RESUMEN
We aimed to investigate preventive effects of All-trans retinoic acid (ATRA) on a lipopolysaccharide (LPS)-induced aged neuroinflammation model. We analyzed behavior, systemic nitric oxide (NO) production, cerebral NO synthase (NOS2) and ß-amyloid (Aß) 1-42 expression and tissue integrity in the neuroinflammation model pretreated with ATRA (150µg/ml/rat/day) for 30days. Our results showed that LPS treatment (500µg/kg/day) for 7days disturbed memory, enhanced systemic NO production, NOS2 and Aß 1-42 cerebral expression and generated an Alzheimer's disease (AD)-like neuronal degeneration. Interestingly, ATRA pretreatment prevented the LPS-induced deleterious effects. ATRA could be a potent preventive approach in AD.
Asunto(s)
Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/biosíntesis , Trastornos de la Memoria/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Fragmentos de Péptidos/biosíntesis , Tretinoina/uso terapéutico , Envejecimiento/efectos de los fármacos , Envejecimiento/patología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Inflamación/metabolismo , Inflamación/patología , Inflamación/prevención & control , Lipopolisacáridos/toxicidad , Masculino , Trastornos de la Memoria/patología , Trastornos de la Memoria/prevención & control , Fármacos Neuroprotectores/farmacología , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Fragmentos de Péptidos/antagonistas & inhibidores , Ratas , Ratas WistarRESUMEN
BACKGROUND: The multi-drug resistance gene (MDR1) has raised increasing interest as a susceptibility gene for Crohn's disease (CD). The role of MDR1 single-nucleotide polymorphisms (SNPs) in the predisposition and behavior of CD in the pediatric population is still elusive. Here, we investigated whether SNPs in MDR1 are associated with CD in Algerian pediatric patients. METHODS: A case-control study was conducted enrolling 47 pediatric CD patients and 100 controls. All subjects were genotyped for the most common MDR1 SNPs (C3434T, C1236T, and G2677A/T) using PCR-RFLP method. We also explored the association between polymorphisms and clinical sub-phenotypes. RESULTS: We have detected no significant association of C3435T SNP and pediatric CD. However, we observed a significantly higher frequency of the risk alleles, 1236T and 2677T/A among the CD patients compared to controls. Moreover, the risk allele 1236T was associated to a higher risk for resective surgery. CONCLUSION: Our data suggest that the C1236T and G2677A/T SNPs in the MDR1 gene are associated with CD and the C1236T risk allele with a more severe course of disease in Algerian pediatric patients. Further analysis using larger patients group and functional studies would be interesting to elucidate the role of MDR1 gene in pediatric CD.Pediatric Research (2016); doi:10.1038/pr.2016.163.
Asunto(s)
Enfermedad de Crohn/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adolescente , Argelia , Estudios de Casos y Controles , Niño , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
BACKGROUND: Alzheimer's disease (AD), the most common form of dementia in the elderly, is a neurodegenerative disorder associated with a complex pathophysiology. It is accepted that inflammation contributes to the pathogenesis of AD. All-trans-retinoic acid (ATRA) is a bioactive derivative of vitamin A that has shown immunomodulatory effects in many immune disorders. OBJECTIVES: In our study, we aimed to investigate in vitro immunomodulatory effects of ATRA on inducible nitric oxide synthase (iNOS) expression and interleukin-17A production during AD. METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from 30 Algerian AD patients and 14 age-matched nondemented controls were treated (or not) with ATRA. Production of NO and IL-17A in culture media was measured by the modified Griess method and enzyme-linked immunosorbent assay, respectively. Expression of iNOS in PBMCs was examined by fluorescence immunostaining. RESULTS: Our results showed higher spontaneous in vitro production of NO related to overexpression of iNOS in AD patients compared to controls. Remarkably, ATRA treatment showed an important downregulatory effect on NO production and iNOS expression in patients. This effect was associated with a reduction in IL-17A production and increased IL-10 release. CONCLUSIONS: Taken together, our results indicate that ATRA exerts anti-inflammatory effects in AD. Furthermore, ATRA represents a promising tool for monitoring inflammatory responses associated with disease progression.
