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- Design, synthesis, and antimalarial evaluation of novel quinazolin-4(3H)-one derivatives with molecular modeling insights into target selectivityPublication . Nascimento, Igor José dos Santos; Menezes, Karla Joane da Silva; Leonardo, Margarida Cochicho; Morais, Inês; Vieira, Carolina Silva Dias; Pereira, Sara Silva; Cortes, Sofia; Moreira, Rui; Nogueira, Fatima; Olimpio de Moura, RicardoMalaria is a tropical disease caused by protozoa of the genus Plasmodium and is responsible for several deaths worldwide. Current therapies are limited by the high incidence of adverse effects and the rising prevalence of parasite drug resistance, underscoring the need for research into new chemical scaffolds that can overcome these limitations and for the identification of novel drug targets to advance antimalarial development. In this context, quinazolines show promising potential as new antimalarials. Therefore, in this study, a new series of quinazolin-4(3H)-one analogs was synthesized and evaluated for antiplasmodial activity. As a result, 36 compounds were synthesized and characterized, of which 3d, 3e, 4a, and 4e showed promising activity in assays against P. falciparum-3D7HT-GFP (IC50 = 4.36, 2.26, 1.70, and 4.10 μM) with no cytotoxicity (CC50 = 44.56, 22.91, 26.42, and 48.15 μM) and acceptable selectivity indexes (10.22, 10.14, 15.55, and 11.75). The compounds were evaluated against Leishmania donovani and Trypanosoma congolense but did not inhibit these parasites, suggesting that this chemical scaffold is selective for plasmodial targets. Accordingly, molecular modeling proposed Nmyristoyltransferase (NMT) as a potential target and identified the specific binding mode of compound 4a for P. falciparum NMT (PfNMT) relative to L. donovani NMT (LdNMT), T. congolense NMT (TcNMT), and Homo sapiens NMT (HsNMT). It was found that the presence of Leu411, Leu369, Ser337, and Phe336 in PfNMT, substituted by Met412, Val370, Val338, and Tyr337 in LdNMT, and Met445, Tyr370, Ile371, and Tyr370 in TcNMT, may be related to the predicted target selectivity and the greater affinity of 4a for PfNMT. Finally, molecular dynamics simulations suggest that 4a is most stable against PfNMT, and MM-PBSA calculations indicate a binding energy for this target (ΔGbinding = −130.873 kJ/mol). These findings corroborate the promising potential of 4a and support its proposed selectivity against PfNMT, yielding a scaffold that can be explored in subsequent optimization studies.
- Aquaporin-1 sustains lymphangiogenic responses in hyperosmotic inflammatory microenvironmentsPublication . Roci, Irena; Kim, Jaeryung; Korodi, Kelly de; Wyss, Tania; Bernier-Latmani, Jeremiah; Arroz-Madeira, Silvia; González-Loyola, Alejandra; Bovay, Esther; Grenningloh, Nadia; Schoofs, Hans; Jeon, Noo Li; Giampietro, Costanza; Mäkinen, Taija; Noël, Agnès; Petrova, Tatiana V.Intestinal lymphatic vessels are essential for dietary lipid absorption and immune cell trafficking. Villus lymphatic capillaries, lacteals, undergo continuous VEGF-C–dependent renewal to function in a hyperosmolar, inflammatory environment exposed to dietary and microbial by-products. To define mechanisms underlying this adaptation, we integrated new and published single-cell RNA-sequencing datasets of murine small intestinal lymphatic endothelial cells (LECs). Lacteal LECs resembled Ptx3+ immune-interacting LECs and were characterized by high expression of water channel AQP1. LEC-specific Aqp1 deletion reduced lacteal length, impaired lipid uptake, and limited weight gain on a high-fat diet, while mosaic deletion revealed a cell-autonomous requirement for AQP1 in LEC positioning at hyperosmolar tip regions. AQP1 promoted LEC migration under hyperosmotic stress by preserving cytoskeletal and junctional remodeling and alleviating osmotic stress–induced transcriptional programs. AQP1 was upregulated during inflammatory remodeling in lymphedema and lymphatic malformations, but not during embryonic lymphangiogenesis. These findings link lacteal regeneration to inflammatory lymphatic remodeling and highlight tissue osmolarity as a biophysical determinant of postnatal lymphangiogenesis.
- Acromegaly and cardiovascular disease: mechanisms, clinical impact, and evolving managementPublication . Araujo-Castro, Marta; Marques, Pedro; Cardoso, Luis Miguel; Pascual-Corrales, Eider; Refardt, Julie; Neggers, Sebastian J. C. M. M.; Cassinello, José María Jiménez; Marazuela, Mónica; Puig-Domingo, Manel; Biagetti, BetinaCardiovascular disease is one of the most common and serious complications of acromegaly and a leading contributor to reduced life expectancy in affected individuals. This review examines the prevalence, mechanisms, diagnosis, and management of cardiovascular complications in patients with acromegaly. Growth hormone and insulin-like growth factor 1 excess promotes a range of cardiovascular disturbances, including structural heart changes, arrhythmias, vascular dysfunction, and an increased burden of traditional cardiovascular risk factors such as hypertension, diabetes, and dyslipidemia. Early recognition and targeted treatment of these complications are critical to reducing cardiovascular morbidity and mortality. While surgery and medical therapies for acromegaly aimed at normalizing hormone levels may lead to partial or full reversal of some cardiovascular alterations, many patients require continued management of comorbid conditions to control their overall cardiometabolic risk. Advances in diagnostic strategies and therapeutic options have contributed to improved survival, yet gaps remain in our understanding of how best to prevent or reverse cardiovascular damage in this population. Multidisciplinary care and individualized risk assessment are essential components of modern acromegaly management.
