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Projeto de investigação
Innovative approaches for pancreatic cancer: Decoding and manipulating immune response to short sialylated O-glycans
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Publicações
Revisiting the immunopathology of congenital disorders of glycosylation
Publication . Pascoal, Carlota; Francisco, Rita; Mexia, Patrícia; Pereira, Beatriz Luís; Granjo, Pedro; Coelho, Helena; Barbosa, Mariana; dos Reis Ferreira, Vanessa; Videira, Paula Alexandra; UCIBIO - Applied Molecular Biosciences Unit; DCV - Departamento de Ciências da Vida; DQ - Departamento de Química; Frontiers
Glycosylation is a critical post-translational modification that plays a pivotal role in several biological processes, such as the immune response. Alterations in glycosylation can modulate the course of various pathologies, such as the case of congenital disorders of glycosylation (CDG), a group of more than 160 rare and complex genetic diseases. Although the link between glycosylation and immune dysfunction has already been recognized, the immune involvement in most CDG remains largely unexplored and poorly understood. In this study, we provide an update on the immune dysfunction and clinical manifestations of the 12 CDG with major immune involvement, organized into 6 categories of inborn errors of immunity according to the International Union of Immunological Societies (IUIS). The immune involvement in phosphomannomutase 2 (PMM2)-CDG - the most frequent CDG - was comprehensively reviewed, highlighting a higher prevalence of immune issues during infancy and childhood and in R141H-bearing genotypes. Finally, using PMM2-CDG as a model, we point to links between abnormal glycosylation patterns in host cells and possibly favored interactions with microorganisms that may explain the higher susceptibility to infection. Further characterizing immunopathology and unusual host-pathogen adhesion in CDG can not only improve immunological standards of care but also pave the way for innovative preventive measures and targeted glycan-based therapies that may improve quality of life for people living with CDG.
Algae-Based Supplements Claiming Weight Loss Properties
Publication . Fernandes, Fátima; Martins, Raquel; Barbosa, Mariana; Valentão, Patrícia; Faculdade de Ciências e Tecnologia (FCT); MDPI - Multidisciplinary Digital Publishing Institute
The worldwide prevalence of obesity impacts more than 600 million adults. Successfully managing weight is effective in reducing the risk of chronic diseases, but sustaining long-term weight loss remains a challenge. Although there are supplements based on algae that claim to aid in weight loss, there is a notable scarcity of scientific evidence supporting their effectiveness, and their regular consumption safety remains inadequately addressed. In this work, commercially available Arthrospira (Spirulina) platensis Gomont and/or Fucus vesiculosus L. supplements showed moderate capacity to inhibit the activity of carbohydrate-metabolizing enzymes, and to scavenge biologically relevant reactive species. IC25 values varying between 4.54 ± 0.81 and 66.73 ± 5.91 µg of dry extract/mL and between 53.74 ± 8.42 and 1737.96 ± 98.26 µg of dry extract/mL were obtained for α-glucosidase and aldose reductase, respectively. A weaker effect towards α-amylase activity was observed, with a maximum activity of the extracts not going beyond 33%, at the highest concentrations tested. Spirulina extracts showed generally better effects than those from F. vesiculosus. Similar results were observed concerning the antiradical capacity. In a general way, the extracts were able to intercept the in vitro-generated reactive species nitric oxide (•NO) and superoxide anion (O2•−) radicals, with better results for O2•−scavenging with the spirulina samples (IC25 values of 67.16 and 122.84 µg of dry extract/mL). Chemically, similar pigment profiles were observed between spirulina supplements and the authenticated counterpart. However, fucoxanthin, the chemotaxonomic marker of brown seaweeds, was not found in F. vesiculosus samples, pointing to the occurrence of a degradation phenomenon before, during, or after raw material processing. Our findings can contribute to providing data to allow regulatory entities (e.g., EFSA and FDA) to better rule these products in a way that can benefit society.
Decoding the Molecular Basis of the Specificity of an Anti-sTn Antibody
Publication . Soares, Cátia O.; Laugieri, Maria Elena; Grosso, Ana Sofia; Natale, Mariangela; Coelho, Helena; Behren, Sandra; Yu, Jin; Cai, Hui; Franconetti, Antonio; Oyenarte, Iker; Magnasco, Maria; Gimeno, Ana; Ramos, Nuno; Chai, Wengang; Corzana, Francisco; Westerlind, Ulrika; Jiménez-Barbero, Jesús; Palma, Angelina S.; Videira, Paula A.; Ereño-Orbea, June; Marcelo, Filipa; DQ - Departamento de Química; UCIBIO - Applied Molecular Biosciences Unit; Faculdade de Ciências e Tecnologia (FCT); ACS - American Chemical Society
The mucin O-glycan sialyl Tn antigen (sTn, Neu5Acα2-6GalNAcα1-O-Ser/Thr) is an antigen associated with different types of cancers, often linked with a higher risk of metastasis and poor prognosis. Despite efforts to develop anti-sTn antibodies with high specificity for diagnostics and immunotherapy, challenges in eliciting high-affinity antibodies for glycan structures have limited their effectiveness, leading to low titers and short protection durations. Experimental structural insights into anti-sTn antibody specificity are lacking, hindering their optimization for cancer cell recognition. In this study, we used a comprehensive structural approach, combining X-ray crystallography, NMR spectroscopy, computational methods, glycan/glycopeptide microarrays, and biophysical techniques, to thoroughly investigate the molecular basis of sTn recognition by L2A5, a novel preclinical anti-sTn monoclonal antibody (mAb). Our data unequivocally show that the L2A5 fragment antigen-binding (Fab) specifically binds to core sTn moieties. NMR and X-ray structural data suggest a similar binding mode for the complexes formed by the sTn moiety linked to Ser or Thr and the L2A5 Fab. The sugar moieties are similarly oriented in the paratope of mAb, with the Neu5Ac moiety establishing key interactions with the receptor and the GalNAc moiety providing additional contacts. Furthermore, L2A5 exhibits fine specificity toward cancer-related MUC1 and MUC4 mucin-derived sTn glycopeptides, which might contribute to its selective targeting against tumor cells. This newfound knowledge holds promise for the rational improvement and potential application of this anti-sTn antibody in diagnosis and targeted therapy against sTn expressing cancers such as breast, colorectal, and bladder cancer, improving patient care.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
Concurso de Projetos de I&D em Todos os Domínios Científicos - 2022
Número da atribuição
2022.04607.PTDC