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1.
Genes Immun ; 13(7): 549-55, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22932816

ABSTRACT

Genome-wide association studies have identified gene regions associated with type 1 diabetes. The aim of this study was to determine how the combined allele frequency of multiple susceptibility genes can stratify islet autoimmunity and/or type 1 diabetes risk. Children of parents with type 1 diabetes and prospectively followed from birth for the development of islet autoantibodies and diabetes were genotyped for single-nucleotide polymorphisms at 12 type 1 diabetes susceptibility genes (ERBB3, PTPN2, IFIH1, PTPN22, KIAA0350, CD25, CTLA4, SH2B3, IL2, IL18RAP, IL10 and COBL). Non-human leukocyte antigen (HLA) risk score was defined by the total number of risk alleles at these genes. Receiver operator curve analysis showed that the non-HLA gene combinations were highly effective in discriminating diabetes and most effective in children with a high-risk HLA genotype. The greatest diabetes discrimination was obtained by the sum of risk alleles for eight genes (IFIH1, CTLA4, PTPN22, IL18RAP, SH2B3, KIAA0350, COBL and ERBB3) in the HLA-risk children. Non-HLA-risk allele scores stratified risk for developing islet autoantibodies and diabetes, and progression from islet autoimmunity to diabetes. Genotyping at multiple susceptibility loci in children from affected families can identify neonates with sufficient genetic risk of type 1 diabetes to be considered for early intervention.


Subject(s)
Diabetes Mellitus, Type 1/genetics , Genetic Predisposition to Disease , Adolescent , Child , Child, Preschool , Gene Frequency , Genetic Loci , HLA Antigens/genetics , Humans , Infant , Polymorphism, Single Nucleotide , Prospective Studies , Young Adult
2.
J Bacteriol ; 180(13): 3368-74, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9642189

ABSTRACT

Sphingomonas herbicidovorans MH was able to completely degrade both enantiomers of the chiral herbicide dichlorprop [(RS)-2-(2,4-dichlorophenoxy)propanoic acid], with preferential degradation of the (S) enantiomer over the (R) enantiomer. These results are in agreement with the recently reported enantioselective degradation of mecoprop [(RS)-2-(4-chloro-2-methylphenoxy)propanoic acid] by this bacterium (C. Zipper, K. Nickel, W. Angst, and H.-P. E. Kohler, Appl. Environ. Microbiol. 62:4318-4322, 1996). Uptake of (R)-dichlorprop, (S)-dichlorporp, and 2,4-D (2,4-dichlorophenoxyacetic acid) was inducible. Initial uptake rates of cells grown on the respective substrate showed substrate saturation kinetics with apparent affinity constants (Kt) of 108, 93, and 117 microM and maximal velocities (Vmax) of 19, 10, and 21 nmol min-1 mg of protein-1 for (R)-dichlorprop, (S)-dichlorprop, and 2,4-D, respectively. Transport of (R)-dichlorprop, (S)-dichlorprop, and 2,4-D was completely inhibited by various uncouplers and by nigericin but was only marginally inhibited by valinomycin and by the ATPase inhibitor N,N'-dicyclohexylcarbodiimine. Experiments on the substrate specificity of the putative transport systems revealed that (R)-dichlorprop uptake was inhibited by (R)-mecoprop but not by (S)-mecoprop, (S)-dichlorprop, or 2,4-D. On the other hand, the (S)-dichlorprop transport was inhibited by (S)-mecoprop but not by (R)-mecoprop, (R)-dichlorprop, or 2,4-D. These results provide evidence that the first step in the degradation of dichlorprop, mecoprop, and 2,4-D by S. herbicidovorans is active transport and that three inducible, proton gradient-driven uptake systems exist: one for (R)-dichlorprop and (R)-mecoprop, another for (S)-dichlorprop and (S)-mecoprop, and a third for 2,4-D.


