NMS: iNOVA4Health - Artigos em revista internacional com arbitragem científica
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- Targeting TNBCPublication . Cruz, Adriana; Abreu, Bruna; Mendes, Cindy; Freitas-Dias, Catarina; Gonçalves, Filipe; Silva, Fernanda; Ramalho, José; André, Saudade; Bonifácio, Vasco D.B.; Serpa, Jacinta; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); iNOVA4Health - pólo NMS; Wiley-BlackwellBreast carcinoma (BC) is the most common malignancy in women, with triple-negative breast cancer (TNBC) making up 10–20% of cases. TNBC has limited targeted therapies and poor survival due to late diagnosis and metastasis. Dendrimers are precise nanostructures with a three-dimensional globular architecture designed to target the negatively charged membranes of cancer cells. This study evaluated the anticancer potential of two novel core–shell polycationic polyurea (PURE) dendrimers, PUREG4-OEI48 and PUREG4-OCEI24, targeting BC cell membranes. Both dendrimers selectively interacted with TNBC cells, inducing apoptosis, necroptosis, and ferroptosis. In vivo, they reduced tumor volume in HCC1806 xenografts, with PUREG4-OEI48 showing no toxicity, while PUREG4-OCEI24 induced mild hepatic toxicity. These results suggest PURE dendrimers are promising TNBC treatments, with further modifications needed to enhance efficacy and reduce toxicity.
- A Short Report on Melanocyte/Melanoma Culture, Senescence, and ReproducibilityPublication . Larue, Lionel; Barral, Duarte C.; Delmas, Veronique; Egea-Rodriguez, Sara; Aldea, Daniel; Etchevers, Heather C.; Galibert, Marie Dominique; Kelsh, Robert N.; Lanfrancone, Luisa; Madigan, Michele; Moura-Alves, Pedro; White, Richard M.; Bosserhoff, Anja; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); iNOVA4Health - pólo NMS; Wiley-BlackwellAt the 2025 ESPCR (European Society for Pigment Cell Research) meeting in Erlangen, a workshop on “Pigment Cell Models: Sensitivity, Innovation, and the Challenges of Cell Culture” brought together researchers to discuss technical, methodological, and reproducibility issues in culturing melanocytes, keratinocytes, fibroblasts, and melanoma cells. The discussion between experts in the field highlighted key and recurrent pitfalls affecting experimental outcomes, including low-density seeding, temperature fluctuations, over-passaging, and mycoplasma contamination, as well as sources of variability arising from media composition, batch effects, and environmental conditions. Importantly, the workshop distinguished between practices supported by evidence and consensus-based guidance derived from collective expert experience. Species- and donor-specific differences, especially between human, mouse, and zebrafish melanocyte models, were identified as additional major determinants of experimental variability. Emerging systems, including human and mouse pluripotent stem cell (PSC)-derived melanocytes, as well as avian and zebrafish melanoma lines, were discussed for their complementary mechanistic and translational value. Overall, the workshop concluded that transparent documentation, explicit reporting standards, and shared best practices are essential to improve reproducibility and further advance pigment cell research.
- Long-term sex differences in symptoms and immune profile in long COVIDPublication . Feliz, José; Gonçalves, Juliana; Cabedo, Carolina; Brito, José; Gamas, Maria; Neves, Maria Inês; Soares, Helena; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); iNOVA4Health - pólo NMS; BioMed Central (BMC)Background: Long COVID (LC) is a post-infectious condition affecting millions worldwide, characterized by persistent multisystem symptoms. Females are disproportionately affected, reporting higher symptom burden, particularly neurocognitive and neurosensory complaints. While short-term immunopathology has been described, the long-term clinical course, immune dysregulation, and sex-specific underpinnings remain poorly understood. Methods: We analyzed 34 participants experiencing persisting symptoms from 9 months to 5 years post-SARS-CoV-2 infection, alongside 26 SARS-CoV-2–infected controls without symptoms. Clinical assessments, symptom inventories, comorbidity analysis, and work capacity evaluation were performed. Immune profiling included flow cytometry of CD4⁺ and CD8⁺ T cells, NK cells, and B cells, as well as quantification of plasma cytokines, soluble factors, and cytotoxic molecules, analyzed in a sex-disaggregated manner. Results: Females with LC exhibited higher symptom burden, particularly persistent fatigue, neurocognitive and neurosensory complaints, which increased with age and tended to increase with disease duration, whereas males showed no clear age- or duration-related patterns. Comorbidities, especially affecting endocrine, metabolic, and circulatory systems, were more frequent in females and aligned with symptom severity. Immune profiling revealed subtle but sex-specific differences: females had reduced CD8⁺ T cell cytotoxic profile, lower NKG2D and granzyme K expression, increased sCD40L and sFAS, and decreased perforin, whereas males displayed elevated TNF-α. NK cell function, B cells, and humoral immunity remained largely intact. Over half of participants reported functional impairments affecting work capacity. Conclusions: Even though our cohort is small it suggests that prolonged LC is characterized by sex-specific differences in symptom burden and immune profiles. Reduced cytotoxic CD8⁺ T cell profile in females may contribute to viral persistence and neurological symptoms, whereas elevated inflammatory markers in males suggest distinct immune pathways. These findings highlight the need for sex- and duration-specific management strategies, the identification of biomarkers, and the development of personalized therapies targeting specific LC endotypes.
