Browsing by Author "Silva, B."
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- Alterações fenotípicas e genéticas do metabolismo do ferro numa população portuguesa com doença de Alzheimer: potenciais implicações no conhecimento da fisiopatologia e no diagnóstico desta demênciaPublication . Crespo, A.C.; Silva, B.; Marques, L.; Marcelino, E.; Maruta, C.; Costa, S.; Timóteo, A.; Vilares, A.; Couto, F.S.; Faustino, Paula; Correia, A.P.; Verdelho, A.; Porto, G.; Guerreiro, M.; Herrero, A.; Costa, C.; Mendonça, A.; Martins, M.; Costa, L.
- Differential Regulation of Ceruloplasmin Isoforms Expression in Macrophages and HepatocytesPublication . Marques, L.; Auriac, A.; Willemetz, A.; Banha, J.; Silva, B.; Canonne-Hergaux, F.; Costa, L.Ceruloplasmin (Cp) is an acute-phase protein that has been implicated in iron metabolism due to its ferroxidase activity, assisting ferroportin (Fpn) on cellular iron efflux. However, Cp exhibits both anti- and pro-oxidant activities and its physiological functions remain unclear. Cp can be expressed as a secreted or as a membrane glycosylphosphatidylinositol-anchored protein (GPI-Cp), this latter one being mostly expressed in the brain. Herein, we studied the expression of both Cp isoforms in human peripheral blood lymphocytes, monocytes, mouse macrophages and human hepatocarcinoma cell line HepG2, using immunofluorescence and immunoblotting techniques. Co-localization of Cp and Fpn was also investigated by immunofluorescence in mouse macrophages. Cp was detected by immunoblotting and immunofluorescence in membrane and cytosol of all cells types studied. The Cp detected at cell surface was identified as the GPI-isoform by PI-PLC test and shown to localize in lipid rafts in monocytes, macrophages and HepG2 cells. In macrophages, increased expression levels and co-localization of Fpn and GPI-Cp at cell surface lipid rafts were observed after iron treatment. Such upregulation of Cp by iron was not observed in HepG2 cells. Our results revealed an unexpected ubiquitous expression of the GPI-Cp isoform in immune and hepatic cells. A differential regulation of Cp in these cells may reflect distinct physiological functions of this oxidase according to cell-type specificity. In macrophages, GPI-Cp and Fpn likely interact in lipid rafts to export iron. A better insight into the expression of both Cp isoforms in different cell types will help to clarify its role in many diseases related to iron metabolism, inflammation and oxidative biology.
- Genetic and biochemical markers in patients with Alzheimer's disease support a concerted systemic iron homeostasis dysregulationPublication . Crespo, A.C.; Silva, B.; Marques, L.; Marcelino, E.; Maruta, C.; Costa, S.; Timóteo, A.; Vilares, A.; Couto, F.S.; Faustino, Paula; Correia, A.P.; Verdelho, A.; Porto, G.; Guerreiro, M.; Herrero, A.; Costa, C.; de Mendonça, A.; Costa, L.; Martins, M.Alzheimer's disease (AD) is the most common form of dementia in the elderly individuals, resulting from a complex interaction between environmental and genetic factors. Impaired brain iron homeostasis has been recognized as an important mechanism underlying the pathogenesis of this disease. Nevertheless, the knowledge gathered so far at the systemic level is clearly insufficient. Herein, we used an integrative approach to study iron metabolism in the periphery, at both genotypic and phenotypic levels, in a sample of 116 patients with AD and 89 healthy control subjects. To assess the potential impact of iron metabolism on the risk of developing AD, genetic analyses were performed along with the evaluation of the iron status profile in peripheral blood by biochemical and gene expression studies. The results obtained showed a significant decrease of serum iron, ferritin, and transferrin concentrations in patients compared with the control subjects. Also, a significant decrease of ferroportin (SLC40A1) and both transferrin receptors TFRC and TFR2 transcripts was found in peripheral blood mononuclear cells from patients. At the genetic level, significant associations with AD were found for single nucleotide polymorphisms in TF, TFR2, ACO1, and SLC40A1 genes. Apolipoprotein E gene, a well-known risk factor for AD, was also found significantly associated with the disease in this study. Taken together, we hypothesize that the alterations on systemic iron status observed in patients could reflect an iron homeostasis dysregulation, particularly in cellular iron efflux. The intracellular iron accumulation would lead to a rise in oxidative damage, contributing to AD pathophysiology.
