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1.
Cell Mol Biol (Noisy-le-grand) ; 65(6): 6-11, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31472041

RESUMO

In traditional medicine, Ficus carica (also known as fig) latex is recognized as a remedy with various therapeutic effects. In the present study we investigated the antitumor activity of Ficus carica extracts and latex. We evaluated the effects of increasing concentrations of Ficus carica extracts and latex on HCT-116 and HT-29 human colorectal cell proliferation using MTT assay and apoptosis induction by evaluating PARP cleavage by Western blot analysis. Peel, pulp, leaves, whole fruit and latex extracts of Ficus carica exerted significant antiproliferative effects on HCT-116 (IC50 values 239, 343, 177, 299, 206 µg/ml) and HT-29 cells (IC50 values 207, 249, 230, 261, 182 µg/ml) after 48h of treatment. Furthermore, treatment with different extracts of Ficus carica induced apoptosis in both HT-29 and HCT-116 cancer cells. Leaves and latex extracts of Ficus carica showed the strongest antiproliferative activities. Overall, our results showed that these natural products are strong apoptosis inducers which suggest their use of for therapeutic purposes.

3.
Medicine (Baltimore) ; 98(3): e13975, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30653102

RESUMO

Pharmacogenomics offers remarkable potential for the rapid translation of discoveries into changes in clinical practice. In the present work, we are interested in evaluating the ability of commercially available genome-wide association sequencing chips to cover genes that have high pharmacogenomics potential.We used a set of 2794 variations within 369 absorption, distribution, metabolism, and elimination (ADME) genes of interest, as previously defined in collaboration with the Pharma ADME consortium. We have compared the Illumina TrueSeq and both Agilent SureSelect and HaloPlex sequencing technologies. We have developed Python scripts to evaluate the coverage for each of these products. In particular, we considered a specific list of 155 allelic variants in 34 genes which present high pharmacogenomics potential. Both the theoretical and practical coverage was assessed.Given the need to have a good coverage to establish confidently the functionality of an enzyme, the observed rates are unlikely to provide sufficient evidence for pharmacogenomics studies. We assessed the coverage using enrichment technology for exome sequencing using the Illumina Trueseq exome, Agilent SureSelectXT1 V4 and V5, and Haloplex exome, which offer a coverage of 96.12%, 91.61%, and 88.38%, respectively.Although pharmacogenomic advances had been limited in the past due in part to the lack of coverage of commercial genotyping chips, it is anticipated that future studies that make use of new sequencing technologies should offer a greater potential for discovery.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Farmacogenética/métodos , Melhoria de Qualidade/normas , Análise de Sequência de DNA/métodos , Exoma , Técnicas de Genotipagem/métodos , Humanos , Transferência de Tecnologia
4.
BMC Res Notes ; 11(1): 783, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30384859

RESUMO

OBJECTIVE: In view of the discrepant data regarding the association between the protein tyrosine phosphatase non-receptor 22 (PTPN22) rs2476601 (R620W, 1858C→T) polymorphism and susceptibility to autoimmune diseases including inflammatory bowel diseases (IBD), we investigated whether this functional single-nucleotide polymorphism influences IBD risk in a group of Moroccan patients. RESULTS: This is the first report on the prevalence of PTPN22 (R620W) variant in a Moroccan cohort. No evidence of statistically significant differences was observed when the PTPN22 (R620W) allele and genotype distribution among IBD, Crohn's disease (CD), ulcerative colitis (UC) patients and healthy controls were compared. The frequency of the variant allele in healthy subjects was 1.77% compared to 2.56% in the IBD patients and 1.85% in CD patients. Furthermore, the frequency of this allele was increased in UC patients compared to controls (4.17% vs. 1.77%, OR = 2.42, 95% CI 0.82-7.08; P = 0.09), but the difference was not statistically significant. Our data suggest a lack of association between PTPN22 R620W variant and IBD susceptibility in Moroccan patients.