- Glucocorticoid-induced arginine vasopressin deficiency and neurohypophyseal T1-hyperintensity transient switch-offPublication . Marques, Pedro; Neto, Lia; Fontes, Luísa; Sapinho, Inês
- Protocol for evaluating ChatGPT in biomedical association generation and verification using a RAG enabled, cross-model majority voting workflowPublication . Hamed, Ahmed Abdeen; Rocha, Luis M.We present a protocol to evaluate ChatGPT’s ability to generate disease-centric biomedical associations. It outlines how we generate the associations, validate the biological entities using biomedical ontologies, and verify associations using literature. The protocol includes a self-consistency strategy to assess generative reliability across ChatGPT models. To address ontology exact-match limitations, we provide a use case performing semantic verification through a workflow enabled by Retrieval-Augmented Generation (RAG) powered by open-source large language models (LLMs). This enables LLMs to establish truth over content generated by other LLMs and expose hallucination.
- Glucocorticoid-induced arginine vasopressin deficiency and neurohypophyseal T1-hyperintensity transient switch-offPublication . Marques, Pedro; Neto, Lia; Fontes, Luísa; Sapinho, Inês
- Protocol for evaluating ChatGPT in biomedical association generation and verification using a RAG enabled, cross-model majority voting workflowPublication . Hamed, Ahmed Abdeen; Rocha, Luis M.We present a protocol to evaluate ChatGPT’s ability to generate disease-centric biomedical associations. It outlines how we generate the associations, validate the biological entities using biomedical ontologies, and verify associations using literature. The protocol includes a self-consistency strategy to assess generative reliability across ChatGPT models. To address ontology exact-match limitations, we provide a use case performing semantic verification through a workflow enabled by Retrieval-Augmented Generation (RAG) powered by open-source large language models (LLMs). This enables LLMs to establish truth over content generated by other LLMs and expose hallucination.
- Urinary-free cortisol-based thresholds for differentiating ACTH-dependent Cushing: a Spanish validation studyPublication . Biagetti, Betina; Marques, Pedro; Soto-Moreno, Alfonso; García-Centeno, Rogelio; González-Fernández, Laura; Garcia, María Dolores Ollero; Echarri, Ana Irigaray; Cardona-Arias, Andres; Rodríguez, Maria Dolores Moure; Paja, Miguel; Castro, Ana; Valero, Lucía Manzano; Guerrero-Pérez, Fernando; Lamas, Cristina; Lázaro, Victoria Alcázar; Gracia, Paola; Sanchis-Pascual, David; ÁLvarez-Escolá, Cristina; Lozano-Aida, Claudia; Hanzu, Felicia A.; Araujo-Castro, MartaContext: Differentiating ectopic ACTH secretion (EAS) from Cushing disease (CD) remains one of the most challenging steps in the diagnostic workup of ACTH-dependent Cushing syndrome (CS). Urinary-free cortisol (UFC) expressed as times above the upper limit of normal (ULN) has been proposed as a simple, noninvasive discriminator, but external validation in independent populations is lacking. Objective: To validate the diagnostic performance of UFC × ULN for distinguishing EAS from CD and explore complementary biochemical markers, including late-night salivary cortisol (LNSC × ULN) and hypokalemia. Design, Setting, and Participants Multicenter retrospective study from the Spanish Cushing Registry including 269 patients with ACTH-dependent Cushing’s syndrome (208 CD, 61 EAS) diagnosed and managed in tertiary referral centers. Main Outcome Measures: Diagnostic accuracy of UFC × ULN and LNSC × ULN for discriminating EAS from CD, expressed as area under the ROC curve (AUC), sensitivity, specificity, and predictive value. Results: EAS patients were older (median 59.0 vs 44.9 years; P < .001) and showed higher UFC × ULN (16.6 vs 3.6; P < .001) and LNSC × ULN (9.3 vs 1.5; P < .001). UFC × ULN and LNSC × ULN achieved excellent discriminative performance (AUC 0.90 and 0.92). No EAS occurred with UFC × ULN < 3 × ULN, while 40.5% of patients with UFC ≥ 10 × ULN had EAS. The combination of severe hypercortisolism (UFC ≥ 10 × ULN and LNSC ≥ 9 × ULN) plus hypokalemia identified 75% of EAS with 98% specificity. Conclusion: UFC × ULN thresholds reliably stratify the probability of EAS vs CD. Severe hypercortisolism and hypokalemia strongly predict EAS, supporting a pragmatic diagnostic approach that prioritizes whole-body imaging in high-risk patients and pituitary-centered evaluation in mild cases.
