransmission. Inactivation of the 5-HTT gene in mice reduces 5-HT clearance resulting in persistently increased concentrations of synaptic 5-HT. In the present study, we investigated the effects of elevated 5-HT levels on adult neurogenesis in the hippocampus of 5-HTT deficient mice, including stem cell proliferation, survival, and differentiation. Using an in vivo approach, we showed an increase in proliferative capacity of hippocampal adult neural stem cells in aged 5-HTT knockout mice (approximately 14.5 months) compared to wildtype controls. In contrast, in vivo and additional in vitro analyses of younger adult 5-HTT knockout mice (approximately 7 weeks and approximately 3.0 months) did not reveal significant changes in proliferation of neural stem cells or survival of newborn cells. We showed that the cellular fate of newly generated cells in 5-HTT knockout mice is not different with respect to the total number and percentage of neurons or glial cells from wildtype controls. Our findings indicate that elevated synaptic 5-HT concentration throughout early development and later life of 5-HTT deficient mice does not induce adult neurogenesis in adult mice, but that elevated 5-HT levels in aged mice influence stem cell proliferation.

  18. Effects of model deficiencies on parameter estimation

    NASA Technical Reports Server (NTRS)

    Hasselman, T. K.

    1988-01-01

    Reliable structural dynamic models will be required as a basis for deriving the reduced-order plant models used in control systems for large space structures. Ground vibration testing and model verification will play an important role in the development of these models; however, fundamental differences between the space environment and earth environment, as well as variations in structural properties due to as-built conditions, will make on-orbit identification essential. The efficiency, and perhaps even the success, of on-orbit identification will depend on having a valid model of the structure. It is envisioned that the identification process will primarily involve parametric methods. Given a correct model, a variety of estimation algorithms may be used to estimate parameter values. This paper explores the effects of modeling errors and model deficiencies on parameter estimation by reviewing previous case histories. The effects depend at least to some extent on the estimation algorithm being used. Bayesian estimation was used in the case histories presented here. It is therefore conceivable that the behavior of an estimation algorithm might be useful in detecting and possibly even diagnosing deficiencies. In practice, the task is complicated by the presence of systematic errors in experimental procedures and data processing and in the use of the estimation procedures themselves.

  19. 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

  20. 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.

  1. Copper deficiency in neonatal mice alters brain catecholamine levels

    SciTech Connect

    Bailey, W.R.; Prohaska, J.R. )

    1991-03-15

    Copper (Cu) deficiency was investigated in Swiss albino mice to develop a model that alters brain catecholamine metabolism without serious growth impairment. Cu deficiency was induced by feeding a diet low in Cu to dams beginning either 7 days (d) prior, 4d prior, 4d after, or on the day of parturition. All 4-week-old male Cu-deficient ({minus}Cu) offspring were anemic and exhibited biochemical characteristics of Cu deficiency when compared to their respective +Cu control mice. However, the best model, which resulted in altered catecholamine metabolism characterized by elevation of dopamine (DA) and depression in norepinephrine (NE) in brain, heart, and spleen, was when treatment began 4d prior to birth. Body and brain weight were not altered. However, levels of Cu in brain and liver of {minus}Cu mice were markedly reduced to 21% and 31% of those measured in +Cu controls, respectively. Furthermore, brain NE and DA concentrations of {minus}Cu mice were 72% and 132% of those quantified in +Cu offspring, respectively. A plausible explanation is that dietary Cu deficiency results in lower activity of brain dopamine-{beta}-monooxygenase, the Cu dependent enzyme that catalyzes conversion of DA to NE. It is not yet known if these changes in Ne and DA pool size altered the quantity or characteristics of the neuronal catecholamine receptors, and more importantly, whether or not the observed changes are reversible by nutritional intervention.

  2. Replication Fork Stability Confers Chemoresistance in BRCA-deficient Cells

    PubMed Central

    Chaudhuri, Arnab Ray; 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

    2016-01-01

    Brca1- and Brca2-deficient cells have reduced capacity to repair DNA double-strand breaks (DSBs) by homologous recombination (HR) 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 HR activity at DSBs. 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 PARPi and cisplatin resistance is associated with replication fork (RF) protection in Brca2-deficient tumor cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of RF protection, highlighting the complexities by which tumor cells evade chemotherapeutic interventions and acquire drug resistance. PMID:27443740

  3. 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- ...

  4. Vitamin K deficiency bleeding of the newborn

    MedlinePlus

    Vitamin K deficiency bleeding of the newborn (VKDB) is a bleeding disorder in babies. It most often develops shortly ... Control and Prevention. Notes from the field: late vitamin K deficiency bleeding in infants whose parents declined vitamin K ...

  5. Genetics Home Reference: beta-ureidopropionase deficiency

    MedlinePlus

    ... down N-carbamyl-beta-alanine to beta-alanine, ammonia, and carbon dioxide. Both beta-aminoisobutyric acid and ... beta-ureidopropionase deficiency Merck Manual Professional Version: Pyrimidine Metabolism Disorders Orphanet: Beta-ureidopropionase deficiency Patient Support and ...

  6. 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

  7. Growth hormone deficiency in treated acromegaly.

    PubMed

    Mazziotti, Gherardo; Marzullo, Paolo; Doga, Mauro; Aimaretti, Gianluca; Giustina, Andrea

    2015-01-01

    Growth hormone deficiency (GHD) of the adult is characterized by reduced quality of life (QoL) and physical fitness, skeletal fragility, and increased weight and cardiovascular risk. Hypopituitarism may develop in patients after definitive treatment of acromegaly, but an exact prevalence of GHD in this population is still uncertain owing to limited awareness and the scarce and conflicting data available on this topic. Because acromegaly and GHD may yield adverse consequences on similar target systems, the final outcomes of some complications of acromegaly may be further affected by the occurrence of GHD. However, it is still largely unknown whether patients with post-acromegaly GHD may benefit from GH replacement. We review the diagnostic, clinical, and therapeutic aspects of GHD in adult patients treated for acromegaly.

  8. Intravenous immunoglobulin therapy for antibody deficiency.

    PubMed Central

    Nolte, M T; Pirofsky, B; Gerritz, G A; Golding, B

    1979-01-01

    Twenty patients with antibody deficiency were treated at random with either intramuscular immune serum globulin (ISG) or intravenous modified immune serum globulin (M-ISG). Fourteen patients received of 259 M-ISG infusions during 242 months of treatment. Catastrophic vasomotor reactions were not observed. A single dose of 150 mg/kilo M-ISG increased serum IgG values a mean 248 mg%. Intravenous M-ISG therapy was effective in reducing the incidence of acute infections. Subjects receiving M-ISG developed 0.103 acute infections per month of treatment. Patients injected with ISG had 0.295 acute infections per month of treatment. Seven subjects had separate courses of both intravenous M-ISG and intramuscular ISG. Acute infections per month of treatment for M-ISG and ISG were 0.104 and 0.406, respectively. PMID:477026

  9. 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.

  10. 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

  11. 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...

  12. 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…

  13. Proton translocation in cytochrome-deficient mutants of Escherichia coli.

    PubMed Central

    Brookman, J J; Downie, J A; Gibson, F; Cox, G B; Rosenberg, H

    1979-01-01

    Cytochrome-deficient cells of a strain of Escherichia coli lacking 5-amino-levulinate synthetase have been used to study proton translocation associated with the reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase region of the electron transport chain. Menadione was used as electron acceptor, and mannitol was used as the substrate for the generation of intracellular NADH. The effects of iron deficiency on NADH- and D-lactate-menadione reductase activities were studied in iron-deficient cells of a mutant strain unable to synthesize the iron chelator enterochelin; both activities were reduced. The NADH- menadione reductase activity in cytochrome-deficient cells was associated with proton translocation and could be coupled to the uptake of proline. However proton translocation associated with the NADH-menadione reductase activity was prevented by a mutation in an unc gene. It was concluded that there is no proton translocation associated with the NADH-dehydrogenase region of the electron transport chain in E. coli and that the proton translocation obtained with mannitol as substrate is due to the activity of membrane-bound adenosine triphosphatase. PMID:154508

  14. 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

  15. Iron deficiency and brain development.

    PubMed

    Lozoff, Betsy; Georgieff, Michael K

    2006-09-01

    Iron deficiency (ID) is common in pregnant women and infants worldwide. Rodent models show that ID during gestation/lactation alters neurometabolism, neurotransmitters, myelination, and gene/protein profiles before and after iron repletion at weaning. Human infants with iron deficiency anemia test lower in cognitive, motor, social-emotional, and neurophysiologic development than comparison group infants. Iron therapy does not consistently improve developmental outcome, with long-term differences observed. Poorer outcome has also been shown in human and monkey infants with fetal/neonatal ID. Recent randomized trials of infant iron supplementation show benefits, indicating that adverse effects can be prevented and/or reversed with iron earlier in development or before ID becomes severe or chronic. This body of research emphasizes the importance of protecting the developing brain from ID.

  16. Oestrogen deficiency after tubal ligation.

    PubMed

    Cattanach, J

    1985-04-13

    4 of 7 women who had undergone tubal ligation within the past seven years were found to have oestrogen excretion concentrations at ovulation below the tenth percentile. A disturbance in the oestrogen/progesterone ratio as a consequence of localised hypertension at the ovary, when the utero-ovarian arterial loop is occluded at tubal ligation, is proposed as a possible cause of oestrogen deficiency syndrome, dysfunctional uterine bleeding, and menorrhagia after tubal ligation. Similar pathophysiology may occur after hysterectomy with ovarian conservation.

  17. Congenital deficiency of factor VII.

    PubMed

    Sikka, M; Gomber, S; Madan, N; Rusia, U; Sharma, S

    1996-01-01

    A case of congenital factor VII deficiency in a five-year-old child is reported. The patient, born of a non-consanguineous marriage, presented with repeated bouts of epistaxis since childhood. The prothrombin time (PT) was markedly prolonged with a normal bleeding time (BT), partial thromboplastin time with Kaolin (PTTK) and platelet count. The patient has been on follow up for the last four years and is doing apparently well.