- EditorialPublication . Delevoye, Cédric; Barral, Duarte C.; Setty, Subba Rao Gangi; iNOVA4Health - pólo NMS; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Frontiers Media
- Chronic caffeine consumption prevents obesity-induced cognitive and memory impairments by reducing neuroinflammation and enhancing neuronal activity in the hippocampusPublication . Capucho, Adriana M.; de Leão, José Ponce; Flor, Karine Correa; Melo, Gonçalo M.; Fernandes, Marcos Vinicius; Sacramento, Joana F.; Conde, Sílvia V.; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); iNOVA4Health - pólo NMS; ElsevierObesity and its associated metabolic disturbances increase the risk of cognitive decline, dementia, and anxiety-related disorders. Chronic caffeine consumption was suggested to prevent synaptic and cognitive deficits, but the underlying mechanisms remain unclear. Here, we investigated whether caffeine protects against cognitive and memory deficits and anxiety induced by a hypercaloric diet, and explored the molecular mechanisms involved. Ten-week-old male Wistar rats were assigned to three groups: normal chow (control), high-fat high-sucrose (HFHSu, 25 weeks), and HFHSu plus caffeine (HFHSuCaff, 1 g/L last 11 weeks). Insulin sensitivity and glucose tolerance were assessed at weeks 14 and 25. Behavioral tests (open field, novel object recognition (NOR), Y-maze, block test, elevated plus maze (EPM)) evaluated memory, cognition, and anxiety. Hippocampal tissues were analyzed by Western blot and immunohistochemistry for insulin signaling, neuronal activity and microglia activation. HFHSu feeding promoted obesity, insulin resistance, and glucose intolerance, accompanied by impaired memory and cognition (reductions in Y-maze, NOR, and block test), increased anxiety (54.5 % time in EPM open arms), reduced hippocampal glutamatergic (41.1 % VGlut) and adenosinergic signaling (22.4 %, 11.1 %, 22.6 % in A1, A2A, A2B receptors), and elevated neuroinflammation (elevated GFAP, IBA-1, IL-6 receptor levels; altered microglial morphology) compared with control. Caffeine intake ameliorated metabolic, cognitive, and neuroinflammatory alterations, except for anxiety. Notably, caffeine increased hippocampal neuronal activity by 25.22, 94.84 and 61.51 % in CA1, CA2 and CA3 areas. In conclusion, chronic caffeine consumption mitigates obesity-induced cognitive and memory deficits via modulation of hippocampal glutamatergic and adenosinergic signaling and reduced neuroinflammation, highlighting its potential as a neuroprotective intervention.
