A carregar...
Projeto de investigação
Sem título
Financiador
Autores
Publicações
Metabolism-targeted therapy in NSCLC – A new theranostics inhalation approach using lactate functionalized and selenium-chrysin loaded nanoparticles (SeChry@PUREG4-LA24)
Publication . Mendes, Cindy; Martins, Filipa; Granja, Sara; Gonçalves, Joana; Barros, Hélio; Casimiro, Teresa; Aguiar-Ricardo, Ana; Silva, Fernanda; Abreu, Bruna; Cristovão, Miguel; André, Saudade; Pereira, Sofia A.; Baltazar, Fátima; Cabral-Marques, Helena; Gaspar, Maria Manuela; Gonçalves, Luís G.; Bonifácio, Vasco D. B.; Serpa, Jacinta; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); LAQV@REQUIMTE; DQ - Departamento de Química; Instituto de Tecnologia Química e Biológica António Xavier (ITQB); Elsevier
Lung cancer is one of the most lethal cancers globally, primarily due to delayed diagnosis and lack of specific and effective therapy. Increased lactate production and consumption, along with cysteine metabolic reliance, are features identified in NSCLC in our recent studies. Cancer metabolic remodeling leads to excessive ROS production, triggering oxidative stress, promoting angiogenesis, causing cellular and tissue damage, and contributing to various pathophysiological changes. This study aimed to investigate the therapeutic potential of selenium–chrysin (SeChry), a cysteine metabolism inhibitor, and its delivery targeted at MCT1 by encapsulation in fourth-generation polyurea dendrimers functionalized with lactic acid (PUREG4-LA24), the nanoformulation SeChry@PUREG4-LA24, in NSCLC. We explored the impact of SeChry nanoformulation on cell death mechanisms, including ferroptosis, and its influence on angiogenesis in in vitro and in vivo models. SeChry@PUREG4-LA24 induces cell death through the induction of intracellular ROS and lipid peroxides, resulting in distinct expression patterns of ferroptosis-associated genes across cell lines. Experiments using chicken embryo chorioallantoic membrane (CAM) and mouse orthotopic xenograft models revealed a trend toward decreased tumor growth and angiogenesis with SeChry@PUREG4-LA24 administration. These findings suggest the potential of SeChry@PUREG4-LA24 as an innovative therapeutic approach for NSCLC, highlighting its impact on cell death mechanisms and anti-angiogenic effects.
Imaging tools for automatic biomarkers analysis to evaluate progression in intermediate age-related macular degeneration
Publication . Lashkov, Vasilli; Matela, Nuno; Tenreiro, Sandra Isabel Nogueira
Age-related macular degeneration (AMD) is a major cause of vision loss in elderly, with no effective treatments available. Ophthalmologists rely on retinal imaging, but manual comparison of features is time-consuming and subjective. We aimed to perform an automated longitudinal analysis of AMD biomarkers using previously developed by our group software. Here, advanced image processing and existing algorithms were used for quantifying drusen features at different timepoints, giving insights into disease progression and software’s limitations.
Optical Coherence Tomography (OCT) images were acquired using the SPECTRALIS platform (Heidelberg Engineering). The study utilized a total of 8 SD-OCT volumes obtained from 4 patients with intermediate AMD. Images quality was ensured by excluding scans with artifacts or those that could not be processed by the software. MATLAB was used for custom image analysis.
The results demonstrated an overall increase in drusen number and size over the follow-up period, consistent with known patterns of AMD progression. However, drusen volume changes were less consistent, possibly reflecting variability in disease mechanisms, patient-specific factors, or software limitations. Hyperreflective foci (HRF) were observed, but due to the small sample size, no clear patterns in their behavior over time could be established. The study's small sample size and variability in drusen dynamics limited the statistical analysis of the findings. Additionally, possible errors in automated segmentation could have contributed to these inconsistencies.
While the study identifies trends in drusen dynamics and their potential role in AMD progression, the limited sample size prevents drawing definitive conclusions, underscoring the need for further research. We also addressed the software’s limitations and proposed directions for future investigation. Follow-up studies should focus on larger sample sizes, incorporate a rigorous manual validation to capture the full range of drusen evolution, and expand the analysis to include other important AMD biomarkers, such as different phenotypes of OCT Reflective Drusen Substructures (ODS), hyporeflective central drusen, or structural changes in retinal pigment epithelium (RPE), external limiting membrane (ELM) and ellipsoid zone (EZ). With continued development and refinement, automated tools hold significant potential for advancing AMD research and improving disease monitoring.