  18. Current issues in iron deficiency.

    PubMed

    Baynes, R D; Cook, J D

    1996-03-01

    This brief review of developments relating to iron deficiency during the past year covers three main areas: iron supplementation, the regulation of iron absorption, and the use of the serum transferrin receptor for the assessment of iron status. The intermittent administration of iron supplement once or twice weekly rather than daily has been advocated by international health agencies in recent years, but radioiron absorption studies in human subjects have failed to demonstrate any absorptive advantage of the intermittent schedule. The value of prophylactic iron supplementation in elderly blood donors was evaluated and shown to offer limited benefit in maintaining donation frequency. A recent model of the regulation of iron absorption involving erythropoietic and store regulators is discussed and a recent article indicating a potential non-hematopoietic effect of hematopoietic growth factors on iron absorption by the gastrointestinal mucosal cell is reviewed. A new measure of functional iron deficiency, namely the serum transferrin receptor, is discussed, with particular reference to its mechanism of production and its great value in distinguishing iron deficiency anemia from the anemia of chronic disease.

  19. 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

  20. Mitochondrial cytochrome c oxidase deficiency.

    PubMed

    Rak, Malgorzata; Bénit, Paule; Chrétien, Dominique; Bouchereau, Juliette; Schiff, Manuel; El-Khoury, Riyad; Tzagoloff, Alexander; Rustin, Pierre

    2016-03-01

    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 of studying 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.

  1. Progesterone Deficiency and Premature Labour

    PubMed Central

    Csapo, A. I.; Pohanka, O.; Kaihola, H. L.

    1974-01-01

    Plasma oestradiol 17β and progesterone levels in 11 patients admitted to hospital for threatened premature labour of unknown aetiology were compared with those of women at similar stages of gestation whose pregnancy was normal. Oestradiol levels in the study group were slightly higher than in the normal controls but their progesterone levels were significantly lower. This progesterone deficiency increased the oestradiol/progesterone ratio in the study group patients, and it increased still more as the progesterone withdrawal continued during premature labour. Since uterine activity during pregnancy is regulated by a balanced action of several factors a deficiency in progesterone, an opponent of uterine activity, creates a regulatory imbalance which, if uncorrected, provokes premature labour. An increase in uterine volume stimulates uterine activity, and the present study reinforced our previous conclusion that the uterine-volume/plasma-progesterone ratio is a more accurate measure of the state of regulatory balance than the progesterone level alone. The cause of the progesterone deficiency in these cases remains unexplained, but we suggest that placental growth and function are contributory factors. We are investigating ways of correcting the resulting imbalance in the regulatory mechanism. PMID:4812406

  2. 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

  3. 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

  4. [Preoperative screening and nutritional support of nutritional deficiencies].

    PubMed

    Zazzo, J-F

    2004-01-01

    Nutritional deficiencies have to be considered as an independent risk factor for postoperative morbidity. Peri-operative nutritional support reduce this risk in elective abdominal surgery for cancer and cardiac surgery. Preoperative nutritional support for 7-10 days reduce postoperative complications in undernourished patients by 10% but is not operant when administered after surgery. Enteral route is as effective. Recent studies using immunonutrients conclude that a short preoperative oral intake is able to reduce complications even in well-nourished patients. Then, a preoperative nutritional screening must be routinely performed leading to a nutritional programme.

  5. 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 ...

  6. Genetics Home Reference: malonyl-CoA decarboxylase deficiency

    MedlinePlus

    ... deficiency of malonyl-CoA decarboxylase malonic aciduria malonyl-coenzyme A decarboxylase deficiency MCD deficiency Related Information How ... molecular characterization of nine new patients with malonyl-coenzyme A decarboxylase deficiency. J Inherit Metab Dis. 2007 ...

  7. Early senescence of the oldest leaves of Fe-deficient barley plants may contribute to phytosiderophore release from the roots.

    PubMed

    Higuchi, Kyoko; Iwase, Jun; Tsukiori, Yoshifumi; Nakura, Daiki; Kobayashi, Nahoko; Ohashi, Hidenori; Saito, Akihiro; Miwa, Eitaro

    2014-07-01

    Barley (Hordeum vulgare), which tolerates iron (Fe) deficiency, secretes a large amount of phytosiderophores from its roots. However, how barley is able to allocate resources for phytosiderophore synthesis when the carbon assimilation rate is reduced by Fe deficiency is unknown. We previously suggested that the acceleration of senescence in older leaves triggered by Fe deficiency may allow the recycling of assimilates to contribute to phytosiderophore synthesis. In this work, we show the relationship between an increase in the C/N ratio in older leaves and Fe-deficiency tolerance among three barley cultivars. The increase in the C/N ratio suggests an enhanced capacity for the retranslocation of carbohydrates or amino acids from older leaves to the sink organs. An increase in the sucrose concentration in Fe-deficient barley also suggests active redistribution of assimilates. This metabolic modulation may be supported by accelerated senescence of older leaves, as Fe deficiency increased the expression of senescence-associated genes. The older leaves of Fe-deficient barley maintained CO2 assimilation under Fe deficiency. Barley that had been Fe-deficient for 3 days preferentially allocated newly assimilated (13) C to the roots and nutrient solution. Interestingly, the oldest leaf of Fe-deficient barley released more (13) C into the nutrient solution than the second oldest leaf. Thus, the balance between anabolism and catabolism in older leaves, supported by highly regulated senescence, plays a key role in metabolic adaptation in Fe-deficient barley.

  8. Deficiencies in the Management of Iron Deficiency Anemia During Childhood.

    PubMed

    Powers, Jacquelyn M; Daniel, Catherine L; McCavit, Timothy L; Buchanan, George R

    2016-04-01

    Limited high-quality evidence supports the management of iron deficiency anemia (IDA). To assess our institutional performance in this area, we retrospectively reviewed IDA treatment practices in 195 consecutive children referred to our center from 2006 to mid-2010. The majority of children were ≤4 years old (64%) and had nutritional IDA (74%). In 11- to 18-year-old patients (31%), the primary etiology was menorrhagia (42%). Many were referred directly to the emergency department and/or prescribed iron doses outside the recommended range. Poor medication adherence and being lost-to-follow-up were common. Substantial improvements are required in the management of IDA.

  9. [Band 3 deficiency as a cause of hereditary spherocytosis].

    PubMed

    Wada, Hideho; Suemori, Shin-Ichiro; Nakanishi, Hidekazu; Sugihara, Takashi

    2015-07-01

    Band 3 protein accounts for the largest percentage of whole erythrocyte membrane proteins. Abnormalities in this protein are closely associated with pathologies including hereditary spherocytosis (HS), Southeast Asian ovalocytosis and distant renal tubular acidosis. Currently, EMA binding capacity measurement in erythrocytes is the most useful screening test for diagnosing HS. We have also demonstrated reduced EMA binding capacity in patients with HS who have deficiencies of membrane proteins such as ankyrin not directly binding to EMA and who have as yet undetectable abnormalities of membrane proteins. However, even patients with hereditary elliptocytosis, who have a partial spectrin deficiency, were found to show reduced EMA binding capacity. Six of 7 had spherocytic elliptocytosis. Therefore, it is necessary to meticulously diagnose HS by ruling out all other possibilities.

  10. Osteopontin Deficiency Increases Bone Fragility but Preserves Bone Mass

    PubMed Central

    Thurner, Philipp J.; Chen, Carol G.; Ionova-Martin, Sophi; Sun, Luling; Harman, Adam; Porter, Alexandra; Ager, Joel W.; Ritchie, Robert O.; Alliston, Tamara

    2010-01-01

    The ability of bone to resist catastrophic failure is critically dependent upon the material properties of bone matrix, a composite of hydroxyapatite, collagen type I, and noncollagenous proteins. These properties include elastic modulus, hardness, and fracture toughness. Like other aspects of bone quality, matrix material properties are biologically-defined and can be disrupted in skeletal disease. While mineral and collagen have been investigated in greater detail, the contribution of noncollagenous proteins such as osteopontin to bone matrix material properties remains unclear. Several roles have been ascribed to osteopontin in bone, many of which have the potential to impact material properties. To elucidate the role of osteopontin in bone quality, we evaluated the structure, composition, and material properties of bone from osteopontin-deficient mice and wild-type littermates at several length scales. Most importantly, the results show that osteopontin deficiency causes a 30% decrease in fracture toughness, suggesting an important role for OPN in preventing crack propagation. This significant decline in fracture toughness is independent of changes in whole bone mass, structure, or matrix porosity. Using nanoindentation and quantitative backscattered electron imaging to evaluate osteopontin-deficient bone matrix at the micrometer level, we observed a significant reduction in elastic modulus and increased variability in calcium concentration. Matrix heterogeneity was also apparent at the ultrastructural level. In conclusion, we find that osteopontin is essential for the fracture toughness of bone, and reduced toughness in osteopontin-deficient bone may be related to the increased matrix heterogeneity observed at the micro-scale. By exploring the effects of osteopontin-deficiency on bone matrix material properties, composition and organization, this study suggests that reduced fracture toughness is one mechanism by which loss of noncollagenous proteins contribute

  11. Osteopontin deficiency increases bone fragility but preserves bone mass.

    PubMed

    Thurner, Philipp J; Chen, Carol G; Ionova-Martin, Sophi; Sun, Luling; Harman, Adam; Porter, Alexandra; Ager, Joel W; Ritchie, Robert O; Alliston, Tamara

    2010-06-01

    The ability of bone to resist catastrophic failure is critically dependent upon the material properties of bone matrix, a composite of hydroxyapatite, collagen type I, and noncollagenous proteins. These properties include elastic modulus, hardness, and fracture toughness. Like other aspects of bone quality, matrix material properties are biologically-defined and can be disrupted in skeletal disease. While mineral and collagen have been investigated in greater detail, the contribution of noncollagenous proteins such as osteopontin to bone matrix material properties remains unclear. Several roles have been ascribed to osteopontin in bone, many of which have the potential to impact material properties. To elucidate the role of osteopontin in bone quality, we evaluated the structure, composition, and material properties of bone from osteopontin-deficient mice and wild-type littermates at several length scales. Most importantly, the results show that osteopontin deficiency causes a 30% decrease in fracture toughness, suggesting an important role for OPN in preventing crack propagation. This significant decline in fracture toughness is independent of changes in whole bone mass, structure, or matrix porosity. Using nanoindentation and quantitative backscattered electron imaging to evaluate osteopontin-deficient bone matrix at the micrometer level, we observed a significant reduction in elastic modulus and increased variability in calcium concentration. Matrix heterogeneity was also apparent at the ultrastructural level. In conclusion, we find that osteopontin is essential for the fracture toughness of bone, and reduced toughness in osteopontin-deficient bone may be related to the increased matrix heterogeneity observed at the micro-scale. By exploring the effects of osteopontin deficiency on bone matrix material properties, composition and organization, this study suggests that reduced fracture toughness is one mechanism by which loss of noncollagenous proteins contribute