Subject(s)
2,4-Dichlorophenoxyacetic Acid/analogs & derivatives , Flavobacterium/metabolism , 2,4-Dichlorophenoxyacetic Acid/metabolism , 2-Methyl-4-chlorophenoxyacetic Acid/analogs & derivatives , 2-Methyl-4-chlorophenoxyacetic Acid/metabolism , Adenosine Triphosphate/metabolism , Biodegradation, Environmental , Biological Transport , Carbon Radioisotopes , Kinetics , Models, Biological , Stereoisomerism
3.
Proc Soc Exp Biol Med ; 190(4): 379-84, 1989 Apr.
Article in English | MEDLINE | ID: mdl-2928352

ABSTRACT

Experiments were conducted to examine the effects of dietary zinc (Zn) upon plasma vitamin E (E) concentrations to test the hypothesis that there may be a significant dietary interaction between these two nutrients. Weanling female Sprague-Dawley rats were fed diets that were (i) Zn-deficient (less than 0.9 micrograms Zn/g diet) ad libitum; (ii) Zn-adequate (50.9 micrograms Zn/g diet), pair-fed to the Zn-deficient group; and (iii) Zn-adequate (50.9 micrograms Zn/g diet) ad libitum. Plasma E in Zn-deficient animals (4.02 +/- 1.20 micrograms/ml) was significantly reduced (P less than or equal to 0.05) compared with results in both Zn-adequate pair-fed (9.21 +/- 0.70 micrograms/ml) and Zn-adequate ad libitum-fed (9.47 +/- 0.90 micrograms/ml) animals. Zn deficiency in this model system also resulted in significant (P less than or equal to 0.05) reductions in femur and plasma Zn concentrations as well as in plasma retinol, plasma triglyceride, and plasma cholesterol concentrations. Plasma albumin and total plasma protein concentrations were normal in Zn-deficient animals. With dietary Zn deficiency, the decrease in plasma E appeared to be out of proportion to associated decreases in plasma triglyceride and plasma cholesterol concentrations. Since E is associated with plasma lipoproteins, these data suggest that lipid and/or E malabsorption may be a consequence of Zn deficiency. In response to increased dietary intake of E, increments of plasma E were lower in Zn-depleted than in Zn-adequate, pair-fed animals. These findings suggest that dietary Zn deficiency possibly may increase the nutritional requirement for E necessary to maintain adequate plasma concentrations.


Subject(s)
Diet , Vitamin E/blood , Zinc/deficiency , Amino Acids/administration & dosage , Animals , Body Weight , Dietary Proteins/administration & dosage , Female , Rats , Rats, Inbred Strains , Weaning , Zinc/administration & dosage , Zinc/blood
4.
Nutr Cancer ; 10(1-2): 79-87, 1987.
Article in English | MEDLINE | ID: mdl-3615218

ABSTRACT

This study examined a) the dietary zinc (Zn) requirement of RIII female weanling mice and b) the cytotoxicity of murine natural killer (NK) cells obtained from spleens of these mice fed varying levels of Zn. Zn was fed in a biotin-enriched egg albumen diet in amounts ranging from 0.9 to 40.4 micrograms/g diet. During a 28-day growth assay, maximum carcass growth was obtained with a diet containing 5.4 micrograms Zn/g diet. Maximal serum levels of Zn, however, were observed in mice fed diets containing 3.4 micrograms Zn/g diet. The cytotoxic activity of NK cells obtained from spleens of selected treatment groups was maximal at 40.4 micrograms Zn/g diet and was significantly higher (p less than or equal to 0.05) than that observed in spleens from mice fed diets that maximized carcass growth rates and serum Zn concentrations. It is concluded that female RIII mice have a dietary Zn requirement for growth similar to that observed for other murine strains but considerably lower than that reported for the rat. Our findings also suggest that RIII NK cells are particularly sensitive to dietary Zn intake: the optimal functional activity of these cells may result from intake of Zn higher than that necessary to maximize carcass growth and serum Zn concentrations.


