RESUMEN
BACKGROUND: N-chlorotaurine (NCT), a long-lived oxidant produced by human leukocytes, can be synthesized chemically and used topically as a well-tolerated antiseptic to different body regions including sensitive ones. The aim of this study was to test the tolerability of inhaled 1% NCT in aqueous solution upon repeated application. METHODS: The study was performed double-blind and randomized with a parallel test group (1% NCT) and control group (0.9% NaCl as placebo). There were two Austrian centres involved, the hospitals, Natters and Vöcklabruck. Healthy, full age volunteers were included, 12 in each centre. A total of 12 patients were treated with NCT, and 12 with placebo, exactly half of each group from each centre. The single dose was 1.2 ml inhaled over a period of 10 min using an AKITA JET nebulizer. One inhalation was done every day for five consecutive days. The primary criterion of evaluation was the forced expiratory volume in 1 second (FEV1). Secondary criteria were subjective sensations, further lung function parameters such as airway resistance, physical examination, and blood analyses (gases, electrolytes, organ function values, pharmacokinetic parameters taurine and methionine, immune parameters). RESULTS: All included 15 females and 9 males completed the treatment and the control examinations according to the study protocol. FEV1 (100.83% ± 8.04% for NCT and 92.92% ± 11.35% for controls) remained unchanged and constant during the treatment and in control examinations 1 week and 3 months after the treatment (98.75% ± 7.37% for NCT and 91.17% ± 9.46% for controls, p > 0.082 between time points within each group). The same was true for all other objective parameters. Subjective mild sensations with a higher frequency in the test group were chlorine taste ( p < 0.01) and occasional tickle in the throat ( p = 0.057). Taurine and methionine plasma concentrations did not change within 60 min after inhalation or later on. CONCLUSIONS: Inhaled NCT is well tolerated as in other applications of different body regions. Side effects are mild, topical and transitory. The study was registered prospectively in the European Clinical Trials Database of the European Medicines Agency. The EudraCT number is 2012-003700-12.
Asunto(s)
Antiinfecciosos Locales/administración & dosificación , Pulmón/fisiología , Taurina/análogos & derivados , Administración por Inhalación , Adulto , Anciano , Antiinfecciosos Locales/efectos adversos , Austria , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Nebulizadores y Vaporizadores , Estudios Prospectivos , Taurina/administración & dosificación , Taurina/efectos adversos , Adulto JovenRESUMEN
Carnosinase 1 (CN1) contributes to diabetic nephropathy by cleaving histidine-dipeptides which scavenge reactive oxygen and carbonyl species and increase nitric oxide (NO) production. In diabetic mice renal CN1 activity is increased, the regulatory mechanisms are unknown. We therefore analysed the in vitro and in vivo regulation of CN1 activity using recombinant and human CN1, and the db/db mouse model of diabetes. Glucose, leptin and insulin did not modify recombinant and human CN1 activity in vitro, glucose did not alter renal CN1 activity of WT or db/db mice ex vivo. Reactive metabolite methylglyoxal and Fenton reagent carbonylated recombinant CN1 and doubled CN1 efficiency. NO S-nitrosylated CN1 and decreased CN1 efficiency for carnosine by 70 % (p < 0.01), but not for anserine. Both CN1 cysteine residues were nitrosylated, the cysteine at position 102 but not at position 229 regulated CN1 activities. In db/db mice, renal CN1 mRNA and protein levels were similar as in non-diabetic controls, CN1 efficiency 1.9 and 1.6 fold higher for carnosine and anserine. Renal carbonyl stress was strongly increased and NO production halved, CN1 highly carbonylated and less S-nitrosylated compared to WT mice. GSH and NO2/3 concentrations were reduced and inversely related with carnosine degradation rate (r = -0.82/-0.85). Thus, reactive metabolites of diabetes upregulate CN1 activity by post-translational modifications, and thus decrease the availability of reactive metabolite-scavenging histidine dipeptides in the kidney in a positive feedback loop. Interference with this vicious circle may represent a new therapeutic target for mitigation of DN.
