Browsing by Author "Costa, Cristina"
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- Biochemical and molecular heterogeneity in carnitine palmitoyltransferase ii deficiencyPublication . Sousa, Carmen; Fonseca, Helena; Rocha, Hugo; Marcão, Ana; Vilarinho, Laura; Diogo, Luísa; Sequeira, Sílvia; Costa, Cristina; Leão, Elisa; Conceição, Isabel; Gaspar, AnaIntroduction: Carnitine palmitoytransferase II (CPTII) deficiency is a recessively inherited disorder of lipid metabolism. CPT II deficiency has several clinical presentations: the adult form is characterized by episodes of rhabdomyolysis, usually triggered by extensive exercice, cold, fever or prolonged fasting and the infantile-type CPT II hepatocardiomuscular form presents as severe attacks of hypoketotic, hypoglycemia, occasionally associated with cardiac damage. Molecular analysis of CPT II gene allows not only confirmation of classical forms, with typical biochemical abnormalities, but is also key for the diagnosis of less severe forms.The authors will present biochemical and molecular findings of eight CPT II, patients. Material and methods: Acylcarnitine profiles, on dried blood spots, were done as previously reported (Vilarinho et al) Molecular analysis of CPT II gene was done by direct sequencing as reported elsewhere (Finocchiaro et al.). From the eight patients, three were detected through newborn screening and five with clinical symptoms. Results: More pronounced abnormalities in the acylcarnitine profiles are associated with neonatal forms of the disease, while the patients with late onset forms present smother alterations or completely normal profiles. This biochemical heterogeneity correlates well with genetics data. The molecular analysis revealed the presence of ten different mutations, which seven were never reported. Discussion: Our results support that newborn screening can efficiently detect infantile CPT II deficiency but is less effective in detecting adult forms, were biochemical abnormalities may only be present during acute episodes. In these cases accurate clinical characterization alongside with molecular analysis are the key for diagnosis. Bibliography: J.P. Bonnefont, F. et al (2004) Mol. Aspects Med. 25 495–520. Rashed MS, et al.(1995) Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids profiling using automated electrospray tandem mass spectrometry. Pediatr Res.38:324–331 Finocchiaro, G. et al (1991). cDNA cloning, sequence analysis, and chomosomal localization of the gene for human carnitinepalmitoyltransferase. Proc. Natl. Acad. Sci. USA 88, 661–665. K. Gempel1 et al. (2002).Screening for Carnitine Palmitoyltransferase II Deficiency by Tandem Mass Spectrometry Anichini A.et al(2011) Genotype-phenotype correlations in a large series of patients with muscle type CPT II deficiency Vilarinho et al. (2009) Four Years of Expanded Newborn Screening in Portugal with MS/MS
- Crosstalk between genetics, gene expression and biochemical markers supports systemic iron homeostasis dysregulation in alzheimer diseasePublication . Crespo, Ângela C.; Silva, Bruno; Ferreira, Catarina; Marques, Liliana; Marcelino, Erica; Maruta, Carolina; Costa, Sónia; Timóteo, Ângela; Vilares, Arminda; Simões, Frederico; Faustino, Paula; Correia, Ana Paula; Verdelho, Ana; Porto, Graça; Guerreiro, Manuela; Herrero, Ana; Costa, Cristina; de Mendonça, Alexandre; Costa, Luciana; Martins, Madalena
- Cyanobacterial blooms in natural waters in southern Portugal: a water management perspectivePublication . Galvão, Helena M.; Reis, Margarida P.; Valério, Elisabete; Domingues, Rita B.; Costa, Cristina; Lourenço, Dulce; Condinho, Sílvia; Miguel, Rute; Barbosa, Ana; Gago, Conceição; Faria, Natália; Paulino, Sérgio; Pereira, PauloThis synthesis of 3 studies from 2 regions of southern Portugal (Alentejo and Algarve) was part of a workshop focusing on cyanobacteria held at the SAME 10. The first study monitored impacts of the large Alqueva dam on the Guadiana estuary since 1996, revealing changes in sediment load, nutrient regime and phytoplankton succession. Prior to dam construction, dense cyanobacterial blooms occurred in the upper estuary during summer and fall. After dam construction, chlorophyll concentration, phytoplankton diversity and abundances of cyanobacteria decreased, contrary to predictions. Mycrocystins remained at low levels in the seston and undetectable in water samples, except during summer 2003 when the particulate fraction contained 1 µg l–1, while chlorophyll concentrations and abundances of potentially toxic cyanobacteria remained low. Algarve reservoirs studied since 2001 revealed differences in phytoplankton dynamics. In the western mesotrophic reservoirs (Bravura and Funcho), 40 to 50% of surface samples contained cyanobacterial concentrations of ≥2000 cells ml–1, while over 80% of samples from the eastern oligotrophic reservoirs (Odeleite and Beliche) exceeded this value. Spring blooms were dominated by Oscillatoriales in Odeleite and Beliche and by Chroococcales in Bravura and Funcho. Bloom composition seemed to depend on water temperature and management strategies, while toxin concentrations reflected the increased biomass of toxic species. Finally, phytoplankton communities and microcystin production in 5 Alentejo freshwater reservoirs were studied from May to December 2005 and April to July 2006. Cyanobacterial blooms occurred, with varying intensities, not only during summer but also occasionally in winter. Microcystins were detected in 23% of the samples (n = 51), but without correlation with cyanobacterial biomass. Although Microcystis aeruginosa seemed to be the major producer of microcystins, other potentially toxic species were found. In summary, the varying pattern of cyanobacterial bloom occurrence and toxicity requires a systematic approach to monitoring programs for adequate risk assessment.
- Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patientsPublication . Guerreiro, Cláudia; Silva, Bruno; Crespo, Ângela; Marques, Liliana; Costa, Sónia; Timóteo, Ângela; Marcelino, Erica; Maruta, Carolina; Vilares, Arminda; Matos, Mafalda; Couto, Frederico S.; Faustino, Paula; Verdelho, Ana; Guerreiro, Manuela; Herrero, Ana; Costa, Cristina; de Mendonça, Alexandre; Martins, Madalena; Costa, LucianaAlzheimer's disease (AD) is a neurodegenerative disorder of still unknown etiology and the leading cause of dementia worldwide. Besides its main neuropathological hallmarks, a dysfunctional homeostasis of transition metals has been reported to play a pivotal role in the pathogenesis of this disease. Dysregulation of iron (Fe) metabolism in AD has been suggested, particularly at the level of cellular iron efflux. Herein, we intended to further clarify the molecular mechanisms underlying Fe homeostasis in AD. In order to achieve this goal, the expression of specific Fe metabolism-related genes directly involved in Fe regulation and export was assessed in peripheral blood mononuclear cells (PBMCs) from 73AD patients and 74 controls by quantitative PCR. The results obtained showed a significant decrease in the expression of aconitase 1 (ACO1; P=0.007); ceruloplasmin (CP; P<0.001) and amyloid-beta precursor protein (APP; P=0.006) genes in AD patients compared with healthy volunteers. These observations point out to a significant downregulation in the expression of genes associated with ferroportin-mediated cellular Fe export in PBMCs from AD patients, when compared to controls. Taken together, these findings support previous studies suggesting impairment of Fe homeostasis in AD, which may lead to cellular Fe retention and oxidative stress, a typical feature of this disease
- Decrease of β-amyloid peptide precursor and ceruloplasmin mRNA levels in patients with Alzheimer’s disease support impairment of cellular iron efflux in this pathologyPublication . Silva, Bruno; Guerreiro, Cláudia; C. Crespo, Ângela; Marques, Liliana; Marcelino, Erica; Maruta, Carolina; Costa, Sónia; Timóteo, Ângela; Vilares, Arminda; Simões Couto, Frederico; Faustino, Paula; Verdelho, Ana; Guerreiro, Manuela; Herrero, Ana; Costa, Cristina; de Mendonça, Alexandre; Martins, Madalena; Costa, LucianaIntroduction: Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia worldwide. Because of the clinical interest in its early diagnosis and prediction of patient evolution and prognosis, the identification of AD biomarkers is of crucial importance. Several lines of evidence implicate an imbalance of the redox-active biometals in AD. Metal-catalyzed hydroxyl radicals are potent mediators of cellular injury and are central to the oxidative injury hypothesis of AD pathogenesis [1,2]. Importantly, previous genetic and biochemical studies in AD patients support a concerted systemic iron metabolism dysregulation, namely at the level of cellular iron efflux [3]. Herein, we intended to further understand the molecular mechanisms underlying iron homeostasis in this pathology. In order to achieve this goal, the expression of specific iron metabolism-related genes directly involved in iron metabolism regulation and cellular iron export was measured in peripheral blood mononuclear cells from AD patients and healthy controls. Also, serum ceruloplasmin (CP) concentration and its oxidase activity were measured in all participants in the study, given the known role of this oxidase in facilitating iron exit from cells. Through this study we expect to further clarify the contribution of iron metabolism disruption to the etiopathogenesis of AD.