- Special Issue “Molecular Research in Retinal Degeneration”Publication . Tenreiro, Sandra; Diaz-Corrales, Francisco J.; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); iNOVA4Health - pólo NMS; MDPI - Multidisciplinary Digital Publishing Institute
- Neurogenetics of confinement-induced behavioral alterationsPublication . Herédia, Fabiana; Zanini, Rebeca; Macedo, André; Varela, Ednilson Mascarenhas; Menezes, Juliane; Ibarra, Julieta; Garelli, Andres; Gontijo, Alisson Marques de Miranda Cabral; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); iNOVA4Health - pólo NMS
- Integrative Proteomics of Extracellular Vesicles from hiPSC-Derived Cardiac Organoids Reveals Heart Tissue-like Molecular RepresentativityPublication . Vital, Carlos Miguel; Inácio, José Manuel; Carvalho, Ana Sofia; Beck, Hans Christian; Matthiesen, Rune; Belo, José António; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); iNOVA4Health - pólo NMS; MDPI - Multidisciplinary Digital Publishing InstituteCardiovascular diseases remain a growing concern worldwide. Hence, it is critical to understand cardiac development and disease in a relevant human-based in vitro model. Human cardiac organoids are an alternative approach to studying cardiogenesis, in the context of cell–cell communication, and disease etiology, using human induced pluripotent stem cells (hiPSCs). Extracellular vesicles (EVs) are nanosized particles harboring proteins, nucleic acids, and metabolites and are implicated in intercellular communication. Since cardiac development requires a complex interplay between several cell types, we hypothesize that EVs may mediate this communication. Here, we isolated EVs from hiPSC-derived cardiac organoids (cardEVs). LC-MS/MS was performed to analyze their protein cargo and compare it with those from a cardiomyocyte cell line (AC10 CM EVs) and from human heart explants of cadaveric donors (heEVs) using a bioinformatic approach. cardEVs share 48.9% of their proteins with heEVs, with important biological processes such as “Metabolism” and “Cardiac Function” highlighted in both proteomes. This overlap between the proteomes of cardEVs and heEVs suggests a molecular similarity between the two models. Therefore, we reiterate the importance of cardiac organoids as an excellent model for studying cardiac development and disease modeling, as well as to explore the complexity of intercellular communication.
- De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosaPublication . Quinodoz, Mathieu; Rodenburg, Kim; Cvackova, Zuzana; Kaminska, Karolina; de Bruijn, Suzanne E.; Iglesias-Romero, Ana Belén; Boonen, Erica G.M.; Ullah, Mukhtar; Zomer, Nick; Folcher, Marc; Bijon, Jacques; Holtes, Lara K.; Tsang, Stephen H.; Corradi, Zelia; Freund, K. Bailey; Shliaga, Stefanida; Panneman, Daan M.; Hitti-Malin, Rebekkah J.; Ali, Manir; AlTalbishi, Ala’a; Andréasson, Sten; Ansari, Georg; Arno, Gavin; Astuti, Galuh D.N.; Ayuso, Carmen; Ayyagari, Radha; Banfi, Sandro; Banin, Eyal; Barakat, Tahsin Stefan; Barboni, Mirella T.S.; Bauwens, Miriam; Ben-Yosef, Tamar; Bernard, Virginie; Birch, David G.; Biswas, Pooja; Blanco-Kelly, Fiona; Bocquet, Beatrice; Boon, Camiel J.F.; Branham, Kari; Bremond-Gignac, Dominique; Britten-Jones, Alexis Ceecee; Bujakowska, Kinga M.; Burin des Roziers, Cyril; Cadena, Elizabeth L.; Calzetti, Giacomo; Cancellieri, Francesca; Cattaneo, Luca; Chadderton, Naomi; Charbel Issa, Peter; Coutinho-Santos, Luísa; Daiger, Stephen P.; De Baere, Elfride; De Bruyne, Marieke; de la Cerda, Berta; De Roach, John N.; De Zaeytijd, Julie; Derks, Ronny; Dhaenens, Claire Marie; Dudakova, Lubica; Duncan, Jacque L.; Farrar, G. Jane; Feltgen, Nicolas; Fenner, Beau J.; Fernández-Caballero, Lidia; Ferraz Sallum, Juliana M.; Gana, Simone; Garanto, Alejandro; Gardner, Jessica C.; Gilissen, Christian; Gonzàlez-Duarte, Roser; Goto, Kensuke; Griffiths-Jones, Sam; Haack, Tobias