  12. Peptic ulceration may be a hormonal deficiency disease.

    PubMed

    Love, Jack W

    2008-01-01

    Evidence is reviewed that Helicobacter pylori infection may cause a deficiency of the hormone secretin that allows peptic ulcer disease to develop by impairing the body's defenses to gastric acid. Secretin is released into the circulation from the S-cells of the duodenal crypts in response to gastric acid entering the duodenum. Once in the circulation, secretin has five well-documented effects that protect the upper intestine from gastric acid: it stimulates secretion of bicarbonate rich exocrine pancreatic juice; it stimulates secretion of alkaline bile; it stimulates secretion of alkaline mucus from the duodenal submucosal glands of Brunner; it inhibits the humoral phase of gastric secretion; and it inhibits gastric motility, thereby delaying gastric emptying. Impaired secretin release and reduced duodenal S-cells have been documented in peptic ulcer patients compared with control patients. Clinical evidence that patients with H. pylori infection and peptic ulceration have increased gastric secretion and motility and decreased duodenal bicarbonate response to gastric acid, all of which normalize after eradication of the infection, could be explained by reversible impairment of the secretin mechanism. Gastric metaplasia in the duodenum with H. pylori infection is known to reduce the S-cell population. The fact that not all patients with H. pylori infection develop peptic ulceration suggests that degree of secretin deficiency determined by extent of the infection must reach a critical level for peptic ulceration to occur. Peptic ulceration may be a hormonal deficiency disease, a result of secretin deficiency caused by H. pylori infection. It may be the first example of a specific hormonal deficiency disease caused by a specific bacterial infection.

  13. Ascorbate Alleviates Fe Deficiency-Induced Stress in Cotton (Gossypium hirsutum) by Modulating ABA Levels.

    PubMed

    Guo, Kai; Tu, Lili; Wang, Pengcheng; Du, Xueqiong; Ye, Shue; Luo, Ming; Zhang, Xianlong

    2016-01-01

    Fe deficiency causes significant losses to crop productivity and quality. To understand better the mechanisms of plant responses to Fe deficiency, we used an in vitro cotton ovule culture system. We found that Fe deficiency suppressed the development of ovules and fibers, and led to tissue browning. RNA-seq analysis showed that the myo-inositol and galacturonic acid pathways were activated and cytosolic APX (ascorbate peroxidase) was suppressed in Fe-deficient treated fibers, which increased ASC (ascorbate) concentrations to prevent tissue browning. Suppression of cytosolic APX by RNAi in cotton increased ASC contents and delayed tissue browning by maintaining ferric reduction activity under Fe-deficient conditions. Meanwhile, APX RNAi line also exhibited the activation of expression of iron-regulated transporter (IRT1) and ferric reductase-oxidase2 (FRO2) to adapt to Fe deficiency. Abscisic acid (ABA) levels were significantly decreased in Fe-deficient treated ovules and fibers, while the upregulated expression of ABA biosynthesis genes and suppression of ABA degradation genes in Fe-deficient ovules slowed down the decreased of ABA in cytosolic APX suppressed lines to delay the tissue browning. Moreover, the application of ABA in Fe-deficient medium suppressed the development of tissue browning and completely restored the ferric reduction activity. In addition, ABA 8'-hydroxylase gene (GhABAH1) overexpressed cotton has a decreased level of ABA and shows more sensitivity to Fe deficiency. Based on the results, we speculate that ASC could improve the tolerance to Fe deficiency through activating Fe uptake and maintaining ABA levels in cotton ovules and fibers, which in turn reduces symptom formation.

  14. Ascorbate Alleviates Fe Deficiency-Induced Stress in Cotton (Gossypium hirsutum) by Modulating ABA Levels

    PubMed Central

    Guo, Kai; Tu, Lili; Wang, Pengcheng; Du, Xueqiong; Ye, Shue; Luo, Ming; Zhang, Xianlong

    2017-01-01

    Fe deficiency causes significant losses to crop productivity and quality. To understand better the mechanisms of plant responses to Fe deficiency, we used an in vitro cotton ovule culture system. We found that Fe deficiency suppressed the development of ovules and fibers, and led to tissue browning. RNA-seq analysis showed that the myo-inositol and galacturonic acid pathways were activated and cytosolic APX (ascorbate peroxidase) was suppressed in Fe-deficient treated fibers, which increased ASC (ascorbate) concentrations to prevent tissue browning. Suppression of cytosolic APX by RNAi in cotton increased ASC contents and delayed tissue browning by maintaining ferric reduction activity under Fe-deficient conditions. Meanwhile, APX RNAi line also exhibited the activation of expression of iron-regulated transporter (IRT1) and ferric reductase–oxidase2 (FRO2) to adapt to Fe deficiency. Abscisic acid (ABA) levels were significantly decreased in Fe-deficient treated ovules and fibers, while the upregulated expression of ABA biosynthesis genes and suppression of ABA degradation genes in Fe-deficient ovules slowed down the decreased of ABA in cytosolic APX suppressed lines to delay the tissue browning. Moreover, the application of ABA in Fe-deficient medium suppressed the development of tissue browning and completely restored the ferric reduction activity. In addition, ABA 8′-hydroxylase gene (GhABAH1) overexpressed cotton has a decreased level of ABA and shows more sensitivity to Fe deficiency. Based on the results, we speculate that ASC could improve the tolerance to Fe deficiency through activating Fe uptake and maintaining ABA levels in cotton ovules and fibers, which in turn reduces symptom formation. PMID:28101095

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

    PubMed Central

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

    1994-01-01

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

  16. Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood

    PubMed Central

    Ng, Joanne; Zhen, Juan; Meyer, Esther; Erreger, Kevin; Li, Yan; Kakar, Naseebullah; Ahmad, Jamil; Thiele, Holger; Kubisch, Christian; Rider, Nicholas L.; Holmes Morton, D.; Strauss, Kevin A.; Puffenberger, Erik G.; D’Agnano, Daniela; Anikster, Yair; Carducci, Claudia; Hyland, Keith; Rotstein, Michael; Leuzzi, Vincenzo; Borck, Guntram; Reith, Maarten E. A.

    2014-01-01

    severely impacted in dopamine transporter mutants causing infantile-onset rather than juvenile-onset disease. Dopamine transporter mutants also showed diminished dopamine binding affinity, reduced cell surface transporter, loss of post-translational dopamine transporter glycosylation and failure of amphetamine-mediated dopamine efflux. Our data series expands the clinical phenotypic continuum of dopamine transporter deficiency syndrome and indicates that there is a phenotypic spectrum from infancy (early onset, rapidly progressive disease) to childhood/adolescence and adulthood (later onset, slower disease progression). Genotype–phenotype analysis in this cohort suggests that higher residual dopamine transporter activity is likely to contribute to postponing disease presentation in these later-onset adult cases. Dopamine transporter deficiency syndrome remains under-recognized and our data highlights that dopamine transporter deficiency syndrome should be considered as a differential diagnosis for both infantile- and juvenile-onset movement disorders, including cerebral palsy and juvenile parkinsonism. PMID:24613933

  17. Scanning electron microscopy of thin and soft shells induced by feeding calcium-deficient or vitamin D-deficient diets to laying hens.

    PubMed

    Narbaitz, R; Tsang, C P; Grunder, A A; Soares, J H

    1987-02-01

    A scanning electron microscopic study was conducted on shells from eggs laid by four groups of hens maintained on different types of diets: a) control, b) vitamin D3-deficient, c) Ca-deficient, and d) vitamin D3-deficient supplemented with 1,25-(OH)2D3. After 1 week for Ca-deficient hens and after 4 weeks for vitamin D3-deficient hens, the thickness of the shell decreased abruptly and numerous thin-shelled and soft-shelled eggs were laid. The study showed that with both Ca-deficient and vitamin D3-deficient diets, the outer layers of the shell (cuticle and spongy) were reduced or absent but the mammillary layer was present even in the thinnest soft-shelled egg. The order in which layers disappeared as treatment progressed was exactly the reverse of the order in which these layers are formed in normal eggs. No eggs were found without mammillary knobs, which suggests that the hens stop laying before Ca concentrations in blood become too low for the formation of the mammillary knobs. Uncalcified portions of the shell organic matrix were never found, suggesting that Ca deposition and matrix formation were inhibited simultaneously. The relationship between fibers of the shell membrane and mammillary knobs was preserved in all cases. The eggshells from hens on 1,25-(OH)2D3-supplemented diets were ultrastructurally indistinguishable from those of hens on diets adequate in vitamin D3.

  18. Toward reassessing data-deficient species.

    PubMed

    Bland, Lucie M; Bielby, Jon; Kearney, Stephen; Orme, C David L; Watson, James E M; Collen, Ben

    2016-10-03

    One in 6 species (13,465 species) on the International Union for Conservation of Nature (IUCN) Red List is classified as data deficient due to lack of information on their taxonomy, population status, or impact of threats. Despite the chance that many are at high risk of extinction, data-deficient species are typically excluded from global and local conservation priorities, as well as funding schemes. The number of data-deficient species will greatly increase as the IUCN Red List becomes more inclusive of poorly known and speciose groups. A strategic approach is urgently needed to enhance the conservation value of data-deficient assessments. To develop this, we reviewed 2879 data-deficient assessments in 6 animal groups and identified 8 main justifications for assigning data-deficient status (type series, few records, old records, uncertain provenance, uncertain population status or distribution, uncertain threats, taxonomic uncertainty, and new species). Assigning a consistent set of justification tags (i.e., consistent assignment to assessment justifications) to species classified as data deficient is a simple way to achieve more strategic assessments. Such tags would clarify the causes of data deficiency; facilitate the prediction of extinction risk; facilitate comparisons of data deficiency among taxonomic groups; and help prioritize species for reassessment. With renewed efforts, it could be straightforward to prevent thousands of data-deficient species slipping unnoticed toward extinction.