- Dynamics and ecology of a multistage expansion of Oropouche virus in BrazilPublication . Tegally, Houriiyah; Dellicour, Simon; Poongavanan, Jenicca; Mavian, Carla; Dor, Graeme; Fonseca, Vagner; Tagliamonte, Massimiliano S.; Dunaiski, Marcel; Moir, Monika; Wilkinson, Eduan; Albuquerque, Carlos Frederico Campelo de; Frutuoso, Livia C. V.; Holmes, Edward C.; Baxter, Cheryl; Lessells, Richard; Kraemer, Moritz U. G.; Lourenco, José; Alcantara, Luiz Carlos Junior; Oliveira, Tulio de; Giovanetti, MartaIn March 2024, Brazil reported an unprecedented Oropouche fever outbreak, driven by the emergence of a reassortant lineage of the Oropouche virus (OROV) expanding beyond the Amazon Basin. To investigate the expansion dynamics of OROV, we implemented complementary phylogeographic and ecological niche modelling approaches that aimed to characterize the environmental factors associated with the range expansion and the risk of local circulation, respectively. Our analyses reveal a multiscale expansion process with both shortand long-distance dispersal events and diffusion velocities in line with air traffic-mediated jumps. We identify banana and cocoa cultivation, temperature, the predicted suitability of the primary vector Culicoides paraensis and human population density as key environmental factors associated with OROV range expansion in new areas. We further show that OROV circulated in areas of enhanced ecological suitability immediately preceding its explosive epidemic expansion in the Amazon. Our study provides valuable insights into the dispersal and ecological dynamics of OROV, highlighting the probable role of human mobility in the long-distance colonization of new areas and raising concern over high viral suitability along the Brazilian coast.
- The emerging role of chemokines and chemokine receptors in the biological and clinical behaviour of pituitary neuroendocrine tumours: an exploratory transcriptomic studyPublication . Silva, Ana Luísa; Barry, Sayka; Hipólito, Ana; Severino, Mariana de Griné; Joaquim, Rita; Hall, Charlotte; Oliveira, Tiago; López-Presa, Dolores; Borrecho, Gonçalo; Tortosa, Francisco; Nobre, Ema; Faria, Claudia C.; Korbonits, Márta; Marques, PedroThe chemokine network in the microenvironment of pituitary neuroendocrine tumours (PitNETs) may modulate tumour biology, aggressiveness, and treatment responses. We aimed to study the role of various chemokines and chemokine receptors in defining PitNET phenotype and clinical outcomes. We included 96 patients (51 females) with available snap-frozen PitNET tissue from surgery between 2014 and 2020. Chemokine and chemokine receptors were studied by RT-qPCR. Fold difference in mRNA expression was calculated using the ΔΔCt method; chemokine and receptor expression levels were normalised to the expression of the control gene TBP, and expressed relative to a reference sample. Ten chemokines and receptors were studied (CCL2, CCL3, CCL4, CXCL8, CX3CL1, CCR2, CCR4, CCR5, CXCR1, CXCR2), and their expression correlated with clinico-pathological and outcome data, as well as other available microenvironment-related data. We found strong positive correlations between all chemokines and chemokine receptors. Higher chemokine and receptor expression levels were seen in patients who had pituitary apoplexy (CCR2, CXCR1), hypopituitarism at diagnosis (CCL2, CCR4), Ki-67 >3% (CCL4, CXCR2), as well as in patients who required re-operation (CCL3, CXCL8, CXCR2), multimodal therapy (CCL2), and had active disease at last-follow-up (CCL2). There was a positive correlation between the number of pituitary surgeries and expression levels of CCL3, CXCL8, CX3CL1, CXCR1, and CXCR2. Compared to nonfunctioning-PitNETs, somatotropinomas had higher expression of CCL2, CCL4, and CCR2, and lower expression of CX3CL1 and CCR4. Expression of CDH1 (encoding E-cadherin) correlated negatively with CCL2, CCL4, CCR2, CCR4, and CXCR2, while the expression of ZEB1 (mesenchymal marker) positively correlated with CCL3, CCL4, and CX3CL1. PitNETs expressing higher levels of CCL4, CX3CL1, CCR4, CCR5, and CXCR1 had more and bigger vessels. Somatotropinomas treated pre-operatively with somatostatin analogues were associated with higher expression of CCL2, CCR4, CXCR1, and CXCR2, while nonfunctioning-PitNETs pre-surgically treated with dopamine agonists were associated with lower expression of CCL3, CCL4, CX3CL1, CCR5, CXCR1, and CXCR2. Our data suggests that chemokines and chemokine receptors may be involved in the modulation of different tumorigenic mechanisms in PitNETs, including tumour proliferation, epithelial-to-mesenchymal transition, and angiogenesis, and may be associated with more aggressive and difficult-to-treat disease.