- Immune cells and hepatocytes express glycosylphosphatidylinositol-anchored ceruloplasmin at their cell surfacePublication . Marques, L.; Auriac, A.; Willemetz, A.; Banha, J.; Silva, B.; Canonne-Hergaux, F.; Costa, L.Ceruloplasmin is a positive acute-phase protein with both anti- and pro-oxidant activities, thus having still unclear physiological functions in inflammatory processes. Importantly, ceruloplasmin has been implicated in iron metabolism due to its ferroxidase activity, assisting ferroportin on cellular iron efflux. Ceruloplasmin can be expressed as a secreted or as a membrane glycosylphosphatidylinositol-anchored protein (GPI-ceruloplasmin), this latter one being reported as expressed mostly in the brain.
- Immune cells and hepatocytes express glycosylphosphatidylinositol-anchored ceruloplasmin at their cell surfacePublication . Marques, L.; Auriac, A.; Willemetz, A.; Banha, J.; Silva, B.; Canonne-Hergaux, F.; Costa, L.Ceruloplasmin is a positive acute-phase protein with both anti- and pro-oxidant activities, thus having still unclear physiological functions in inflammatory processes. Importantly, ceruloplasmin has been implicated in iron metabolism due to its ferroxidase activity, assisting ferroportin on cellular iron efflux. Ceruloplasmin can be expressed as a secreted or as a membrane glycosylphosphatidylinositol-anchored protein (GPI-ceruloplasmin), this latter one being reported as expressed mostly in the brain.
- Influence of interleukin-6 gene polymorphisms in epicardial adipose tissue and coronary artery calcification in patients with psoriasisPublication . Torres, T.; Bettencourt, N.; Ferreira, J.; Carvalho, C.; Mendonça, D.; Pinho-Costa, P.; Vasconcelos, C.; Selores, M.; Silva, B.Psoriasis is currently considered a systemic inflammatory disorder associated with several comorbidities and increased risk of cardiovascular disease (CVD)1 cytokines are overexpressed cutaneous and systemically and may be responsible for skin lesions but also for psoriasis-associated conditions surrounding the heart, is now regarded as an important factor in the pathogenesis of coronary atherosclerosis and CVD, through inflammatory burden proximal to the coronary arteries, and has been shown to be increased in psoriasis patients independently of abdominal visceral fat (AVF) and to be associated with sub-clinical atherosclerosis IL-6 has been implicated in the pathogenesis of psoriasis1 but also of abdominal obesity atherosclerosis and CVD4 30% of total circulating concentrations in healthy subjects thought to be influenced by polymorphisms in their gene loci, and this may contribute to the development of psoriasis, but also excess adiposity and psoriasis has been investigated that could predict which patients are at risk of developing psoriasis-linked cardiovascular comorbidities may permit an earlier management, with important clinical implications. This study aimed to evaluate the potential contribution of four IL-6 genetic variants (rs1800795[-174G>C], rs1800796[-572G>C], rs2069827[-1426G>T], rs2069840[-1753C>G]) in psoriasis susceptibility and its influence in EAT and coronary artery calcification (CAC) in severe psoriasis patients.