5.
J Trace Elem Med Biol ; 48: 30-37, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29773190

RESUMO

The present work aims to study the metallic contamination of four sampling sites located nearby major sewage outfalls of the Casablanca coast (Morocco), using indigenous mussels Mytilus galloprovincialis as bioindicators of pollution. This research offered the opportunity to study trace metals bioaccumulation mechanisms, which represent a major factor in assessment processes of the pollution effects in coastal ecosystem health. The bioavailability and the bioaccumulation of trace metals (Cu, Zn, Ni, Pb) were evaluated in order to compare the metallic contamination in mussels' tissues and find a possible correlation with physiological parameters of this filter feeding species. Our results showed a significant spatiotemporal variation of bioaccumulation, compared to control. A significant correlation coefficient between metals (Zn and Pb) bioavailability and physiological index (CI) was revealed in mussels from the most polluted location. The seasonal variation of trace metal accumulation was also raised; the highest values recorded during the dry period.


Assuntos
Monitoramento Ambiental , Contaminação de Alimentos/análise , Oligoelementos/análise , Poluentes Químicos da Água/análise , Animais , Disponibilidade Biológica , Marrocos , Mytilus , Oligoelementos/metabolismo , Poluentes Químicos da Água/metabolismo
6.
Pharmacognosy Res ; 9(4): 390-395, 2017 Oct-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29263634

RESUMO

Background: Caralluma europaea (CE) has been studied for its chemical constituents, and no information is available on its toxicity or its pharmacological activities. Objective: To determine the toxicity of an aqueous extract of CE stems in vitro and in vivo after acute and subchronic oral gavages in Swiss albino's mice and its immunomodulatory and inflammatory activities. Materials and Methods: The extract was administrated in single oral dose at 5 g/kg body weight for the acute toxicity test and by gavages daily at doses of 1, 2.5, or 5 g/kg for 30 consecutive days for the subchronic toxicity test. The immunomodulatory activities and inflammatory activities were tested by the evaluation of hemagglutination antibodies (HAs) titers and delayed-type hypersensitivity (DTH) response. Results: For the dose of 1 g/kg, no visible toxic effects were observed. However, for the higher doses, clinical observations of toxicity were noted after 1 week of treatment. This was confirmed by the biochemical parameters values and the histology analyses of the spleen, liver, and kidney tissues. The high cellular mortality rate in vitro when treated with CE extract confirmed their toxicity potential. There was also increase of "HA titer" and "DTH" response in mice treated with nontoxic dose of CE (1 g/kg) compared to control group. This immune activity was confirmed by the high number of lymphocytes infiltrates noted in the different organs. Conclusion: We conclude that CE at the dose up of 1 g/kg produced toxic effect in mice that induced an immune inflammatory reaction. SUMMARY: Caralluma europaea (CE) has been studied for its chemical constituents, and no information is available on its toxicity or its pharmacological activities. The objective is to determine the toxicity of an aqueous extract of CE stems in vitro and in vivo after acute and subchronic oral gavages in Swiss albino's mice and its immunomodulatory and inflammatory activities. For the dose of 1 g/kg, no visible toxic effects were observed. However, for the higher doses, clinical observations of toxicity were noted after 1 week of treatment. This was confirmed by the biochemical parameters values and the histology analyses of the spleen, liver, and kidney tissues. The high cellular mortality rate in vitro confirmed their toxicity potential. There was also increase of "hemagglutination antibody titer" and "delayed-type hypersensitivity" response in mice treated with nontoxic dose of CE (1 g/kg) compared to control group. This immune activity was confirmed by the high number of lymphocytes infiltrates noted in the different organs. We conclude that CE at the dose up of 1 g/kg produced toxic effect in mice that induced an immune inflammatory reaction. Abbreviations Used: CE: Caralluma europaea, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, RRBCs: Rat red blood cells, DTH: Delayed-type hypersensitivity response, PBS: Phosphate buffer solution.