Asunto(s)
Carnosina/metabolismo , Diabetes Mellitus/metabolismo , Óxido Nítrico/metabolismo , Piruvaldehído/metabolismo , Animales , Carnosina/genética , Diabetes Mellitus/genética , Diabetes Mellitus/patología , Dipeptidasas/genética , Dipeptidasas/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Hierro/metabolismo , Ratones , Ratones Mutantes , MutaciónRESUMEN
Inherited diseases are the result of DNA sequence changes. In recessive diseases, the clinical phenotype results from the combined functional effects of variants in both copies of the gene. In some diseases there is often considerable variability of clinical presentation or disease severity, which may be predicted by the genotype. Additional effects may be triggered by environmental factors, as well as genetic modifiers which could be nucleotide polymorphisms in related genes, e.g. maternal ApoE or ABCA1 genotypes which may have an influence on the phenotype of SLOS individuals. Here we report the establishment of genotype variation databases for various rare diseases which provide individual clinical phenotypes associated with genotypes and include data about possible genetic modifiers. These databases aim to be an easy public access to information on rare and private variants with clinical data, which will facilitate the interpretation of genetic variants. The created databases include ACAD8 (isobutyryl-CoA dehydrogenase deficiency (IBD)), ACADSB (short-chain acyl-CoA dehydrogenase (SCAD) deficiency), AUH (3-methylglutaconic aciduria (3-MGCA)), DHCR7 (Smith-Lemli-Opitz syndrome), HMGCS2 (3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency), HSD17B10 (17-beta-hydroxysteroid dehydrogenase X deficiency), FKBP14 (Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss; EDSKMH) and ROGDI (Kohlschütter-Tönz syndrome). These genes have been selected because of our specific research interests in these rare and metabolic diseases. The aim of the database was to include all identified individuals with variants in these specific genes. Identical genotypes are listed multiple times if they were found in several patients, phenotypic descriptions and biochemical data are included as detailed as possible in view also of validating the proposed pathogenicity of these genotypes. For DHCR7 genetic modifier data (maternal APOE and ABCA1 genotypes) is also included. Databases are available at http://databases.lovd.nl/shared/genes and will be updated based on periodic literature reviews and submitted reports.
Asunto(s)
Bases de Datos Genéticas , Estudios de Asociación Genética/estadística & datos numéricos , Mutación , Enfermedades Raras/genética , 3-Hidroxiacil-CoA Deshidrogenasas , Transportador 1 de Casete de Unión a ATP/genética , Acil-CoA Deshidrogenasa/deficiencia , Acil-CoA Deshidrogenasa/genética , Acil-CoA Deshidrogenasas/genética , Amelogénesis Imperfecta/genética , Amelogénesis Imperfecta/patología , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/patología , Apolipoproteínas E/genética , Demencia/genética , Demencia/patología , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Enoil-CoA Hidratasa/genética , Epilepsia/genética , Epilepsia/patología , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Hidroximetilglutaril-CoA Sintasa/deficiencia , Hidroximetilglutaril-CoA Sintasa/genética , Hipoglucemia/genética , Hipoglucemia/patología , Internet , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/patología , Proteínas de la Membrana/genética , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/patología , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Proteínas Nucleares/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Isomerasa de Peptidilprolil/genética , Fenotipo , Proteínas de Unión al ARN/genética , Enfermedades Raras/patología , Síndrome de Smith-Lemli-Opitz/genética , Síndrome de Smith-Lemli-Opitz/patologíaRESUMEN
The Smith-Lemli-Opitz syndrome (SLOS [MIM 270400]) is an autosomal recessive malformation syndrome that shows a great variability with regard to severity. SLOS is caused by mutations in the Δ7sterol-reductase gene (DHCR7), which disrupt cholesterol biosynthesis. Phenotypic variability of the disease is already known to be associated with maternal apolipoprotein E (ApoE) genotype. The aim of this study was to detect additional modifiers of the SLOS phenotype. We examined the association of SLOS severity with variants in the genes for ApoC-III, lecithin-cholesterol acyltransferase, cholesteryl-ester transfer protein, ATP-binding cassette transporter A1 (ABCA1), and methylene tetrahydrofolate reductase. Our study group included 59 SLOS patients, their mothers, and 49 of their fathers. In addition, we investigated whether ApoE and ABCA1 genotypes are associated with the viability of severe SLOS cases (n=21) caused by two null mutations in the DHCR7 gene. Maternal ABCA1 genotypes show a highly significant correlation with clinical severity in SLOS patients (P=0.007). The rare maternal p.1587Lys allele in the ABCA1 gene was associated with milder phenotypes. ANOVA analysis demonstrated an association of maternal ABCA1 genotypes with severity scores (logarithmised) of SLOS patients of P=0.004. Maternal ABCA1 explains 15.4% (R²) of severity of SLOS patients. There was no association between maternal ApoE genotype and survival of the SLOS fetus carrying two null mutations. Regarding ABCA1 p.Arg1587Lys in mothers of latter SLOS cases, a significant deviation from Hardy-Weinberg equilibrium (HWE) was observed (P=0.005). ABCA1 is an additional genetic modifier in SLOS. Modifying placental cholesterol transfer pathways may be an approach for prenatal therapy of SLOS.