Browsing by Author "Peixoto, Vanda"
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- Avaliação do stress oxidativo na disfunção erétilPublication . Peixoto, Vanda; Fernandes, Rúben; Carvalho, José; Vieira, MónicaAs sequelas fisiopatológicas do stress oxidativo são difíceis de quantificar. Apesar dos obstáculos, a relevância médica do stress oxidativo tem vindo a ser cada vez mais reconhecida, sendo hoje em dia encarado como um componente chave de virtualmente todas as doenças. A disfunção erétil (DE) surge neste contexto como uma espécie de barómetro da função endotelial e do dano oxidativo. A quantificação de biomarcadores de stress oxidativo poderá apresentar um enorme impacto na avaliação de pacientes com DE. O rácio glutationa reduzida/oxidada (GSH/GSSG) e a nitrotirosina (3-NT) têm vindo a demonstrar relevância clínica. A consideração de polimorfismos genéticos constitui ainda uma abordagem promissora na avaliação destas relações no futuro. Um método altamente sensível de cromatografia líquida de alta performance (HPLC) foi desenvolvido para a determinação de 3-NT em plasma humano. As concentrações de 3-NT medidos em indivíduos com DE foram 6,6±2,1μM (média±S.D., n = 46). A medição da concentração plasmática de 3-NT poderá revelar-se útil como marcador de dano oxidativo dependente do óxido nítrico (NO). O nível de stress oxidativo pode também ser quantificado através da medição do decréscimo do rácio GSH/GSSG, que tem mostrado alterações numa miríade de patologias, como a DE e a diabetes mellitus. O método proposto para a quantificação do rácio GSH/GSSG em HPLC apresenta a vantagem de avaliação concomitante dos dois parâmetros em apenas uma corrida. O valor do rácio GSH/GSSG obtido a partir de sangue de indivíduos com DE foi 11,9±9,8 (média±S.D., n = 49). Os resultados estatísticos revelaram diferenças significativas (p<0,001) entre ambos a concentração plasmática de 3-NT e o rácio GSH/GSSG de sangue de indivíduos com DE e as respetivas medições em indivíduos saudáveis. Observaram-se ainda diferenças estatisticamente significativas (p≈0,027) entre o rácio GSH/GSSG do sangue de pacientes apenas com diagnóstico de DE e a medição respetiva em indivíduos com DE e comorbilidades cardiovasculares. Estes resultados enfatizam o papel do dano oxidativo na biopatologia da DE, elucidado com o auxílio destas duas metodologias, que poderão ter um amplo campo de aplicação no futuro, dado que se mostraram simples, não dispendiosas e rápidas, podendo eventualmente adequar-se a estudos de rastreio em larga escala.
- Evaluation of the impact of two C5 genetic variants on C5-eculizumab complex stability at the molecular levelPublication . Peixoto, Vanda; Prudêncio, Cristina; Vieira, Mónica; Sousa, Sérgio F.Complement C5 is the target of the monoclonal antibody eculizumab, used in complement dysregulating disorders, like the rare disease Paroxysmal Nocturnal Hemoglobinuria (PNH). PNH is an acquired hematopoietic stem cell condition characterized by aberrant destruction of erythrocytes, chronic hemolytic anemia, and thromboembolism propensity. C5 is a protein component of the complement system which is part of the immune system of the body and plays a prominent role in the destruction of red blood cells, misidentifying them as a threat. This work describes the application of molecular dynamics simulations to the study of the underlying interactions between complement C5 and eculizumab. This study also reveals the importance of single nucleotide polymorphisms on C5 protein concerning the effective inhibition of the mAB, involving the mechanistic events taking place at the interface spots of the complex. The predicted conformational change in the C5 Arg885/His/Cys mutation has implications on the protein’s interaction with eculizumab, compromising their compatibility. The acquired insights into the conformational changes, dynamics, flexibility, and interactions shed light on the knowledge of the function of this biomolecule providing answers about the poor response to the treatment in PNH patient carriers of the mutations. By investigating the intricate dynamics, significant connections between C5 and eculizumab can be uncovered. Such insights may aid in the creation of novel compounds or lead to the enhancement of eculizumab’s efficacy.