7.
J Gastroenterol Hepatol ; 32(6): 1212-1220, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27869326

RESUMO

BACKGROUND: Inflammatory bowel diseases (IBD) are chronic multi-factorial inflammatory disorders. Accumulating investigations have provided compelling evidence that describe the interplay of a complex genetic landscape and inappropriate inflammatory response to intestinal microbes in disease etiopathogenesis but still pose challenges in diagnostic practices. METHOD: In this study, comparative proteomic analysis was conducted to identify disease specific proteins underlying IBD pathogenetic mechanisms. Total blood proteins of the IBD patients and healthy subjects were analyzed with one-dimensional electrophoresis; differentially expressed bands were excised and subjected to matrix-assisted laser desorption ionization-time of flight mass spectrometry along with nanoflow liquid chromatography electrospray ionization-tandem mass spectrometry analysis. Presence of glycosylation, hydroxylation, and phosphorylation post-translational modifications was further investigated by immunoprecipitation. RESULTS: Peroxiredoxin-2 (PRDX2) and hemoglobin-subunits proteins, which are closely involved in the response to oxidative stress, were identified. PRDX2 was selected for further validation using western blot and reverse transcription-polymerase chain reaction. PRDX2 overexpression was restricted to the protein level within the membrane fraction. Immunoprecipitation identified PRDX2 to be post-translationally glycosylated and phosphorylated. CONCLUSION: Our findings demonstrate the implication of PRDX2 in IBD. Future studies are required to establish its functional role and to determine the clinical utility.


Assuntos
Expressão Gênica , Doenças Inflamatórias Intestinais/genética , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Regulação para Cima , Adulto , Feminino , Glicosilação , Humanos , Hidroxilação , Masculino , Estresse Oxidativo/genética , Fosforilação
8.
World J Gastroenterol ; 23(47): 8300-8307, 2017 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-29307990

RESUMO

AIM: To investigate whether common variants in the oxidative pathway genes influence inflammatory bowel disease (IBD) risk among Moroccan patients. METHODS: The distribution of (TAAA)n_rs12720460 and (CCTTT)n _rs3833912 NOS2A microsatellite repeats, HIF-1A_rs11549467 and NFKB1-94ins/delATTG_rs28362491 was analyzed in 507 subjects grouped in 199 IBD and 308 healthy controls. Genotyping was performed with polymerase chain reaction-fluorescent method and the TaqMan® allelic discrimination technology. RESULTS: The allele and genotype frequencies of HIF1A_ rs11549467, NFKB1_rs28362491 and NOS2A_ (TAAA)n did not differ significantly between patients and controls. Analysis of NOS2A_ (CCTTT)n markers evidenced differences between patients and healthy controls. A preferential presence of the (CCTTT)8 (P = 0.02; OR = 1.71, 95%CI: 1.07-2.74), (CCTTT)14 (P = 0.02; OR = 1.71, 95%CI: 1.06-2.76) alleles in IBD, (CCTTT)8 (P = 0.008; OR = 1.95, 95%CI: 1.17-3.23) in CD and (CCTTT)7 (P = 0.009; OR = 7.61, 95%CI: 1.25-46.08), (CCTTT)11 (P = 0.05; OR = 0.51, 95%CI: 0.25-1.01), (CCTTT)14 (P = 0.02; OR = 2.05, 95%CI: 1.07-3.94), (CCTTT)15 (P = 0.01; OR = 2.25, 95%CI: 1.16-4.35) repeats in UC patients indicated its possible association with higher disease risk which need to be confirmed in a larger sample size. CONCLUSION: Our results suggest that the NOS2A_ (CCTTT)n gene variations may influence IBD susceptibility in the Moroccan population.