- Influence of TNF-α gene polymorphisms in coronary artery calcification in psoriasis patientsPublication . Torres, T.; Bettencourt, N.; Ferreira, J.; Carvalho, C.; Mendonca, D.; Pinho-Costa, P.; Vasconcelos, C.; Selores, M.; Silva, B.Psoriasis is a systemic inflammatory disorder associated with numerous medical comorbidities and increased risk of cardiovascular disease (CVD. Psoriasis’ systemic inflammation may play an important role in the accelerated atherosclerosis observed in these patients2 as inflammatory processes play a key role in atherogenesis. Psoriasis and atherosclerosis share some pathological features including endothelial dysfunction, alteration in angiogenesis and some inflammatory pathways. TNF-a is a potent pro-inflammatory cytokine that has been implicated in psoriasis and atherosclerosis pathogenesis and its synthesis is tightly regulated at gene transcription level. TNF-a gene promoter region contains several single-nucleotide polymorphisms (SNP) that influence TNF-a production. Several TNF-a gene polymorphisms have been associated with psoriasis and CVD. A recent meta-analysis suggested that TNF-a rs1800629(308G/A) polymorphism was associated with decreased risk of psoriasis, whereas TNF-a rs361525(238G/A) was associated with increased risk. Regarding TNF-a rs1799964 (1031T/C) polymorphism, existing data are limited and contradictory.8 Since psoriasis morbidity and mortality are strongly linked to accelerated atherosclerosis, determining the genetic contribution for cardiovascular morbidity in psoriasis patients becomes an issue of major importance. The aim of this study was to evaluate the contribution of TNF-a rs361525(238G/A), TNF-a rs1800629(308G/A) and TNFa rs1799964(1031T/C) gene polymorphisms to coronary artery calcification (CAC) in severe psoriasis patients.
- Preliminar study on BDNF regulation by DNA methylation in Mesial Temporal Lobe EpilepsyPublication . Ferreira, R.; Leal, B.; Chaves, J.M.M.; Carvalho, C.; Bettencourt, A.; Freitas, J.; Ramalheira, J.E.D.P.; Lopes, J.M.C.F.; Martins da Silva, A.; Costa, P.P.; Silva, B.Background and aims: Brain-derived neurotrophic factor (BDNF) is a neurothrophin associated with a wide range of neurophysiological processes, such as neurogenesis, gliogenesis, synaptogenesis and neuroprotection. BDNF has been described as overexpressed in hippocampus of both animal models and Mesial Temporal Lobe Epilepsy (MTLE) patients. Gene expression may be modulated by DNA methylation of the respective promoter regions. We sought to analyze, the DNA methylation of the BDNF exon I promoter, a region associated with neuronal imbalance
- The hepcidin gene promoter nc.-1010C > T; -582A > G haplotype modulates serum ferritin in individuals carrying the common H63D mutation in HFE genePublication . Silva, B.; Pita, L.; Gomes, S.; Gonçalves, J.; Faustino, P.Hereditary hemochromatosis is an autosomal recessive disorder characterized by severe iron overload. It is usually associated with homozygosity for the HFE gene mutation c.845G > A; p.C282Y. However, in some cases, another HFE mutation (c.187C > G; p.H63D) seems to be associated with the disease. Its penetrance is very low, suggesting the possibility of other iron genetic modulators being involved. In this work, we have screened for HAMP promoter polymorphisms in 409 individuals presenting normal or increased serum ferritin levels together with normal or H63D-mutated HFE genotypes. Our results show that the hepcidin gene promoter TG haplotype, originated by linkage of the nc.-1010C > T and nc.-582A > G polymorphisms, is more frequent in the HFE_H63D individuals presenting serum ferritin levels higher than 300 μg/L than in those presenting the HFE_H63D mutation but with normal serum ferritin levels or in the normal control group.Moreover, it was observed that the TG haplotype was associated to increased serum ferritin levels in the overall pool of HFE_H63D individuals. Thus, our data suggest that screening for these polymorphisms could be of interest in order to explain the phenotype. However, this genetic condition seems to have no clinical significance.
- The role of KIR2DS1 in multiple sclerosis - KIR in Portuguese MS patientsPublication . Bettencourt, A.; Martins Silva, A.; Carvalho, C.; Leal, B.; Santos, E.; Pinho-Costa, P.; Silva, B.Killer Immunoglobulin-like Receptor (KIR) genes may influence both resistance and susceptibility to different autoimmune diseases, but their role in the pathogenesis of Multiple Sclerosis (MS) is still unclear. We investigated the influence of KIR genes on MS susceptibility in 447 MS Portuguese patients, and also whether genetic interactions between specific KIR genes and their HLA class I ligands could contribute to the pathogenesis of MS. Weobserved a negative association between the activating KIR2DS1 gene and MS (adjusted OR = 0.450, p = 0.030)independently from the presence of HLA-DRB1*15 allele. The activating KIR2DS1 receptor seems to confer protection against MS most probably through modulation of autoreactive T cells by Natural Killer cells.