Subject(s)
Cytotoxicity, Immunologic , Killer Cells, Natural/immunology , Mice, Inbred Strains/growth & development , Zinc/blood , Animals , Body Weight , Diet , Female , Mice , Nutritional Requirements , Retinol-Binding Proteins/analysis , Spleen/cytology , Vitamin A/blood , Weaning
5.
Cancer Lett ; 26(3): 319-26, 1985 Apr.
Article in English | MEDLINE | ID: mdl-2986832

ABSTRACT

The biotransformation of N-(4-hydroxyphenyl)retinamide (HPR), and interactions of parent compound and/or metabolites with the cellular retinoid binding proteins (CRBPs) and cellular retinoic acid binding proteins (CRABPs) were examined in murine mammary tumor virus (MuMTV)-induced murine mammary tumor cells (GR-3A) grown in monolayer cell culture. Soluble fractions (cytosols) obtained from the extracts of GR-3A cells after high speed centrifugation were found to contain proteins of approx. 15,000 daltons which bound retinol and retinoic acid, but did not bind HPR or HPR metabolites. Moreover, HPLC analysis of GR-3A cell extracts demonstrated that [3H]retinol and [3H]retinoic acid were not detected in cells that had been exposed to [3H]HPR for 48 h. These findings, that under in vitro conditions there is no appreciable enzymatic hydrolysis of HPR to retinoic acid or conversion to retinol, suggests that the metabolism and cytological effects of HPR may be distinct from those of retinol or retinoic acid within murine mammary epithelial cells.


Subject(s)
Carrier Proteins/metabolism , Mammary Neoplasms, Experimental/metabolism , Retinol-Binding Proteins/metabolism , Tretinoin/analogs & derivatives , Animals , Biotransformation , Cells, Cultured , Female , Fenretinide , Mice , Protein Binding , Receptors, Retinoic Acid , Tretinoin/metabolism , Vitamin A/metabolism
6.
Nutr Cancer ; 7(1-2): 105-15, 1985.
Article in English | MEDLINE | ID: mdl-2999720

ABSTRACT

The effects of N-(4-hydroxyphenyl)retinamide (HPR), a synthetic analogue of vitamin A, on cell morphology, cell cycle kinetics, cytoplasmic matrix, and expression of murine mammary tumor virus (MuMTV) in MuMTV-infected murine mammary tumor cells (GR-3A) were determined. Cellular uptake of HPR was rapid and linear, with zero-order kinetics, during the first 30 minutes of incubation. Flow cytometric analysis of cells treated with nontoxic levels of HPR (10 microM) for 48 hours revealed a reduction in percent cells in the DNA synthetic (S) phase of the cell cycle with a concomitant increase in percent cells in the G1 phase of the cell cycle. Dexamethasone-stimulated MuMTV expression was not affected after 48 hours of HPR exposure, whereas the virus expression was significantly reduced in cells treated with HPR for seven days. The reduction in MuMTV expression was preceded by changes in cell morphology (decreased cell-cell contact and reduced cell flattening) and altered F-actin aggregation. Continuous exposure to HPR (10 microM) for 14 days resulted in reduced cell proliferation rates and decreased cell plating efficiency of GR-3A cells. Taken together, these results indicate that HPR is rapidly incorporated into GR-3A cells and that the effects of HPR on cell profileration, cytoskeletal organization, and cell morphology appear to precede the effects of this retinoid on the expression of the etiological agent of murine mammary tumorigenesis, MuMTV.


Subject(s)
Cell Division/drug effects , Cell Survival/drug effects , Tretinoin/analogs & derivatives , Actin Cytoskeleton/drug effects , Actins/metabolism , Animals , Cell Cycle/drug effects , Cell Line , Cell Transformation, Neoplastic/drug effects , Female , Fenretinide , Mammary Neoplasms, Experimental , Mammary Tumor Virus, Mouse , Mice , Microscopy, Electron, Scanning , Tretinoin/metabolism , Tretinoin/pharmacology
7.
Cancer Lett ; 20(1): 83-92, 1983 Aug.
Article in English | MEDLINE | ID: mdl-6318967

ABSTRACT

Cellular retinol (CRBP) and retinoic acid binding proteins (CRABP) were measured in normal (C57Bl) and Murine Mammary Tumor Virus (MuMTV)-induced murine mammary tumor cells (C57BlfRIII) grown in monolayer culture. High speed supernatant fractions (cytosols) from transformed cells contained elevated levels of CRBP and CRABP (0.276 and 1.410 pmol/mg protein, respectively) compared to cytosol from non-transformed murine mammary cells which contained only low levels of CRBP (0.099 pmol/mg protein). Our findings suggest that malignant transformation of mammary epithelial cells, induced by MuMTV infection, results in changes in the expression of cellular retinoid binding proteins and possibly in the sensitivity of these cells to various retinoids.