Assuntos
Predisposição Genética para Doença , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Doenças Inflamatórias Intestinais/genética , Subunidade p50 de NF-kappa B/genética , Óxido Nítrico Sintase Tipo II/genética , Estresse Oxidativo/genética , Adolescente , Adulto , Alelos , Feminino , Haplótipos , Humanos , Masculino , Repetições de Microssatélites/genética , Marrocos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Adulto Jovem
9.
J Toxicol Sci ; 41(3): 403-16, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27193732

RESUMO

Ochratoxin A (OTA) is a natural fungal secondary metabolite that contaminates food and animal feed. Human exposure and involvement of this mycotoxin in several pathologies have been demonstrated worldwide. We investigated OTA immunotoxicity on H9 cells, a human cutaneous CD4+ T lymphoma cell line. Cells were treated with 0, 1, 5, 10, and 20 µM OTA for up to 24 hr. Western blotting revealed increased phosphorylation of all three major mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun amino-terminal kinase, p38). OTA triggered mitochondrial transmembrane potential loss and caspase-3 activation. The 24-hr OTA treatment caused marked changes in cell morphology and DNA fragmentation, suggesting the occurrence of apoptotic events that involved a mitochondria-dependent pathway. Moreover, OTA triggered significant modulation of survivin, interleukin 2 (IL-2) and tumor necrosis factor α (TNF-α): mRNA expression of survivin and IL-2 were decreased, while TNF-α was increased. OTA also caused caspase-8 activation in a time-dependent manner, which evokes the death receptor pathway activation; we suspect that this occurred via the autocrine pro-apoptotic effect of TNF-α on H9 cells.


Assuntos
Apoptose/efeitos dos fármacos , Interleucina-2/metabolismo , Mitocôndrias/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Ocratoxinas/toxicidade , RNA Mensageiro/metabolismo , Linfócitos T/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Comunicação Autócrina/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/genética , Caspase 8/metabolismo , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ativação Enzimática , Regulação da Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Interleucina-2/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/imunologia , Mitocôndrias/patologia , RNA Mensageiro/genética , Transdução de Sinais/efeitos dos fármacos , Survivina , Linfócitos T/enzimologia , Linfócitos T/imunologia , Linfócitos T/patologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/genética
10.
J Toxicol Sci ; 41(1): 123-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26763399

RESUMO

Paraphenylene daimine (PPD) is an aromatic amine that is widely used in several industrial products; however, its toxicity has been reported in several cases of cardiac arrests. As platelets play a key role in cardiovascular diseases, we aimed to determine the impact of PPD in vitro and in vivo on platelet function. Our findings demonstrated that platelet activation and aggregation were strongly enhanced by PPD. Treatment with PPD primed human platelets that became more reactive in response to low doses of collagen. Furthermore, PPD exacerbated thrombus formation in rats in comparison with those untreated. Our results suggest that PPD is an important platelet primer predisposing platelets to promote thrombus formation in response to vascular injury. This should prompt the authorities to consider controlling the marketing of this product.


Assuntos
Colágeno/farmacologia , Fenilenodiaminas/toxicidade , Agregação Plaquetária/efeitos dos fármacos , Trombose/etiologia , Animais , Feminino , Humanos , Técnicas In Vitro , Masculino , Ativação Plaquetária/efeitos dos fármacos , Ratos Sprague-Dawley
11.
Front Immunol ; 6: 529, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26528290

RESUMO

Inflammatory bowel disease (IBD) is a chronic and multifactorial disease of the gastrointestinal tract. The exact etiology of IBD remains complex and unclear involving an inadequately defined relationship between microbial insult, genetic predisposition, altered intestinal barrier permeability, oxidative stress components and abnormal immune responses. The role of the co-stimulatory system made up of cluster of differentiation 40 protein (CD40) and its ligand (CD40L) in the response of the immune system to pathogens is now widely accepted. The implication of CD40/CD40L axis in immune system disorders due to its important role as signal transduction pathway among immune cells is well documented. Several studies have suggested that CD40/CD40L interactions regulate oxidative stress; this can affect various signaling pathways leading to IBD development. Hence, CD40/CD40L signaling pathway may become a new target for IBD treatment. This review will cover the general contribution of the CD40/CD40L dyad in the development of IBD in order to facilitate future approaches aiming to elucidate the immunological mechanisms that control gut inflammation.