- Diminuição da expressão dos genes APP e CP em doentes de Alzheimer sugere alteração da exportação de ferro celular nesta demênciaPublication . Cláudia, Guerreiro; Bruno, Silva; Crespo, Ângela C.; Marques, Liliana; Costa, Sónia; Timóteo, Ângela; Marcelino, Erica; Maruta, Carolina; Vilares, Arminda; Matos, Mafalda; Couto, Frederico Simões; Faustino, Paula; Verdelho, Ana; Guerreiro, Manuela; Herrero, Ana; Costa, Cristina; Mendonça, Alexandre de; Martins, Madalena; Costa, LucianaRecentemente tem-se assistido a um acumular de evidência sugerindo a implicação de uma desregulação do metabolismo do ferro (Fe) na fisiopatologia da doença de Alzheimer (DA). Neste trabalho, pretendemos esclarecer melhor os mecanismos moleculares subjacentes à homeostasia deste metal na DA, particularmente ao nível do efluxo celular. Assim, mediu-se em células mononucleares do sangue periférico de 73 doentes com DA e 74 controlos a expressão de genes diretamente envolvidos na regulação e exportação celular de Fe, utilizando a técnica de PCR quantitativo. Os resultados mostraram uma diminuição significativa na expressão dos genes aconitase (ACO1; P=0,007); ceruloplasmina (CP; P<0,001) e proteína precursora de beta amilóide (APP; P=0,006) em doentes com DA comparativamente com os voluntários saudáveis. Estas observações apontam para uma diminuição significativa da expressão dos genes associados com a exportação de Fe celular mediada pela ferroportina na DA. Assim, o presente estudo reforça resultados anteriores que mostram alterações no metabolismo do Fe e podem estar na origem da retenção intracelular deste metal e aumento de stress oxidativo caraterísticos desta patologia.
- Iron Related Gene Expression and Biochemical Phenotype Support Iron Homeostasis Dysregulation in Alzheimer’s DiseasePublication . Crespo, Ângela; Silva, Bruno; Marques, Liliana; Marcelino, Erica; Maruta, Carolina; Costa, Sónia; Timóteo, Ângela; Vilares, Arminda; Couto, Frederico; Faustino, Paula; Correia, Ana; Verdelho, Ana; Porto, Graça; Guerreiro, Manuela; Herrero, Ana; Costa, Cristina; Mendonça, Alexandre; Martins, Madalena; Luciana, Costa
- Iron/copper metabolism in Alzheimer’s disease: genetics and biomarkers in a Portuguese populationPublication . C. Crespo, Ângela; Marques, Liliana; Marcelino, Erica; Maruta, Carolina; Costa, Sónia; Timóteo, Ângela; Vilares, Arminda; Silva, Bruno; Simões Couto, Frederico; Faustino, Paula; Correia, Ana Paula; Verdelho, Ana; Porto, Graça; Guerreiro, Manuela; Herrero, Ana; Costa, Cristina; de Mendonça, Alexandre; Costa, Luciana; Martins, MadalenaThe distinction between normal aging and Alzheimer's disease (AD) is a relevant step to combat this disease efficiently. Thus, the identification of biomarkers and genetic factors underlying AD pathology is extremely important. Oxidative injury in the brain, mediated by the imbalance of redox-active metals as iron (Fe) and copper (Cu) has been recognized to contribute to the pathology of AD. In this context, we further investigated this hypothesis by: (I) comparing serum biochemical markers of Fe/Cu metabolism in a sample of 117 AD patients and 91 healthy controls; (II) testing in the same sample a set of Fe/Cu metabolism-related genes and APOE for association with AD. Genetic analysis was performed through high density SNP genotyping of the candidate genes CP, CYBRD1, HAMP, HFE, IREB1, IREB2, SLC11A2, SLC40A1, TF, TFR2, FB19, CALR, and APOE. Biochemical analysis was assessed for: serum Fe, transferrin, transferrin saturation and serum ferritin levels. The most significant difference was found between AD patients and controls for serum Fe concentration (76.63 ± 26.36 μg/dL and 86.67 ± 25.18 μg/dL, respectively, P=0.003), although other significant differences were also found for transferrin and ferritin levels (P=0.016 and P=0.033, respectively). Significant associations with AD were found for two SNPs in TF (P=0.0147 and P=0.0415), one SNP in TFR2 (P=0.0055) and for the first time in IREB1 (P=0.0258) and SLC40A1 (P=0.0210) genes. In addition to the significant independent effects, evidence for interaction between IREB1 and TFR2, CP, IREB2 and SLC40A1 markers was also found. The overall results suggest the involvement of these iron metabolism genes in Alzheimer etiology. APOE was also significantly associated with AD (P=0.0007), in agreement with previous studies. We hypothesize that the lower serum Fe concentration observed in AD patients can be due to impaired Fe excretion from cells, since Fpn codified by SLC40A1 is the only known Fe exporter in mammalian cells. Also, the TFR2 polymorphism found to be associated with AD is located at the putative promoter region of the TfR2_beta isoform which seems to be involved in SLC40A1 transcriptional regulation. On the other hand, IREB1 codifies a cytosolic protein which binds to iron-responsive elements (IREs) found in RNA from several iron metabolism-related proteins as ferritin, TfR, Fpn itself and importantly GEECD, Tomar, Portugal, Jun2012 APP. The intracellular accumulation of Fe, particularly in the brain where Fpn is also expressed, would lead to a rise in oxidative damage, contributing to the AD physiopathology. Further research is demanded in a greater sample to confirm the results obtained in this pilot study. Noteworthy, an integrative approach was followed to deal with heterogeneity in this complex disorder, and new directions were raised related to the study of Fe metabolism involvement in AD.