Repositório Científico do Instituto Nacional de Saúde
Entradas recentes
Dysregulated gene expression in colorectal cancer upon exposure to bisphenol A alternatives - a new approach
Publication . Lacerda, Rafaela; Ventura, Célia; Louro, Henriqueta; Silva, Maria João; Romão, Luísa
Bisphenol A (BPA) has been widely used in plastics and resins since the 1950s, making it a common part of everyday products like food containers and bottle linings. Alternative substances are increasingly replacing BPA, but they are raising health and environmental concerns. Some mimic BPA’s endocrine-disrupting effects, while others affect different biological pathways. Substitutions in bisphenols can alter their biological properties, including nuclear receptor activation. Some BPA alternatives, like BPS, BPF and BPZ, may also pose cancer risks by activating oestrogen receptors, potentially even more than BPA itself. They may also contribute to colorectal cancer (CRC). Research suggests that BPA and its substitutes can influence cancer progression by altering cellular pathways, promoting metastasis and affecting gene expression. One of the key steps in gene expression regulation is translation initiation, whose canonical pathway is globally impaired under stress conditions, like exposure to BPA alternatives. Thus, we will subject NCM460 (normal intestinal mucosa) and HCT116 (colorectal carcinoma) cells to BPS, BPF and BPZ exposure and identify the transcripts actively being translated in such conditions, using ribosome profiling. We will analyse data with the R package anota2seq and evaluate the positively identified targets (compared to total RNA sequencing) for the existence of alternative mechanisms of translation initiation regulating their expression. The accurate characterisation of such mechanisms will be crucial for designing antisense RNA oligomers (ASOs) for potential therapeutic approaches. We will evaluate the cytotoxic effects of BPS, BPF and BPZ in the presence or absence of the selected alternatively translated transcripts (functional or targeted with the designed ASOs). Cytotoxic effects will be assessed through in vitro assays, analysing metabolic activity, membrane integrity, and cell proliferation. Thus, our research explores protein synthesis dysregulation to reduce CRC risks from BPS, BPF and BPZ exposure — an emerging public health issue.
Lyso-GB3: Usefulness and limitations
Publication . da Silva Gaspar, Paulo Jorge Miranda
A lecture on Fabry Disease: A Rare Genetic Disorder.
Early Diagnosis of Mucopolysaccharidoses in Pediatrics
Publication . da Silva Gaspar, Paulo Jorge Miranda; Neiva, Raquel; Sousa e Silva, Lisbeth Elena; Diogo, Luisa; Ferreira, A.; Miranda, A.; Ribeiro, S.; Antunes, D.; Garcia, P.; Rodrigues, E.; Campos, T.; Janeiro, P.; Lopes, Altina; Pereira, Cristina; Nogueira, Célia; Sousa, S.; Ferreira, S.; Alves, Sandra; Leão Teles, Elisa; Vilarinho, Laura
Introduction: Mucopolysaccharidoses (MPSs) are a group of Lysosomal Storage Disorders with multisystem involvement, presenting different degrees of severity and evolution. At early disease stages and late onset forms, diagnosis can be postponed for years or even missed. The FIND PROJECT was designed to claim awareness to the redflags of MPSs at pediatric age and to provide a useful tool for physicians to diagnose these pathologies, since most of them are amenable to enzyme replacement therapy.
Can enzyme replacement therapy revert¨iNKT¨cell dysfunction in acid sphingomyelinase deficiency patients?
Publication . Chaves, João; da Silva Gaspar, Paulo Jorge Miranda; Macedo, Fatima
Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of the enzyme acid sphingomyelinase (ASM), resulting in an abnormal accumulation of sphingomyelin in lysosomes. The abnormal accumulation of sphingomyelin, a crucial cell membrane component, ultimately impairs pulmonary, hepatic, and sometimes neurological functions, with severe forms of the disease being fatal in the first years of life.
Invariant Natural Killer T (iNKT) cells are lipid-reactive T cells that play a central role in a wide range of immune responses including cancer, infection and inflammation. iNKT cells are restricted to CD1d, depending on the presentation of lipids by this molecule for their function. Sphingomyelin is a lipid with affinity for CD1d and its accumulation in ASMD influences the role of iNKT cells by impairing normal lipid antigen presentation to these cells.
Interestingly, ASM-/- mice have reduced number of iNKT cells and impaired iNKT cell activity, in ASMD patients a reduced frequency of iNKT cells is also observed (1). Noteworthy, enzyme replacement therapy (ERT) with recombinant ASM can prevent iNKT cell deficiency in ASM-/- mice (1). In the current study we are investigating the effect of ERT on iNKT cells in ASMD adult patients.
Differential Diagnosis of Alpha-Mannosidosis in MPSs
Publication . da Silva Gaspar, Paulo Jorge Miranda; Gonçalves, Diana; Neiva, Raquel; Sousa e Silva, Lisbeth Elena; Vilarinho, Laura
Introduction: Mucopolysaccharidosis (MPSs) and oligosaccharidosis, two subgroups of lysosomal storage disorders (LSDs), face diagnostic challenges due to their wide spectrum of clinical presentations and overlapping symptoms.
One of the oligosaccharidose is α-mannosidosis, an extremely rare and often undiagnosed disorder. It is characterized by a deficiency in the enzymatic activity of α-mannosidase, which is responsible for cleaving mannose from N-linked oligosaccharides. This study aimed to investigate the activity of α-mannosidase in dried blood spot (DBS) samples that had undergone screening for MPSs.