12.
Biochem Biophys Res Commun ; 468(4): 636-41, 2015 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-26549226

RESUMO

Single amino acid mutations in valosin containing protein (VCP/p97), a highly conserved member of the ATPases associated with diverse cellular activities (AAA) family of ATPases has been linked to a severe degenerative disease affecting brain, muscle and bone tissue. Previous studies have demonstrated the role of VCP mutations in altering the ATPase activity of the D2 ring; however the structural consequences of these mutations remain unclear. In this study, we report the three-dimensional (3D) map of the pathogenic VCP variant, R155P, as revealed by single-particle Cryo-Electron Microscopy (EM) analysis at 14 Å resolution. We show that the N-terminal R155P mutation induces a large structural reorganisation of the D2 ATPase ring. Results from docking studies using crystal structure data of available wild-type VCP in the EM density maps indicate that the major difference is localized at the interface between two protomers within the D2 ring. Consistent with a conformational change, the VCP R155P variant shifted the isoelectric point of the protein and reduced its interaction with its well-characterized cofactor, nuclear protein localization-4 (Npl4). Together, our results demonstrate that a single amino acid substitution in the N-terminal domain can relay long-range conformational changes to the distal D2 ATPase ring. Our results provide the first structural clues of how VCP mutations may influence the activity and function of the D2 ATPase ring.


Assuntos
Adenosina Trifosfatases/genética , Adenosina Trifosfatases/ultraestrutura , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/ultraestrutura , Microscopia Crioeletrônica/métodos , Adenosina Trifosfatases/química , Substituição de Aminoácidos , Proteínas de Ciclo Celular/química , Variação Genética/genética , Mutação/genética , Conformação Proteica , Estrutura Terciária de Proteína , Proteína com Valosina
13.
J Transl Med ; 13: 353, 2015 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-26552480

RESUMO

BACKGROUND: Endothelial progenitor cells (EPCs) have been implicated in neoangiogenesis, endothelial repair and cell-based therapies for cardiovascular diseases. We have previously shown that the recruitment of EPCs to sites of vascular lesions is facilitated by platelets where EPCs, in turn, modulate platelet function and thrombosis. However, EPCs encompass a heterogeneous population of progenitor cells that may exert different effects on platelet function. Recent evidence suggests the existence of two EPC subtypes: early outgrowth cells (EOCs) and endothelial colony-forming cells (ECFCs). We aimed at characterizing these two EPC subtypes and at identifying their role in platelet aggregation. METHODS: EOCs and ECFCs were generated from human peripheral blood mononuclear cells (PBMCs) seeded in conditioned media on fibronectin and collagen, respectively. The morphological, phenotypical and functional characteristics of EOCs and ECFCs were assessed by optical and confocal laser scanning microscopes, cell surface markers expression, and Matrigel tube formation. The impact of EOCs and ECFCs on platelet aggregation was monitored in collagen-induced optical aggregometry and compared with PBMCs and human umbilical vein endothelial cells (HUVECs). The levels of the anti-platelet agents' nitric oxide (NO) and prostacyclin (PGI2) released from cultured cells as well as the expression of their respective producing enzymes NO synthases (NOS) and cyclooxygenases (COX) were also assessed. RESULTS: We showed that EOCs display a monocytic-like phenotype whereas ECFCs have an endothelial-like phenotype. We demonstrated that both EOCs and ECFCs and their supernatants inhibited platelet aggregation; however ECFCs were more efficient than EOCs. This could be related to the release of significantly higher amounts of NO and PGI2 from ECFCs, in comparison to EOCs. Indeed, ECFCs, like HUVECs, constitutively express the endothelial (eNOS)-and inducible (iNOS)-NOS isoforms, and COX-1 and weakly express COX-2, whereas EOCs do not constitutively express these NO and PGI2 producing enzymes. CONCLUSION: The different morphological, phenotypic and more importantly the release of the anti-aggregating agents PGI2 and NO in each EPC subtype are implicated in their respective roles in platelet function and thus, may be linked to the increased efficiency of ECFCs in inhibiting platelet aggregation as compared to EOCs.