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Enfermedad de Alzheimer/patología , Antineoplásicos/farmacología , Interleucina-17/sangre , Leucocitos Mononucleares/efectos de los fármacos , Óxido Nítrico/sangre , Tretinoina/farmacología , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Estudios de Casos y Controles , Células Cultivadas , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIM: To analyse allelic frequency of NOD2 gene variants and to assess their correlation with inflammatory bowel disease (IBD) in Algeria. METHODS: We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn's disease (CD) and 46 with ulcerative colitis (UC). Data was prospectively collected between January 2011 and December 2013. The demographic and clinical characteristics were recorded for all the patients. A group of 114 healthy unrelated individuals were selected as controls. All groups studied originated from different regions of North Algeria and confirmed the Algerian origin of their parents and grandparents. Informed and written consent was obtained from each of the participants. All individuals were genotyped for the three CD-associated NOD2 variants (p.Arg(702)Trp, p.Gly908Arg and p.Leu(1007)fsinsC mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ(2) test and Fisher's exact test where appropriate. Odds ratios (OR) and 95% confidence intervals (95%CI) were also estimated. Association analyses were performed to study the influence of these variants on IBD and on clinical phenotypes. RESULTS: The p.Arg(702)Trp mutation showed the highest frequency in CD patients (8%) compared to UC patients (2%) (P = 0.09, OR = 3.67, 95%CI: 0.48-4.87) and controls (5%) (P = 0.4, OR = 1.47, 95%CI: 0.65-3.31). In CD patients allelic frequencies of p.Gly908Arg and p.Leu(1007)fsinsC variants compared to HC were 3% vs 2% (P = 0.5, OR = 1.67, 95%CI: 0.44-6.34); 2% vs 1% (P = 0.4 OR = 2.69 95%CI: 0.48-14.87 respectively). In UC patients, allelic frequencies of p.Gly908Arg and p.Leu(1007)fsinsC variants compared to HC were 1% vs 2% (P = 1, OR = 1.62, 95%CI: 0.17-4.74) and 2% vs 1% (P = 0.32, OR = 0.39, 95%CI: 0.05-2.87). The total frequency of the mutated NOD2 chromosomes was higher in CD (13%), than in HC (8%) and UC (5%). In addition, NOD2 variants were linked to a particular clinical sub-phenotype in CD in this Algerian cohort. As expected, the three NOD2 variants showed a significant association with CD but did not reach statistical significance, despite the fact that the allele frequency of NOD2 variants was in the range found in most of the European populations. This might be due to the non-exposure of the NOD2 carriers to environmental factors, required for the expression of the disease. CONCLUSION: Further analyses are necessary to study genetic and environmental factors in IBD in the Algerian population, using larger patient groups.
Asunto(s)
Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Mutación , Proteína Adaptadora de Señalización NOD2/genética , Adolescente , Adulto , Argelia/epidemiología , Población Negra/genética , Distribución de Chi-Cuadrado , Niño , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/etnología , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/etnología , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Oportunidad Relativa , Fenotipo , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
An epidemiological molecular study was carried out to evaluate the spectrum and allelic frequency of alpha-thalassemia (alpha-thal) defects in Algeria. A series of 153 randomly selected blood donors was screened for 10 alpha-thal alleles described in the Mediterranean area. In addition, six unrelated cases with hematological and biochemical data suggestive of Hb H disease were investigated. Our data revealed an allele frequency of 4.6%. The presence of alpha(0)-thal determinants (-alpha(20.5) and --MED I) was observed both in Hb H patients and in the randomly collected samples. Overall, the -alpha(3.7) deletion was the most prevalent allele (2.9%), followed by the alpha(Nco I)alpha (HBA2:c.1A>G) allele (0.6%) and by the alpha(Hph I)alpha (HBA2:c.95 + 2_95 + 6delTGAGG), -alpha(20.5), --(MED I) alleles (0.3% each). The -alpha(4.2) deletion was observed in only one Hb H patient. These results outline the heterogeneity of the alpha-thal alleles in Algeria which reflects the anthropological history of the country. Because of their frequency, alpha-thal alleles are probably frequent modulators of prevalent beta-globin gene-related hemoglobinopathies in Algeria.