- Exploring treatment strategies for paroxysmal nocturnal hemoglobinuria: an overview of registered clinical trialsPublication . Peixoto, Vanda; Prudêncio, Cristina; Vieira, MónicaParoxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease in which blood cells lack anchored proteins that regulate the complement system. The erythrocytes are then destroyed because of uncontrolled complement activity, leading to intravascular hemolysis (IVH) and a high risk of thrombosis outcome. A huge alteration in the treatment of the disease was the development of terminal complement inhibitors, with the achievement of IVH blockade, reduction or abolishment of red blood cell (RBC) transfusions, and thromboembolic events prevention. However, patients treated with these inhibitors can still present extravascular hemolysis (EVH) caused by C3 activation and residual IVH or clinically relevant levels of breakthrough hemolysis (BTH). Proximal complement inhibitors turned out to be the key to the solution of this problem by targeting components of the proximal complement pathway, avoiding intra and extravascular hemolysis. FDA approved eculizumab, ravulizumab (terminal inhibitors), pegcetacoplan, iptacopan, and danicopan (proximal inhibitors) as a treatment for PNH so far. Various clinical trials are underway to find the most effective method to treat patients with PNH. This review aimed to summarize 71 registered clinical trials in the ClinicalTrials.gov database with the various treatment drugs, possible mechanisms, and novel findings related to PNH treatment.
- Mechanisms of paroxysmal nocturnal hemoglobinuria clonal expansionPublication . Peixoto, Vanda; Vieira da Silva, Manuela; Prudêncio, CristinaParoxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired clonal disease of bone marrow stem-cells, genetically characterized by the somatic mutation of the phosphatidylinositol glycan class A (PIG-A) gene. That leads to defective synthesis of glycosylphosphatidylinositol (GPI) responsible for anchorage and fixation of surface proteins like complement decay-accelerating factor (DAF/CD55) and membrane inhibitor of reactive lysis (MIRL/CD59). These proteins protect red blood cells from lysis by activated complement, leading to intravascular hemolysis.
- Paroxysmal nocturnal hemoglobinuria: a case report in a pandemic environmentPublication . Peixoto, Vanda; Carneiro, Ana; Trigo, Fernanda; Vieira, Mónica; Prudêncio, CristinaParoxysmal nocturnal hemoglobinuria (PNH) is a clonal, rare, complement-mediated hemolytic anemia. PNH can be associated with marrow failure and thrombophilia. We present a clinical report of splenic vein thrombosis in a patient with classic PNH. A 41-year-old male with classic PNH, naïve to complement inhibitor therapy, developed splenic vein thrombosis as a major adverse effect after vaccination protocol to prevent meningococcal disease. We also report anticoagulant and eculizumab treatment outcomes. In PNH patients, vaccination should be monitored to prevent major outcome events, like vaccine-induced thrombosis. Eculizumab proves effective for treating intravascular hemolysis and preventing more thrombotic events. The potential protective role of eculizumab on controlling complement activity and consequent inflammation may help the patient to not experience breakthrough hemolysis when infected with SARS-CoV-2. Extravascular hemolysis remains present, but new molecules are being studied to inhibit proximal complement and there is a good health prospective for PNH patients.
- Relação entre os hábitos alimentares e actividade física com o excesso de peso em adolescentes portuguesesPublication . Prudêncio, Cristina; Dores, Artemisa Rocha; Fernandes, Ruben; Peixoto, Vanda; Pereira, Ana Cláudia; Borges, CristinaA obesidade é uma patologia que tem aumentado drasticamente nos últimos anos, sendo que a mesma se tem manifestado de forma particularmente assustadora em crianças e adolescentes.