Assuntos
Plaquetas/citologia , Células Endoteliais/citologia , Agregação Plaquetária , Células-Tronco/citologia , Adulto , Doenças Cardiovasculares/metabolismo , Células Cultivadas , Colágeno/química , Meios de Cultivo Condicionados/química , Epoprostenol/metabolismo , Fibronectinas/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucócitos Mononucleares/citologia , Microscopia Confocal , Pessoa de Meia-Idade , Óxido Nítrico/química , Óxido Nítrico Sintase/metabolismo , Fenótipo , Prostaglandina-Endoperóxido Sintases/metabolismo , Adulto Jovem
14.
BMC Gastroenterol ; 14: 206, 2014 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-25492126

RESUMO

BACKGROUND: The pathogenesis of inflammatory bowel disease (IBD) involves interactions between the host genetic susceptibility, intestinal microflora and mucosal immune responses through the pattern recognition receptor. Polymorphisms in toll-like receptor 4 (TLR4) induce an aberrant immune response to indigenous intestinal flora, which might favor IBD development. In this study, we aimed to determine whether TLR4 gene was associated with Crohn's disease (CD) and ulcerative colitis (UC) among Moroccan patients, and evaluated its correlation with clinical manifestation of the disease. METHODS: The study population comprised 117 patients with IBD and 112 healthy unrelated blood donors. TLR4 polymorphisms: Asp299Gly and Thr399Ile were genotyped by polymerase chain reaction-restriction fragment length polymorphism. PCR products were cleaved with Nco I for the Asp299Gly polymorphism and Hinf I for the Thr399Ile polymorphism. Meta-analysis was performed to test the association of 299Gly and 399Ileu carriage with CD, UC and the overall IBD risk. RESULTS: Our study revealed that the frequency of Asp299Gly and Thr399Ile did not differ significantly between patients and controls in the Moroccan population. However, meta-analysis demonstrated significantly higher frequencies of both Asp299Gly and Thr399Ile SNPs in IBD and CD and for 399Ileu carriage in UC patients. CONCLUSION: The meta-analysis provides evidence that TLR4 polymorphisms confer a significant increased risk for the overall IBD development.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Polimorfismo Genético , Receptor 4 Toll-Like/genética , Adulto , Humanos , Doenças Inflamatórias Intestinais/genética , Marrocos , Polimorfismo de Fragmento de Restrição
15.
J Mol Neurosci ; 53(2): 189-95, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24627227

RESUMO

In Morocco, Alzheimer's disease (AD) affects almost 30,000 individuals, and this number could increase to 75,000 by 2020. To our knowledge, the genes predisposing individuals to AD and predicting disease incidence remain elusive. In this study, we aimed to evaluate the genetic contribution of mutations in the amyloid precursor protein (APP) gene exons 16 and 17 to familial and sporadic AD cases. Seventeen sporadic cases and eight family cases were seen at the memory clinic of the University of Casablanca Neurology Department. These patients underwent standard somatic neurological examination, cognitive function assessment, brain imaging, and laboratory tests. Direct sequencing of exons 16 and 17 of the APP gene was performed on genomic DNA of AD patients. In this original Moroccan study, we identified seven novel frameshift mutations in exons 16 and 17 of the APP gene. Interestingly, only one novel splice mutation was detected in a family case. There is a strong correlation between clinical symptoms and genetic factors in Moroccan patients with a family history of AD. Therefore, mutations in APP gene exons 16 and 17 may eventually become genetic markers for AD predisposition.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Mutação da Fase de Leitura , Idoso , Doença de Alzheimer/diagnóstico , Estudos de Casos e Controles , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Marrocos , Linhagem
16.
PLoS One ; 8(12): e84289, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24358353