B.; Haer-Wigman, Lonneke; Hardcastle, Alison J.; Hayashi, Takaaki; Héon, Elise; Hoefsloot, Lies H.; Hoischen, Alexander; Holtan, Josephine P.; Hoyng, Carel B.; Ibanez, Manuel Benjamin B.; Inglehearn, Chris F.; Iwata, Takeshi; Jensson, Brynjar O.; Jones, Kaylie; Kalatzis, Vasiliki; Kamakari, Smaragda; Karali, Marianthi; Kellner, Ulrich; Klaver, Caroline C.W.; Knézy, Krisztina; Koenekoop, Robert K.; Kohl, Susanne; Kominami, Taro; Kühlewein, Laura; Lamey, Tina M.; Leibu, Rina; Leroy, Bart P.; Liskova, Petra; Lopez, Irma; López-Rodríguez, Victor R.de J.; Mahieu, Quinten; Mahroo, Omar A.; Manes, Gaël; Mansard, Luke; Martín-Gutiérrez, M. Pilar; Martins, Nelson; Mauring, Laura; McKibbin, Martin; McLaren, Terri L.; Meunier, Isabelle; Michaelides, Michel; Millán, José M.; Mizobuchi, Kei; Mukherjee, Rajarshi; Nagy, Zoltán Zsolt; Neveling, Kornelia; Ołdak, Monika; Oorsprong, Michiel; Pan, Yang; Papachristou, Anastasia; Percesepe, Antonio; Pfau, Maximilian; Pierce, Eric A.; Place, Emily; Ramesar, Raj; Ramond, Francis; Rasquin, Florence Andrée; Rice, Gillian I.; Roberts, Lisa; Rodríguez-Hidalgo, María; Ruiz-Ederra, Javier; Sabir, Ataf H.; Sajiki, Ai Fujita; Sánchez-Barbero, Ana Isabel; Sarma, Asodu Sandeep; Sangermano, Riccardo; Santos, Cristina M.; Scarpato, Margherita; Scholl, Hendrik P.N.; Sharon, Dror; Signorini, Sabrina G.; Simonelli, Francesca; Sousa, Ana Berta; Stefaniotou, Maria; Stefansson, Kari; Stingl, Katarina; Suga, Akiko; Sulem, Patrick; Sullivan, Lori S.; Szabó, Viktória; Szaflik, Jacek P.; Taurina, Gita; Thiadens, Alberta A.H.J.; Toomes, Carmel; Tran, Viet H.; Tsilimbaris, Miltiadis K.; Tsoka, Pavlina; Vaclavik, Veronika; Vajter, Marie; Valeina, Sandra; Valente, Enza Maria; Valentine, Casey; Valero, Rebeca; Valleix, Sophie; van Aerschot, Joseph; van den Born, L. Ingeborgh; Van Heetvelde, Mattias; Verhoeven, Virginie J.M.; Vincent, Andrea L.; Webster, Andrew R.; Whelan, Laura; Wissinger, Bernd; Yioti, Georgia G.; Yoshitake, Kazutoshi; Zenteno, Juan C.; Zeuli, Roberta; Zuleger, Theresia; Landau, Chaim; Jacob, Allan I.; Lin, Siying; Cremers, Frans P.M.; Lee, Winston; Ellingford, Jamie M.; Stanek, David; Roosing, Susanne; Rivolta, Carlo; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); iNOVA4Health - pólo NMS; Nature Publishing GroupSmall nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.
- Modelling Cardiovascular Diseases Using Human Microphysiological SystemsPublication . Ribeiro, Quélia; Lopes, Elizeth; Ferreira, Inês S.; Guerreiro Simões, Catarina; Vital, Carlos Miguel; Inácio, José Manuel; Belo, José António; Rybak-Wolf, Agnieszka; Marques, André R.A.; Vieira, Otília V.; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); iNOVA4Health - pólo NMS; Springer OpenDespite pharmacological-, technological- and medical- advances, cardiovascular diseases (CVDs) remain the main cause of death and disability in the world. This underscores the urgent need to better understand the early stages of these diseases for effective prevention, as well as to develop patient-specific pharmacological approaches (personalized medicine) and novel therapies. Traditional in vitro and in vivo models often fail to accurately mimic human physiology, limiting their translational potential. In this context, microphysiological systems (MPS) have emerged as advanced in vitro platforms that integrate key physiological features of cardiovascular tissues. This review summarizes the state-of-the-art advancements in in vitro models for studying CVDs, with a particular focus on emerging 3D cardiac and vascular models. These models serve as essential tools for disease modelling, drug development, and toxicity testing. Key parameters to consider when developing cardiovascular MPS are highlighted, along with a discussion of the advantages and challenges associated with each model system.