  19. Aromatase deficiency, a rare syndrome: case report.

    PubMed

    Baykan, Emine Kartal; Erdoğan, Mehmet; Özen, Samim; Darcan, Şükran; Saygılı, L Füsun

    2013-01-01

    Aromatase deficiency (AD) is a rare autosomal recessive inheritance syndrome. Its worldwide incidence is unknown, and there are few case reports in the literature. Aromatase dysfunction develops due to CYP19A1 gene mutation and a decrease in estrogen synthesis. Estrogen deficiency can induce delayed epiphyseal closure, eunuchoid body habitus, osteopenia, and osteoporosis in both genders. Our patient was a 27-year-old male who presented with bone pain, recurrent bone fractures associated with minimal trauma starting in puberty, and a progressive increase in height. Laboratory tests revealed that the blood levels of follicle-stimulating hormone and luteinizing hormone were above normal, testosterone level was normal, and estrogen was undetectable. Plain bone radiography of the left wrist and hand demonstrated that the epiphyses were still unfused. Lumbar osteoporosis was detected in bone densitometry. In the genetic analysis, homozygous R375H guanine-adenine (G-A) mutation was detected in the CYP19A1 gene, and a diagnosis of AD was reached. Treatment with 25 μg transdermal estradiol was started. All family members were examined. Homozygous R375H G-A mutation was detected in the patient's younger brother. Heterozygous R375H G-A mutation was found in his mother, father, and older brother. In conclusion, this AD patient requires lifetime estrogen replacement in order to provide sufficient bone mineralization, to reduce the risk of bone fractures, and to lead a healthy life. The best method to prevent the possible complications is to diagnose the AD syndrome at early ages and to provide adequate estrogen replacement starting at puberty.

  20. Unresponsiveness to tetrahydrobiopterin of phenylalanine hydroxylase deficiency.

    PubMed

    Ponzone, Alberto; Porta, Francesco; Mussa, Alessandro; Alluto, Alessandra; Ferraris, Silvio; Spada, Marco

    2010-05-01

    Conflicting results have been reported concerning the efficacy of tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydroxylase, for reducing phenylalanine (Phe) concentration in phenylketonuria (PKU). We aimed to test quantitatively the effects of BH4 in PKU patients. Seven fully characterized patients were selected among a population of 130 PKU subjects as harboring PKU mutations predicted as BH4 responsive and previously considered responsive to a cofactor challenge. They received a simple Phe (100 mg/kg) and 2 combined Phe (100 mg/kg) and BH4 (20 mg/kg) oral loading tests. Cofactor was administered either before or after the amino acid. The concentrations of Phe, tyrosine (Tyr), and biopterin were measured over 24 hours after loading. The comparative analysis of the loading tests showed that in all patients plasma Phe concentrations peaked within 3 hours, and fell within 24 hours by about 50% in benign, 20% in mild, and 15% in severe phenylalanine hydroxylase deficiency regardless of BH4 administration. A consistent or moderate increase of plasma Tyr, again independent of the cofactor challenge, was observed only in the less severe forms of PAH deficiency. Mean blood biopterin concentration increased 6 times after simple Phe and 34 to 39 times after combined loading tests. The administration of BH4 does not alter Phe and Tyr metabolism in PKU patients. The clearance of plasma Phe after oral loading and, as well as Tyr production, is not related to cofactor challenge but to patient's phenotype. The assessment of BH4 responsiveness by the methods so far used is not reliable, and the occurrence of BH4-responsive forms of PKU still has to be definitely proven.

  1. Structural insights into sulfite oxidase deficiency.

    PubMed

    Karakas, Erkan; Wilson, Heather L; Graf, Tyler N; Xiang, Song; Jaramillo-Busquets, Sandra; Rajagopalan, K V; Kisker, Caroline

    2005-09-30

    Sulfite oxidase deficiency is a lethal genetic disease that results from defects either in the genes encoding proteins involved in molybdenum cofactor biosynthesis or in the sulfite oxidase gene itself. Several point mutations in the sulfite oxidase gene have been identified from patients suffering from this disease worldwide. Although detailed biochemical analyses have been carried out on these mutations, no structural data could be obtained because of problems in crystallizing recombinant human and rat sulfite oxidases and the failure to clone the chicken sulfite oxidase gene. We synthesized the gene for chicken sulfite oxidase de novo, working backward from the amino acid sequence of the native chicken liver enzyme by PCR amplification of a series of 72 overlapping primers. The recombinant protein displayed the characteristic absorption spectrum of sulfite oxidase and exhibited steady state and rapid kinetic parameters comparable with those of the tissue-derived enzyme. We solved the crystal structures of the wild type and the sulfite oxidase deficiency-causing R138Q (R160Q in humans) variant of recombinant chicken sulfite oxidase in the resting and sulfate-bound forms. Significant alterations in the substrate-binding pocket were detected in the structure of the mutant, and a comparison between the wild type and mutant protein revealed that the active site residue Arg-450 adopts different conformations in the presence and absence of bound sulfate. The size of the binding pocket is thereby considerably reduced, and its position relative to the cofactor is shifted, causing an increase in the distance of the sulfur atom of the bound sulfate to the molybdenum.

  2. Perforin deficiency attenuates collagen-induced arthritis

    PubMed Central

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

    2005-01-01

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

  3. Alcoholic Myelopathy and Nutritional Deficiency

    PubMed Central

    Koike, Haruki; Nakamura, Tomohiko; Ikeda, Shohei; Takahashi, Mie; Kawagashira, Yuichi; Iijima, Masahiro; Katsuno, Masahisa; Sobue, Gen

    2017-01-01

    A patient with chronic alcoholism presented with myelopathy and low serum folate and cobalamin levels. A 42-year-old alcoholic man had gait disturbance for 4 months. A neurological examination revealed marked spasticity with increased deep tendon reflexes and extensor plantar responses of the lower limbs. His cobalamin level was decreased and his serum folate level was particularly low. His plasma ammonia level was not increased. Abstinence and folic acid and cobalamin supplementation stopped the progression of his neurological deficits. This case indicates that nutritional deficiency should be monitored closely in patients with chronic alcoholism who present with myelopathy. PMID:28049986

  4. Thymic deficiency in Down's syndrome.

    PubMed

    Levin, S; Schlesinger, M; Handzel, Z; Hahn, T; Altman, Y; Czernobilsky, B; Boss, J

    1979-01-01

    Children with Down's syndrome (DS) often have small and abnormal thymuses, with lymphocyte depletion, diminution of the cortex, and loss of corticomedullary demarcation--a picture resembling thymic involution. Besides this, they have markedly enlarged Hassall's corpuscles, some surrounded by a sheath of lymphocytes. Patients with DS are known to have increased numbers of respiratory infections; they also have a higher incidence of lymphatic leukemia than do individuals who do not have DS. Studies of cell-mediated (thymic-dependent) immunity demonstrate that children with DS have both diminished numbers of T cells as well as functional deficiency of these cells.

  5. Prevalence of iron deficiency anemia among adolescent schoolgirls from Kermanshah, Western Iran.

    PubMed

    Akramipour, Reza; Rezaei, Mansour; Rahimi, Zohreh

    2008-12-01

    Iron deficiency anemia is a major health problem in developing countries. Anemia reduces physical work capacity and cognitive function and adversely affects learning and scholastic performance in schoolgirls entering adolescence. A cross-sectional study was conducted to determine the prevalence of iron deficiency, iron deficiency anemia and anemia among adolescent school girls aged 14-20 years from 20 different high schools located in three educational areas of Kermanshah, the capital of Kermanshah province in Western Iran. The prevalence of anemia (Hb<12 mg/dl) among adolescent school girls was 21.4%. Iron deficiency using a ferritin level <12 microg/l was found in 23.7% of studied girls. There were 47 girls (12.2%) with iron deficiency anemia (Hb<12 g/dl and ferritin <20 microg/l). Around 57.3% of anemic girls were iron deficient. There were no significant differences between the presence of anemia and the level of education of parents. The mean levels of hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean cell hemoglobin (MCH) and mean cell hemoglobin concentration (MCHC) in studied adolescent girls from Western Iran were found to be lower than those reported for females aged 12-18 years. In conclusion, regarding the detrimental long-term effects and high prevalence of iron deficiency, iron deficiency anemia and anemia in Kermanshah, Western Iran its prevention could be a high priority in the programs of health system of the country and supplementation of a weekly iron dose is recommended.

  6. Molecular basis of human transcobalamin II deficiency in an affected family

    SciTech Connect

    Li, N.; Seetharam, S.; Seetharam, B.

    1994-09-01

    Transcobalamin II (TC II) deficiency is an autosomal recessive disease leading to cobalamin (Cbl, Vitamin B{sub 12}) deficiency. Patients with this disorder fail to absorb and transport Cbl across cellular membranes and develop Cbl deficiency, symptoms of which include failure to thrive, megaloblastic anemia, impaired immunodefence and neurological disorders. The molecular basis for this disease is not known. By means of Southern blotting and sequence analysis of TC II, cDNA amplified from fibroblasts of an affected child and his parents, we have identified two mutant TC II alleles. The maternally derived allele had a gross deletion, while the paternally derived allele had a 4-nucleotide ({sup 1023}TCTG) deletion which caused a reading frame shift and generation of a premature termination codon, 146 nucleotides downstream from the deletion. Both these deletions caused markedly reduced levels of TC II mRNA and protein. In addition, these two deletions were unique to this family and were not detected in four other unrelated TC II deficient patients who also exhibited the same (TC II protein/mRNA deficiency) phenotypes. Based on this study we suggest, (1) that the molecular defect in the most common form of human TC II deficiency (lack of immunoprecipitable plasma TC II) is heterogeneous and (2) these mutations cause TC II mRNA and protein deficiency leading to defective plasma transport of Cbl and the development of Cbl deficiency.