Subject(s)
Cell Transformation, Neoplastic/metabolism , Mammary Glands, Animal/metabolism , Mammary Neoplasms, Experimental/metabolism , Neoplasm Proteins/metabolism , Retinol-Binding Proteins/metabolism , Animals , Carrier Proteins/metabolism , Cell Line , Chromatography, Gel , Cytosol/metabolism , Female , Mammary Tumor Virus, Mouse , Mice , Mice, Inbred C57BL , Receptors, Retinoic Acid , Retinol-Binding Proteins, Cellular
8.
J Nutr ; 111(9): 1611-20, 1981 Sep.
Article in English | MEDLINE | ID: mdl-7277038

ABSTRACT

Experiments were conducted to determine the relationship of selenium-dependent glutathione peroxidase (SeGSHpx) activity to the onset of nutritional pancreatic atrophy (NPA) in chicks. Chicks produced from hens fed a low Se, low vitamin E practical diet had low activities of SeGSHpx in plasma and pancreas at hatching. The SeGSHpx activity remained at a low level before and during all stages of the onset of NPA. Selenium supplementation of the diet prevented NPA and resulted in significant elevations in SeGSHpx activity. Although the early stages of NPA are believed to involve mitochondrial swelling, no significant differences were found in rate of oxygen uptake, respiratory control index or adenosine diphosphate to oxygen ratio between pancreatic mitochondria isolated from Se-deficient or Se-adequate chicks. Improvements in maternal Se status significantly increased chick pancreatic SeGSHpx activity at hatching and delayed the onset of NPA in chicks fed a Se-deficient diet. A significant proportion of the second-generation Se- and vitamin E-depleted chicks used in these studies was found to grow at nearly normal rates when fed the Se-deficient diet. These chicks, designated as refractory to the growth-depressing effect of severe Se-deficiency, were biochemically deficient (i.e., had very low SeGSHpx activities) and showed NPA. It is concluded that the Se-responsive lesion which results in NPA in the chick is different from that which results in depressed growth.


Subject(s)
Chickens/metabolism , Glutathione Peroxidase/metabolism , Pancreas/enzymology , Pancreatic Diseases/enzymology , Peroxidases/metabolism , Selenium/deficiency , Animals , Atrophy , Female , Male , Mitochondria/metabolism , Oviposition , Pancreas/pathology , Selenium/pharmacology , Vitamin E Deficiency/metabolism
10.
J Nutr ; 110(4): 743-9, 1980 Apr.
Article in English | MEDLINE | ID: mdl-7365543

ABSTRACT

Experiments were conducted to determine the initial effects of oral selenium administration on selenium-deficient chicks. Administration of 5 microgram selenium as seleno-DL-methionine increased voluntary feed consumption within 2-3 hours, whereas selenite did not have a significant effect until 3-4 hours. Spontaneous activity, body weight gain and plasma glucose concentration increased 6-8 hours after selenium administration. The earliest response in the specific activity of selenium-dependent glutathione peroxidase occurred in plasma at 8 hours and in liver at 24 hours after selenium administration. The onset of pancreatic atrophy, however, was not affected by the level of feed intake suggesting that the effect of selenium upon appetite may be distinct from the involvement of selenium in nutritional pancreatic atrophy and fibrosis.


Subject(s)
Appetite/drug effects , Chickens/metabolism , Pancreatic Diseases/etiology , Selenium/deficiency , Animals , Atrophy , Blood Glucose/metabolism , Body Weight , Eating/drug effects , Glutathione Peroxidase/metabolism , Male , Selenious Acid , Selenium/therapeutic use , Selenomethionine/therapeutic use
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