RESUMO

The role of endothelial progenitor cells in vascular repair is related to their incorporation at sites of vascular lesions, differentiation into endothelial cells, and release of various angiogenic factors specifically by a subset of early outgrowth endothelial progenitor cells (EOCs). It has been shown that patients suffering from cardiovascular disease exhibit increased levels of circulating and soluble CD40 ligand (sCD40L), which may influence the function of EOCs. We have previously shown that the inflammatory receptor CD40 is expressed on EOCs and its ligation with sCD40L impairs the anti-platelet function of EOCs. In the present study, we aimed at investigating the effect of sCD40L on the function of EOCs in endothelial repair. Human peripheral blood mononuclear cell-derived EOCs express CD40 and its adaptor proteins, the tumor necrosis factor receptor-associated factors; TRAF1, TRAF2 and TRAF3. Stimulation of EOCs with sCD40L increased the expression of TRAF1, binding of TRAF2 to CD40 and phosphorylation of p38 mitogen activated protein kinase (MAPK). In an in vitro wound healing assay, stimulation of EOCs with sCD40L increased the release of matrix metalloproteinase 9 (MMP-9) in a concentration-dependent manner and significantly enhanced the angiogenic potential of cultured human umbilical vein endothelial cells (HUVECs). Inhibition of p38 MAPK reversed sCD40L-induced MMP-9 release by EOCs, whereas inhibition of MMP-9 reversed their pro-angiogenic effect on HUVECs. This study reveals the existence of a CD40L/CD40/TRAF axis in EOCs and shows that sCD40L increases the pro-angiogenic function of EOCs on cultured HUVECs by inducing a significant increase in MMP-9 release via, at least, the p38 MAPK signaling pathway.


Assuntos
Ligante de CD40/metabolismo , Células Endoteliais/metabolismo , Metaloproteinase 9 da Matriz/biossíntese , Células-Tronco/metabolismo , Antígenos CD40/metabolismo , Ligante de CD40/sangue , Células Cultivadas , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucócitos Mononucleares/metabolismo , Fosforilação , Ligação Proteica , Transdução de Sinais , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Cicatrização , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Biochem Biophys Res Commun ; 425(1): 58-63, 2012 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-22820189

RESUMO

CD40 ligand (CD40L) is a thrombo-inflammatory molecule that predicts cardiovascular events. Platelets constitute the major source of soluble CD40L (sCD40L), which has been shown to potentiate platelet activation and aggregation, in a CD40-dependent manner, via p38 mitogen activated protein kinase (MAPK) and Rac1 signaling. In many cells, the CD40L/CD40 dyad also induces activation of nuclear factor kappa B (NF-κB). Given that platelets contain NF-κB, we hypothesized that it may be involved in platelet CD40 signaling and function. In human platelets, sCD40L induces association of CD40 with its adaptor protein the tumor necrosis factor receptor associated factor 2 and triggers phosphorylation of IκBα, which are abolished by CD40L blockade. Inhibition of IκBα phosphorylation reverses sCD40L-induced IκBα phosphorylation without affecting p38 MAPK phosphorylation. On the other hand, inhibition of p38 MAPK phosphorylation has no effect on IκBα phosphorylation, indicating a divergence in the signaling pathway originating from CD40 upon its ligation. In functional studies, inhibition of IκBα phosphorylation reverses sCD40L-induced platelet activation and potentiation of platelet aggregation in response to a sub-threshold concentration of collagen. This study demonstrates that the sCD40L/CD40 axis triggers NF-κB activation in platelets. This signaling pathway plays a critical role in platelet activation and aggregation upon sCD40L stimulation and may represent an important target against thrombo-inflammatory disorders.


Assuntos
Plaquetas/metabolismo , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , NF-kappa B/metabolismo , Plaquetas/fisiologia , Células Cultivadas , Humanos , Proteínas I-kappa B/metabolismo , Inibidor de NF-kappaB alfa , Fosforilação , Ativação Plaquetária , Agregação Plaquetária , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/metabolismo
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