  7. Transcriptome Changes Associated with Boron Deficiency in Leaves of Two Citrus Scion-Rootstock Combinations

    PubMed Central

    Liu, Xiao; Zhang, Jia-Wei; Guo, Ling-Xia; Liu, Yong-Zhong; Jin, Long-Fei; Hussain, Syed Bilal; Du, Wei; Deng, Zhao; Peng, Shu-Ang

    2017-01-01

    Boron (B) deficiency stress is frequently observed in citrus orchards and causes considerable loss of productivity and fruit quality. Carrizo citrange (Cc) has been reported as a rootstock more tolerant to B deficiency than Trifoliate orange (To). The ‘Newhall’ navel orange (Ns) performed better when grafted onto Cc (Ns/Cc) than when grafted onto To (Ns/To) under long-term B deficiency. The present study confirmed that Ns/Cc had higher boron content, leaf fresh weight, lower leaf chlorosis and stronger photosynthesis ability than Ns/To. Moreover, B-deficiency significantly reduced the chlorophyll and carotenoid content in Ns/To. The content of total soluble sugar and lignin were dramatically increased and the expression levels of photosynthesis-related genes were substantially down-regulated in Ns/To by B-deficient treatment. B-deficiency also strongly induced expression levels of chlorophyll decomposition-related genes, glucose synthesis-related genes and lignin synthesis-related genes, and significantly inhibited the expression of carotenoid synthesis-related genes in Ns/To. Overall, these findings suggested that the influence of To on the scion of Ns was worse than that of Cc due to differently regulating these metabolic pathways under the long term of B-deficiency. The transcriptome analysis provided further information for understanding the mechanism of the different responses of scion-rootstock combinations to B-deficiency stress. PMID:28352276

  8. Vitamin D deficiency: a new risk factor for type 2 diabetes?.

    PubMed

    Mezza, T; Muscogiuri, G; Sorice, G P; Prioletta, A; Salomone, E; Pontecorvi, A; Giaccari, A

    2012-01-01

    Recent compelling evidence suggests a role of vitamin D deficiency in the pathogenesis of insulin resistance and insulin secretion derangements, with a consequent possible interference with type 2 diabetes mellitus. The mechanism of this link is incompletely understood. In fact, vitamin D deficiency is usually detected in obesity in which insulin resistance is also a common finding. The coexistence of insulin resistance and vitamin D deficiency has generated several hypotheses. Some cross-sectional and prospective studies have suggested that vitamin D deficiency may play a role in worsening insulin resistance; others have identified obesity as a risk factor predisposing individuals to exhibit both vitamin D deficiency and insulin resistance. The available data from intervention studies are largely confounded, and inadequate considerations of seasonal effects on 25(OH)D concentrations are also a common design flaw in many studies. On the contrary, there is strong evidence that obesity might cause both vitamin D deficiency and insulin resistance, leaving open the possibility that vitamin D and diabetes are not related at all. Although it might seem premature to draw firm conclusions on the role of vitamin D supplementation in reducing insulin resistance and preventing type 2 diabetes, this manuscript will review the circumstances leading to vitamin D deficiency and how such a deficiency can eventually independently affect insulin sensitivity.

  9. Impaired synaptic vesicle recycling contributes to presynaptic dysfunction in lipoprotein lipase-deficient mice.

    PubMed

    Liu, X; Zhang, B; Yang, H; Wang, H; Liu, Y; Huang, A; Liu, T; Tian, X; Tong, Y; Zhou, T; Zhang, T; Xing, G; Xiao, W; Guo, X; Fan, D; Han, X; Liu, G; Zhou, Z; Chui, D

    2014-11-07

    Lipoprotein lipase (LPL) is expressed at high levels in hippocampal neurons, although its function is unclear. We previously reported that LPL-deficient mice have learning and memory impairment and fewer synaptic vesicles in hippocampal neurons, but properties of synaptic activity in LPL-deficient neurons remain unexplored. In this study, we found reduced frequency of miniature excitatory postsynaptic currents (mEPSCs) and readily releasable pool (RRP) size in LPL-deficient neurons, which led to presynaptic dysfunction and plasticity impairment without altering postsynaptic activity. We demonstrated that synaptic vesicle recycling, which is known to play an important role in maintaining the RRP size in active synapses, is impaired in LPL-deficient neurons. Moreover, lipid assay revealed deficient docosahexaenoic acid (DHA) and arachidonic acid (AA) in the hippocampus of LPL-deficient mice; exogenous DHA or AA supplement partially restored synaptic vesicle recycling capability. These results suggest that impaired synaptic vesicle recycling results from deficient DHA and AA and contributes to the presynaptic dysfunction and plasticity impairment in LPL-deficient neurons.

  10. Vitamin A Deficiency Impairs Induction of Oral Tolerance in Mice.

    PubMed

    Nakamoto, Akiko; Shuto, Emi; Tsutsumi, Rie; Nakamoto, Mariko; Nii, Yoshitaka; Sakai, Tohru

    2015-01-01

    Oral tolerance is a phenomenon of induction of systemic unresponsiveness to antigens ingested by the oral route and loss of immune response. Studies have shown the importance of vitamin A in oral tolerance in vitro but not in an in vivo experimental model. Therefore, we carried out experiments to determine how vitamin A deficiency affects tolerance induction and the ability of mesenteric lymph node (MLN) CD11c(+) cells to induce regulatory T cells (Tregs). Immunological tolerance was induced by oral ovalbumin (OVA) administration in vitamin A-sufficient mice. OVA-specific antibody and cytokine production were significantly reduced. On the other hand, in vitamin A-deficient mice, both OVA-specific antibody and cytokine production were not suppressed by oral OVA administration. Regarding induction of Tregs, the conversion rate of Foxp3(+) cells from naïve CD4(+) cell by CD11c(+) cells was decreased in vitamin A-deficient mice. Our study indicates that vitamin A deficiency causes the breakdown of oral tolerance in vivo.

  11. Selected Systems Engineering Process Deficiencies and Their Consequences

    NASA Technical Reports Server (NTRS)

    Thomas, Lawrence Dale

    2006-01-01

    The systems engineering process is well established and well understood. While this statement could be argued in the light of the many systems engineering guidelines and that have been developed, comparative review of these respective descriptions reveal that they differ primarily in the number of discrete steps or other nuances, and are at their core essentially common. Likewise, the systems engineering textbooks differ primarily in the context for application of systems engineering or in the utilization of evolved tools and techniques, not in the basic method. Thus, failures in systems engineering cannot credibly be attributed to implementation of the wrong systems engineering process among alternatives. However, numerous systems failures can be attributed to deficient implementation of the systems engineering process. What may clearly be perceived as a system engineering deficiency in retrospect can appear to be a well considered system engineering efficiency in real time - an efficiency taken to reduce cost or meet a schedule, or more often both. Typically these efficiencies are grounded on apparently solid rationale, such as reuse of heritage hardware or software. Over time, unintended consequences of a systems engineering process deficiency may begin to be realized, and unfortunately often the consequence is system failure. This paper describes several actual cases of system failures that resulted from deficiencies in their systems engineering process implementation, including the Ariane 5 and the Hubble Space Telescope.

  12. Spectral characteristics 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.

    1972-01-01

    Reflectance, transmittance and absorbance spectra of normal and six types of mineral-deficient (N,P,K,S,Mg and Ca) maize (Zea mays L.) leaves were analyzed at 30 selected wavelengths along the electromagnetic spectrum from 500 to 2600 nm. Chlorophyll content and percent leaf moisture were also determined. Leaf thermograms were obtained for normal, N- and S- deficient leaves. The results of the analysis of variance showed significant differences in reflectance, transmittance and absorbance in the visible wavelengths among leaf numbers 3, 4, and 5, among the seven nutrient treatments, and among the interactions of leaves and treatments. In the reflective infrared wavelengths only treatments produced significant differences. The chlorophyll content of leaves was reduced in all deficiencies in comparison to controls. Percent moisture was increased in S-, Mg- and N- deficiencies. Positive correlation (r = 0.707) between moisture content and percent absorption at both 1450 and 1930 nm were obtained. Polynomial regression analysis of leaf thickness and leaf moisture content showed that these two variables were significantly and directly related (r = 0.894).

  13. Molecular basis of human carbonic anhydrase II deficiency.

    PubMed Central

    Roth, D E; Venta, P J; Tashian, R E; Sly, W S

    1992-01-01

    Deficiency of carbonic anhydrase II (carbonate hydro-lyase, EC 4.2.1.1) is the primary defect in the syndrome of osteopetrosis, renal tubular acidosis, and cerebral calcification. In this report we describe the molecular basis for carbonic anhydrase II deficiency in the American family in which the association of carbonic anhydrase II deficiency with this syndrome was first recognized. The three affected siblings from this family are compound heterozygotes, each having inherited two different mutations in the structural gene for carbonic anhydrase II. The paternal mutation is a splice acceptor site mutation at the 3' end of intron 5. The maternal mutation is a missense mutation in exon 3 that substitutes a tyrosine for histidine-107. We show that the mutant enzyme expressed in bacteria from the cDNA containing the His-107----Tyr mutation has detectable, though greatly reduced, activity. We suggest that residual activity of the His-107----Tyr mutant enzyme may explain the absence of mental retardation and the relatively mild phenotype of carbonic anhydrase II deficiency in affected members of this family. Images PMID:1542674

  14. Vitamin D deficiency impairs skeletal muscle function in a smoking mouse model

    PubMed Central

    Cielen, Nele; Heulens, Nele; Maes, Karen; Carmeliet, Geert; Mathieu, Chantal; Janssens, Wim

    2016-01-01

    Chronic obstructive pulmonary disease (COPD) is associated with skeletal muscle dysfunction. Vitamin D plays an important role in muscle strength and performance in healthy individuals. Vitamin D deficiency is highly prevalent in COPD, but its role in skeletal muscle dysfunction remains unclear. We examined the time-course effect of vitamin D deficiency on limb muscle function in mice with normal or deficient vitamin D serum levels exposed to air or cigarette smoke for 6, 12 or 18 weeks. The synergy of smoking and vitamin D deficiency increased lung inflammation and lung compliance from 6 weeks on with highest emphysema scores observed at 18 weeks. Smoking reduced body and muscle mass of the soleus and extensor digitorum longus (EDL), but did not affect contractility, despite type II atrophy. Vitamin D deficiency did not alter muscle mass but reduced muscle force over time, downregulated vitamin D receptor expression, and increased muscle lipid peroxidation but did not alter actin and myosin expression, fiber dimensions or twitch relaxation time. The combined effect of smoking and vitamin D deficiency did not further deteriorate muscle function but worsened soleus mass loss and EDL fiber atrophy at 18 weeks. We conclude that the synergy of smoking and vitamin D deficiency in contrast to its effect on lung disease, had different, independent but important noxious effects on skeletal muscles in a mouse model of mild COPD. PMID:26906744

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

    PubMed

    Gielen, Heidi; Vangronsveld, Jaco; Cuypers, Ann

    2017-03-01

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

  16. Mevalonate kinase deficiency: current perspectives

    PubMed Central

    Favier, Leslie A; Schulert, Grant S

    2016-01-01

    Mevalonate kinase deficiency (MKD) is a recessively inherited autoinflammatory disorder with a spectrum of manifestations, including the well-defined clinical phenotypes of hyperimmunoglobulinemia D and periodic fever syndrome and mevalonic aciduria. Patients with MKD have recurrent attacks of hyperinflammation associated with fever, abdominal pain, arthralgias, and mucocutaneous lesions, and more severely affected patients also have dysmorphisms and central nervous system anomalies. MKD is caused by mutations in the gene encoding mevalonate kinase, with the degree of residual enzyme activity largely determining disease severity. Mevalonate kinase is essential for the biosynthesis of nonsterol isoprenoids, which mediate protein prenylation. Although the precise pathogenesis of MKD remains unclear, increasing evidence suggests that deficiency in protein prenylation leads to innate immune activation and systemic hyperinflammation. Given the emerging understanding of MKD as an autoinflammatory disorder, recent treatment approaches have largely focused on cytokine-directed biologic therapy. Herein, we review the current genetic and pathologic understanding of MKD, its various clinical phenotypes, and the evolving treatment approach for this multifaceted disorder. PMID:27499643

  17. Management of ornithine transcarbamylase deficiency in pregnancy.

    PubMed

    Mendez-Figueroa, Hector; Lamance, Kerri; Sutton, V Reid; Aagaard-Tillery, Kjersti; Van den Veyver, Ignatia

    2010-11-01

    Ornithine transcarbamylase (OTC) deficiency is the most common enzymatic deficiency in the urea cycle. In catabolic states, such as the intrapartum and immediate postpartum periods, hyperammonemic comas with permanent neurological damage and death can develop. We report six cases of OTC deficiency during pregnancy managed at our institution and review the literature on OTC deficiency during pregnancy. Using the patient database from our Metabolic Clinic, pregnant OTC deficiency carriers were identified. The antenatal, intrapartum, and postpartum periods were analyzed. Corresponding literature was reviewed and an extensive multidisciplinary management plan developed. All six pregnant women had favorable outcomes. No hyperammonemic episodes occurred, and intensive care unit admissions and hemodialysis were not required. Although risk to women with OTC deficiency during the intra- and postpartum period exists, multidisciplinary management and a coherent plan usually result in successful labor, delivery, and postpartum. A comprehensive plan for patients who develop hyperammonemia is recommended.

  18. New insights into iron deficiency and iron deficiency anemia.

    PubMed

    Camaschella, Clara

    2017-02-13

    Recent advances in iron metabolism have stimulated new interest in iron deficiency (ID) and its anemia (IDA), common conditions worldwide. Absolute ID/IDA, i.e. the decrease of total body iron, is easily diagnosed based on decreased levels of serum ferritin and transferrin saturation. Relative lack of iron in specific organs/tissues, and IDA in the context of inflammatory disorders, are diagnosed based on arbitrary cut offs of ferritin and transferrin saturation and/or marker combination (as the soluble transferrin receptor/ferritin index) in an appropriate clinical context. Most ID patients are candidate to traditional treatment with oral iron salts, while high hepcidin levels block their absorption in inflammatory disorders. New iron preparations and new treatment modalities are available: high-dose intravenous iron compounds are becoming popular and indications to their use are increasing, although long-term side effects remain to be evaluated.

  19. Cerebral Developmental Abnormalities in a Mouse with Systemic Pyruvate Dehydrogenase Deficiency

    PubMed Central

    Pliss, Lioudmila; Hausknecht, Kathryn A.; Stachowiak, Michal K.; Dlugos, Cynthia A.; Richards, Jerry B.; Patel, Mulchand S.

    2013-01-01

    Pyruvate dehydrogenase (PDH) complex (PDC) deficiency is an inborn error of pyruvate metabolism causing a variety of neurologic manifestations. Systematic analyses of development of affected brain structures and the cellular processes responsible for their impairment have not been performed due to the lack of an animal model for PDC deficiency. METHODS: In the present study we investigated a murine model of systemic PDC deficiency by interrupting the X-linked Pdha1 gene encoding the α subunit of PDH to study its role on brain development and behavioral studies. RESULTS: Male embryos died prenatally but heterozygous females were born. PDC activity was reduced in the brain and other tissues in female progeny compared to age-matched control females. Immunohistochemical analysis of several brain regions showed that approximately 40% of cells were PDH−. The oxidation of glucose to CO2 and incorporation of glucose-carbon into fatty acids were reduced in brain slices from 15 day-old PDC-deficient females. Histological analyses showed alterations in several structures in white and gray matters in 35 day-old PDC-deficient females. Reduction in total cell number and reduced dendritic arbors in Purkinje neurons were observed in PDC-deficient females. Furthermore, cell proliferation, migration and differentiation into neurons by newly generated cells were reduced in the affected females during pre- and postnatal periods. PDC-deficient mice had normal locomotor activity in a novel environment but displayed decreased startle responses to loud noises and there was evidence of abnormal pre-pulse inhibition of the startle reflex. CONCLUSIONS: The results show that a reduction in glucose metabolism resulting in deficit in energy production and fatty acid biosynthesis impairs cellular differentiation and brain development in PDC-deficient mice. PMID:23840713

  20. Monocular Elevation Deficiency - Double Elevator Palsy

    MedlinePlus

    ... sucking thus creating a "wink" when chewing or sucking. Is Monocular Elevation Deficiency associated with other diseases or developmental problems? There is no known association between Monocular Elevation ...

  1. Biotinidase deficiency: novel mutations in Algerian patients.

    PubMed

    Tiar, A; Mekki, A; Nagara, M; Rhouma, F Ben; Messaoud, O; Halim, N Ben; Kefi, R; Hamlaoui, M T; Lebied, A; Abdelhak, S

    2014-02-15

    Biotinidase deficiency is an autosomal recessive disorder of biotin metabolism leading to varying degrees of neurologic and cutaneous symptoms when untreated. In the present study, we report the clinical features and the molecular investigation of biotinidase deficiency in four unrelated consanguineous Algerian families including five patients with profound biotinidase deficiency and one child characterized as partial biotinidase deficiency. Mutation analysis revealed three novel mutations, c.del631C and c.1557T>G within exon 4 and c.324-325insTA in exon 3. Since newborn screening is not available in Algeria, cascade screening in affected families would be very helpful to identify at risk individuals.

  2. Atypical B12 Deficiency with Nonresolving Paraesthesia

    PubMed Central

    Haider, S.; Ahmad, N.; Anaissie, E. J.; Abdel Karim, N.

    2013-01-01

    Vitamin B12 deficiency can present with various hematological, gastrointestinal and neurological manifestations. We report a case of elderly female who presented with neuropathy and vitamin B12 deficiency where the final work-up revealed polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS). This case suggests that, although POEMS syndrome is a rare entity, it can present with vitamin-B12 deficiency and thus specific work up for early diagnosis of POEMS should be considered in patients with B12 deficiency unresponsive to therapy. PMID:24349810

  3. Cryptosporidiosis in the acquired immune deficiency syndrome.

    PubMed

    Cooper, D A; Wodak, A; Marriot, D J; Harkness, J L; Ralston, M; Hill, A; Penny, R

    1984-10-01

    Cryptosporidiosis was found in a patient with the acquired immune deficiency syndrome. The microbiological and morphological features of this newly recognized opportunistic infection are distinctive and diagnostic.

  4. Iron deficiency anemia in heart failure.

    PubMed

    Arora, Natasha P; Ghali, Jalal K

    2013-07-01

    Anemia and iron deficiency are quite prevalent in patients with heart failure (HF) and may overlap. Both anemia and iron deficiency are associated with worse symptoms and adverse clinical outcomes. In the past few years, there has been an enormous interest in the subject of iron deficiency and its management in patients with HF. In this review, the etiology and relevance of iron deficiency, iron metabolism in the setting of HF, studies on iron supplementation in patients with HF and potential cardiovascular effects of subclinical iron overload are discussed.

  5. Proteomics, pigment composition, and organization of thylakoid membranes in iron-deficient spinach leaves.

    PubMed

    Timperio, Anna Maria; D'Amici, Gian Maria; Barta, Csengele; Loreto, Francesco; Zolla, Lello

    2007-01-01

    The changes induced in the photosynthetic apparatus of spinach (Spinacia oleracea L.) seedlings exposed to iron deficiency shortly after germination were characterized with two proteomic approaches coupled with chlorophyll and xanthophyll analysis and in vivo measurements of photosynthesis. During the first 10 d of iron deficiency the concentrations of chlorophyll b and violaxanthin were greatly reduced, but all xanthophylls recovered after 13-17 d of iron deficiency, when both chlorophylls were negatively affected. No new protein was formed in iron-deficient leaves, and no protein disappeared altogether. Photosystem I (PSI) proteins were largely reduced, but the stoichiometry of the antenna composition of PSI was not compromised. On the contrary, PSII proteins were less affected by the stress, but the specific antennae Lhcb4 and Lhcb6, Lhcb2 and its isoform Lhcb1.1 were all reduced, while the concentration of Lhcb3 increased. A strong reduction in thylakoid bending and an altered distribution pattern for the reduced PSI and PSII complexes were observed microscopically in iron-deficient leaves. Supercomplex organization was also affected by the stress. The trimeric organization of Lhcb and the dimerization of Lhca were reduced, while monomerization of Lhcb increased. However, the trimerization of Lhcb was partially recovered after 13-17 d of iron deficiency. In iron-deficient leaves, photosynthesis was strongly inhibited at different light intensities, and a high de-epoxidation status of the xanthophylls was observed, in association with a strong impairment of photochemical efficiency and an increase of heat dissipation as monitored by the non-photochemical quenching of fluorescence. All these negative effects of iron deficiency were attenuated but not fully reversed after again supplying iron to iron-deficient leaves for 7-13 d. These results indicate that iron deficiency has a strong impact on the proteomic structure of spinach photosystems and suggest that, in

  6. Effects of Iron Deficiency on Cognitive Function in School Going Adolescent Females in Rural Area of Central India

    PubMed Central

    More, Sarika; Shivkumar, V. B.; Gangane, Nitin; Shende, Sumeet

    2013-01-01

    Iron deficiency anemia is most common nutritional deficiency disorder in India and remains a formidable health challenge. Girls in the period of later school age and early adolescence are prone to develop iron deficiency. Iron deficiency leads to many non-hematological disturbances which include growth and development, depressed immune function in infants; reduces physical work capacity; decreases the cognitive function in both infants and adolescents. Present study was done to know the prevalence of iron deficiency in both the anemic and non anemic school going adolescent girls, to assess the effect of iron deficiency on cognitive functions in anemic iron deficient and non-anemic iron deficient school girls in a village school situated in central India. Methods. A secondary school having girl students in the age group of 12–15 years studying in sixth to ninth standard was selected. Serum ferritin concentration was estimated by ELISA. For assessing the cognitive function mathematics score, one multi-component test for memory, attention and verbal learning and Intelligent Quotient scores of the students were used. Results. Scholastic Performance, IQ and Scores of Mental balance, Attention & Concentration, Verbal Memory and Recognition were decreased in iron deficient girls, both anemic and non anemic as compared to the non iron deficient girls. PMID:24386560

  7. Effects of iron deficiency on cognitive function in school going adolescent females in rural area of central India.

    PubMed

    More, Sarika; Shivkumar, V B; Gangane, Nitin; Shende, Sumeet

    2013-01-01

    Iron deficiency anemia is most common nutritional deficiency disorder in India and remains a formidable health challenge. Girls in the period of later school age and early adolescence are prone to develop iron deficiency. Iron deficiency leads to many non-hematological disturbances which include growth and development, depressed immune function in infants; reduces physical work capacity; decreases the cognitive function in both infants and adolescents. Present study was done to know the prevalence of iron deficiency in both the anemic and non anemic school going adolescent girls, to assess the effect of iron deficiency on cognitive functions in anemic iron deficient and non-anemic iron deficient school girls in a village school situated in central India. Methods. A secondary school having girl students in the age group of 12-15 years studying in sixth to ninth standard was selected. Serum ferritin concentration was estimated by ELISA. For assessing the cognitive function mathematics score, one multi-component test for memory, attention and verbal learning and Intelligent Quotient scores of the students were used. Results. Scholastic Performance, IQ and Scores of Mental balance, Attention & Concentration, Verbal Memory and Recognition were decreased in iron deficient girls, both anemic and non anemic as compared to the non iron deficient girls.

  8. Iron-deficiency anemia and the cycle of poverty among human immunodeficiency virus-infected women in the inner city.

    PubMed

    Semba, Richard D

    2003-01-01

    The prevalence of iron-deficiency anemia appears to be extremely high among female injection drug users in the inner city who have human immunodeficiency virus (HIV) and/or hepatitis C (HCV) infections. Iron deficiency and its associated anemia may contribute to reduced energetic efficiency, lower aerobic capacity, decreased endurance, and fatigue. In practical terms, the functional limitations of iron deficiency and iron-deficiency anemia may affect the ability of women to participate in work, school, social, and family activities. Iron deficiency may contribute to the cycle of poverty in the inner city by limiting the ability of women to work, earn money, and afford iron-rich sources of food. Although iron supplementation may prevent or treat iron deficiency, the use of iron supplements needs to be approached with caution in women with HIV and HCV infections.

  9. Restoration of normal embryogenesis by mitochondrial supplementation in pig oocytes exhibiting mitochondrial DNA deficiency

    PubMed Central

    Cagnone, Gael L. M.; Tsai, Te-Sha; Makanji, Yogeshwar; Matthews, Pamela; Gould, Jodee; Bonkowski, Michael S.; Elgass, Kirstin D.; Wong, Ashley S. A.; Wu, Lindsay E.; McKenzie, Matthew; Sinclair, David A.; John, Justin C. St.

    2016-01-01

    An increasing number of women fail to achieve pregnancy due to either failed fertilization or embryo arrest during preimplantation development. This often results from decreased oocyte quality. Indeed, reduced mitochondrial DNA copy number (mitochondrial DNA deficiency) may disrupt oocyte quality in some women. To overcome mitochondrial DNA deficiency, whilst maintaining genetic identity, we supplemented pig oocytes selected for mitochondrial DNA deficiency, reduced cytoplasmic maturation and lower developmental competence, with autologous populations of mitochondrial isolate at fertilization. Supplementation increased development to blastocyst, the final stage of preimplantation development, and promoted mitochondrial DNA replication prior to embryonic genome activation in mitochondrial DNA deficient oocytes but not in oocytes with normal levels of mitochondrial DNA. Blastocysts exhibited transcriptome profiles more closely resembling those of blastocysts from developmentally competent oocytes. Furthermore, mitochondrial supplementation reduced gene expression patterns associated with metabolic disorders that were identified in blastocysts from mitochondrial DNA deficient oocytes. These results demonstrate the importance of the oocyte’s mitochondrial DNA investment in fertilization outcome and subsequent embryo development to mitochondrial DNA deficient oocytes. PMID:26987907

  10. Haploinsufficiency of COQ4 causes coenzyme Q10 deficiency

    PubMed Central

    Salviati, Leonardo; Trevisson, Eva; Hernandez, Maria Angeles Rodriguez; Casarin, Alberto; Pertegato, Vanessa; Doimo, Mara; Cassina, Matteo; Agosto, Caterina; Desbats, Maria Andrea; Sartori, Geppo; Sacconi, Sabrina; Memo, Luigi; Zuffardi, Orsetta; Artuch, Rafael; Quinzii, Catarina; DiMauro, Salvatore; Hirano, Michio; Santos-Ocaña, Carlos; Navas, Plácido

    2013-01-01

    Background COQ4 encodes a protein that organises the multienzyme complex for the synthesis of coenzyme Q10 (CoQ10). A 3.9 Mb deletion of chromosome 9q34.13 was identified in a 3-year-old boy with mental retardation, encephalomyopathy and dysmorphic features. Because the deletion encompassed COQ4, the patient was screened for CoQ10 deficiency. Methods A complete molecular and biochemical characterisation of the patient’s fibroblasts and of a yeast model were performed. Results The study found reduced COQ4 expression (48% of controls), CoQ10 content and biosynthetic rate (44% and 43% of controls), and activities of respiratory chain complex II+III. Cells displayed a growth defect that was corrected by the addition of CoQ10 to the culture medium. Knockdown of COQ4 in HeLa cells also resulted in a reduction of CoQ10. Diploid yeast haploinsufficient for COQ4 displayed similar CoQ deficiency. Haploinsufficency of other genes involved in CoQ10 biosynthesis does not cause CoQ deficiency, underscoring the critical role of COQ4. Oral CoQ10 supplementation resulted in a significant improvement of neuromuscular symptoms, which reappeared after supplementation was temporarily discontinued. Conclusion Mutations of COQ4 should be searched for in patients with CoQ10 deficiency and encephalomyopathy; patients with genomic rearrangements involving COQ4 should be screened for CoQ10 deficiency, as they could benefit from supplementation. PMID:22368301

  11. ASC deficiency suppresses proliferation and prevents medulloblastoma incidence.

    PubMed

    Knight, E R W; Patel, E Y; Flowers, C A; Crowther, A J; Ting, J P; Miller, C R; Gershon, T R; Deshmukh, M

    2015-01-15

    Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC's role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer; ASC is also expressed in human medulloblastomas. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knockout mice on the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and a delayed tumor onset. A similar decrease in tumorigenesis with ASC deficiency was also seen in the hGFAP-Cre:SmoM2 mouse model of medulloblastoma. Interestingly, hyperproliferation of the external granule layer (EGL) was comparable at P20 in both wild-type and ASC-deficient SmoA1 mice. However, while the apoptosis and differentiation markers remained unchanged at this age, proliferation makers were decreased, and the EGL was reduced in thickness and area by P60. This reduction in proliferation with ASC deficiency was also seen in isolated SmoA1 cerebellar granule precursor cells in vitro, indicating that the effect of ASC deletion on proliferation was cell autonomous. Interestingly, ASC-deficient SmoA1 cerebella exhibited disrupted expression of genes in the transforming growth factor-β pathway and increased level of nuclear Smad3. Taken together, these results demonstrate an unexpected role for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for antitumor therapy.

  12. Lack of global epigenetic methylation defects in CBS deficient mice.

    PubMed

    Lee, Hyung-Ok; Wang, Liqun; Kuo, Yin-Ming; Gupta, Sapna; Slifker, Michael J; Li, Yue-Sheng; Andrews, Andrew J; Kruger, Warren D

    2017-01-01

    Cystathionine β-synthase (CBS) deficiency is a recessive inborn error of metabolism in which patients have extremely elevated plasma total homocysteine and have clinical manifestations in the vascular, visual, skeletal, and nervous systems. Homocysteine is an intermediary metabolite produced from the hydrolysis of S-adenosylhomocysteine (SAH), which is a by-product of methylation reactions involving the methyl-donor S-adenosylmethionine (SAM). Here, we have measured SAM, SAH, DNA and histone methylation status in an inducible mouse model of CBS deficiency to test the hypothesis that homocysteine-related phenotypes are caused by inhibition of methylation due to elevated SAH and reduced SAM/SAH ratio. We found that mice lacking CBS have elevated cellular SAH and reduced SAM/SAH ratios in both liver and kidney, but this was not associated with alterations in the level of 5-methylcytosine or various histone modifications. Using methylated DNA immunoprecipitation in combination with microarray, we found that of the 241 most differentially methylated promoter probes, 89 % were actually hypermethylated in CBS deficient mice. In addition, we did not find that changes in DNA methylation correlated well with changes in RNA expression in the livers of induced and uninduced CBS mice. Our data indicates that reduction in the SAM/SAH ratio, due to loss of CBS activity, does not result in overall hypomethylation of either DNA or histones.

  13. A mouse model for an erythropoietin-deficiency anemia.

    PubMed

    Zeigler, Brandon M; Vajdos, Janis; Qin, Wenning; Loverro, Linda; Niss, Knut

    2010-01-01

    In mammals, the production of red blood cells is tightly regulated by the growth factor erythropoietin (EPO). Mice lacking a functional Epo gene are embryonic lethal, and studying erythropoiesis in EPO-deficient adult animals has therefore been limited. In order to obtain a preclinical model for an EPO-deficient anemia, we developed a mouse in which Epo can be silenced by Cre recombinase. After induction of Cre activity, Epo(KO/flox) mice experience a significant reduction of serum EPO levels and consequently develop a chronic, normocytic and normochromic anemia. Furthermore, compared with wild-type mice, Epo expression in Epo(KO/flox) mice is dramatically reduced in the kidney, and expression of a well-known target gene of EPO signaling, Bcl2l1, is reduced in the bone marrow. These observations are similar to the clinical display of anemia in patients with chronic kidney disease. In addition, during stress-induced erythropoiesis these mice display the same recovery rate as their heterozygous counterparts. Taken together, these results demonstrate that this model can serve as a valuable preclinical model for the anemia of EPO deficiency, as well as a tool for the study of stress-induced erythropoiesis during limiting conditions of EPO.

  14. Antibody deficiency in patients with frequent exacerbations of Chronic Obstructive Pulmonary Disease (COPD)

    PubMed Central

    McCullagh, Brian N.; Comellas, Alejandro P.; Ballas, Zuhair K.; Newell, John D.; Zimmerman, M. Bridget

    2017-01-01

    Chronic Obstructive Pulmonary Disease is the third leading cause of death in the US, and is associated with periodic exacerbations, which account for the largest proportion of health care utilization, and lead to significant morbidity, mortality, and worsening lung function. A subset of patients with COPD have frequent exacerbations, occurring 2 or more times per year. Despite many interventions to reduce COPD exacerbations, there is a significant lack of knowledge in regards to their mechanisms and predisposing factors. We describe here an important observation that defines antibody deficiency as a potential risk factor for frequent COPD exacerbations. We report a case series of patients who have frequent COPD exacerbations, and who were found to have an underlying primary antibody deficiency syndrome. We also report on the outcome of COPD exacerbations following treatment in a subset with of these patients with antibody deficiency. We identified patients with COPD who had 2 or more moderate to severe exacerbations per year; immune evaluation including serum immunoglobulin levels and pneumococcal IgG titers was performed. Patients diagnosed with an antibody deficiency syndrome were treated with either immunoglobulin replacement therapy or prophylactic antibiotics, and their COPD exacerbations were monitored over time. A total of 42 patients were identified who had 2 or more moderate to severe COPD exacerbations per year. Twenty-nine patients had an underlying antibody deficiency syndrome: common variable immunodeficiency (8), specific antibody deficiency (20), and selective IgA deficiency (1). Twenty-two patients had a follow-up for at least 1 year after treatment of their antibody deficiency, which resulted in a significant reduction of COPD exacerbations, courses of oral corticosteroid use and cumulative annual dose of oral corticosteroid use, rescue antibiotic use, and hospitalizations for COPD exacerbations. This case series identifies antibody deficiency as a

  15. Screening for medium chain acyl-CoA dehydrogenase deficiency using electrospray ionisation tandem mass spectrometry

    PubMed Central

    Clayton, P.; Doig, M.; Ghafari, S.; Meaney, C.; Taylor, C.; Leonard, J.; Morris, M.; Johnson, A.

    1998-01-01

    OBJECTIVE—To establish criteria for the diagnosis of medium chain acyl-CoA dehydrogenase (MCAD) deficiency in the UK population using a method in which carnitine species eluted from blood spots are butylated and analysed by electrospray ionisation tandem mass spectrometry (ESI-MS/MS).
DESIGN—Four groups were studied: (1) 35 children, aged 4 days to 16.2 years, with proven MCAD deficiency (mostly homozygous for the A985G mutation, none receiving carnitine supplements); (2) 2168control children; (3) 482 neonates; and (4) 15 MCAD heterozygotes.
RESULTS—All patients with MCAD deficiency had an octanoylcarnitine concentration ([C8-Cn]) > 0.38 µM and no accumulation of carnitine species > C10 or < C6. Among the patients with MCAD deficiency, the [C8-Cn] was significantly lower in children > 10 weeks old and in children with carnitine depletion (free carnitine < 20 µM). Neonatal blood spots from patients with MCAD deficiency had a [C8-Cn] > 1.5 µM, whereas in heterozygotes and other normal neonates the [C8-Cn] was < 1.0 µM. In contrast, the blood spot [C8-Cn] in eight of 27 patients with MCAD deficiency > 10 weeks old fell within the same range as five of 15 MCAD heterozygotes (0.38-1.0 µM). However, the free carnitine concentrations were reduced (< 20 µM) in the patients with MCAD deficiency but normal in the heterozygotes.
CONCLUSIONS—Criteria for the diagnosis of MCAD deficiency using ESI-MS/MS must take account of age and carnitine depletion. If screening is undertaken at 7-10 days, the number of false positive and negative results should be negligible. Because there have been no instances of death or neurological damage following diagnosis of MCAD deficiency in our patient group, a strong case can be made for neonatal screening for MCAD deficiency in the UK.

 PMID:9797589

  16. Risk Factors for Postoperative Fibrinogen Deficiency after Surgical Removal of Intracranial Tumors.

    PubMed

    Wei, Naili; Jia, Yanfei; Wang, Xiu; Zhang, Yinian; Yuan, Guoqiang; Zhao, Baotian; Wang, Yao; Zhang, Kai; Zhang, Xinding; Pan, Yawen; Zhang, Jianguo

    2015-01-01

    bleeding and poor outcomes and merits careful attention. Practitioners should monitor plasma fibrinogen levels in patients with risk factors for postoperative fibrinogen deficiency. In addition, postoperative fibrinogen deficiency should be remediated as soon as possible to reduce postoperative bleeding, especially when postoperative bleeding is confirmed.

  17. Pyridoxine deficiency affects biomechanical properties of chick tibial bone

    NASA Technical Reports Server (NTRS)

    Masse, P. G.; Rimnac, C. M.; Yamauchi, M.; Coburn, S. P.; Rucker, R. B.; Howell, D. S.; Boskey, A. L.

    1996-01-01

    The mechanical integrity of bone is dependent on the bone matrix, which is believed to account for the plastic deformation of the tissue, and the mineral, which is believed to account for the elastic deformation. The validity of this model is shown in this study based on analysis of the bones of vitamin B6-deficient and vitamin B6-replete chick bones. In this model, when B6-deficient and control animals are compared, vitamin B6 deficiency has no effect on the mineral content or composition of cortical bone as measured by ash weight (63 +/- 6 vs. 58 +/- 3); mineral to matrix ratio of the FTIR spectra (4.2 +/- 0.6 vs. 4.5 +/- 0.2), line-broadening analyses of the X-ray diffraction 002 peak (beta 002 = 0.50 +/- 0.1 vs. 0.49 +/- 0.01), or other features of the infrared spectra. In contrast, collagen was significantly more extractable from vitamin B6-deficient chick bones (20 +/- 2% of total hydroxyproline extracted vs. 10 +/- 3% p < or = 0.001). The B6-deficient bones also contained an increased amount of the reducible cross-links DHLNL, dehydro-dihydroxylysinonorleucine, (1.03 +/- 0.07 vs. 0.84 +/- 0.13 p < or = 0.001); and a nonsignificant increase in HLNL, dehydro-hydroxylysinonorleucine, (0.51 +/- 0.03 vs. 0.43 +/- 0.03, p < or = 0.10). There were no significant changes in bone length, bone diameter, or area moment of inertia. In four-point bending, no significant changes in elastic modulus, stiffness, offset yield deflection, or fracture deflection were detected. However, fracture load in the B6-deficient animals was decreased from 203 +/- 35 MPa to 151 +/- 23 MPa, p < or = 0.01, and offset yield load was decreased from 165 +/- 9 MPa to 125 +/- 14 MPa, p < or = 0.05. Since earlier histomorphometric studies had demonstrated that the B6-deficient bones were osteopenic, these data suggest that although proper cortical bone mineralization occurred, the alterations of the collagen resulted in changes to bone mechanical performance.

  18. [Iron deficiency in the elderly].

    PubMed

    Helsen, Tuur; Joosten, Etienne

    2016-06-01

    Anemia is a common diagnosis in the geriatric population, especially in institutionalized and hospitalized elderly. Most common etiologies for anemia in elderly people admitted to a geriatric ward are iron-deficiency anemia and anemia associated with chronic disease. Determination of serum ferritin is the most used assay in the differential diagnosis, despite low sensitivity and moderate specificity. New insights into iron homeostasis lead to new diagnostic assays such as serum hepcidin, serum transferrin receptor and reticulocyte hemoglobin equivalent.Importance of proper diagnosis and treatment for this population is large since there is a correlation between anemia and morbidity - mortality. Anemia is usually defined as hemoglobin less than 12 g/dl for women and less than 13 g/dl for men. There is no consensus for which hemoglobinvalue an investigation into underlying pathology is obligatory. This needs to be evaluated depending on functional condition of the patient.