Collagen–Chitosan Composites Enhanced with Hydroxytyrosol for Prospective Wound Healing Uses
Publication . Batista, Miguel P.; Pimenta, Margarida; Fernández, Naiara; Duarte, Ana Rita C.; Bronze, Maria do Rosário; Marto, Joana; Gaspar, Frédéric Bustos; DQ - Departamento de Química; LAQV@REQUIMTE; Instituto de Tecnologia Química e Biológica António Xavier (ITQB); MDPI - Multidisciplinary Digital Publishing Institute
Background/Objectives: Recent studies highlight the excellent wound-healing properties of collagen and chitosan materials. Combining these polymers with a bioactive compound could enhance their effectiveness as next-generation wound dressings. Hydroxytyrosol (HT), an antioxidant derived from olive oil, may aid wound healing due to its anti-inflammatory, antimicrobial, and angiogenesis-stimulating properties, making it a beneficial addition to collagen–chitosan dressings. It could be a beneficial addition to collagen–chitosan dressings, thus improving their therapeutic effects. This study screens the potential of collagen–chitosan composites with HT for wound-healing applications and assesses the influence of the compound’s incorporation on the materials’ properties. Methods: The material production involved incorporating chitosan and HT into a marine collagen extract. The resulting collagen–chitosan–HT material was obtained through freeze-drying. Prototype dressing characterization included morphology by scanning electron microscopy, solid and hydrated state by textural and rheological studies, and in vitro HT release studies. The materials’ cytocompatibility screening was assessed using a mouse fibroblast cell line, and the antibacterial activity was evaluated against microorganisms commonly implicated in wound infections. Results: Burst strength, viscosity, frequency sweep test, tackiness, and adhesion results indicate that chitosan contributes to the material’s mechanical robustness by maintaining a high viscosity and preserving the material’s gel structure. The in vitro release studies suggest an HT-controlled release profile with a maximum release (70%) achieved after 10 h. Biological experiments confirmed the materials’ cytocompatibility with skin cells and very promising antibacterial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa. Conclusions: In conclusion, HT was successfully incorporated into a collagen–chitosan matrix, enhancing the therapeutic prospect of the resultant material. The collagen–chitosan–HT composite presents a promising potential as an advanced wound-healing material.
Bacterial cellulose-FucoPol composite hydrogel dressings for advanced wound treatment
Publication . Esmail, Asiyah; Rovisco, Ana; Morais, Maria; Pimentel, Ana; Fortunato, Elvira; Serra, Ana Teresa; Freitas, Filomena; DQ - Departamento de Química; UCIBIO - Applied Molecular Biosciences Unit; UNINOVA-Instituto de Desenvolvimento de Novas Tecnologias; CENIMAT-i3N - Centro de Investigação de Materiais (Lab. Associado I3N); DCM - Departamento de Ciência dos Materiais; Instituto de Tecnologia Química e Biológica António Xavier (ITQB); Faculdade de Ciências e Tecnologia (FCT); Elsevier
Effective wound management relies on dressings that prevent infection and facilitate healing, which has driven research into advanced, cost-effective therapeutic dressings. Bacterial cellulose (BC) is highly valued for use in wound dressings given its mechanical strength, nanoporous structure, high water-holding capacity, and excellent biocompatibility. While BC promotes debridement and maintains moisture for wound healing, it lacks essential bio-functional properties, which can be addressed through incorporation of other compounds. FucoPol (FP), a fucose-rich natural polysaccharide, offers wound-healing potential, alongside adhesive, photoprotective, and bioactive properties. In this study, BC and FP were combined to develop an active wound dressing, leveraging the unique properties of each polymer. BC was impregnated with FP, which was gelled using Fe3+ as a crosslinking agent. Increasing FP concentration (1.0, 1.5, 2.0 wt%) improved the composite's mechanical strength, but reduced its crystallinity index (43–38 %), water holding capacity (72–39 g/g) and water retention, compared to BC by itself (crystallinity index: 59 %; water holding capacity: 123 g/g). The BC/FP composite dressings (containing 13–25 % FP) demonstrated non-cytotoxicity, with cell viability exceeding 80 % in HaCaT cells (human skin keratinocytes) and NCTC clone L929 (mouse fibroblast) cell lines, and enhanced both cell lines' adhesion, thus supporting their suitability for active wound dressing applications.
Lactylation in HEPG2 toxicity response
Publication . Pereira, Rita Tomás Gonçalves Rodrigues; Jacinto, António
RESUMO: A regeneração de tecidos permite aos organismos restaurar estruturas danificadas através de vias de sinalização complexas e coordenadas que promovem a proliferação e diferenciação celular. No entanto, esta capacidade regenerativa varia entre espécies. Enquanto alguns animais conseguem regenerar totalmente os tecidos, os mamíferos — incluindo os humanos — dependem principalmente da cicatrização, um processo que frequentemente falha em restaurar plenamente a função original do tecido, podendo resultar em consequências clínicas prolongadas. Para ultrapassar estas limitações, é fundamental compreender os mecanismos que regulam as respostas celulares ao dano e à reparação. O metabolismo celular desempenha um papel central na adaptação ao stress e na regeneração, sendo comum as células alterarem o seu perfil metabólico para a glicólise aeróbica, favorecendo a sobrevivência e o restabelecimento do tecido. Esta reprogramação metabólica leva ao aumento da produção de lactato, que atua como molécula sinalizadora e reguladora epigenética. Estudos prévios do nosso laboratório em peixe-zebra demonstram que a atividade glicolítica aumentada durante a regeneração da barbatana caudal promove a formação do blastema e a regeneração eficaz do osso. Adicionalmente, a intensificação da glicólise foi associada a níveis elevados de lactilação de histonas em osteoblastos, com regiões de cromatina lactiladas enriquecidas junto a genes regulados por Oct4. Estes resultados sugerem que a remodelação da cromatina mediada por lactato pode modular programas de transcrição relevantes para a reparação de tecidos. No entanto, esta relação permanece inexplorada em modelos mamíferos. Neste estudo, investigámos se o dano celular induzido por toxicidade em células hepáticas humanas promove a acumulação de lactato e a lactilação de histonas, facilitando potencialmente a remodelação da cromatina nos locais de ligação de Oct4 e ativando uma resposta transcricional. Para testar a dependência da lactilação face ao metabolismo glicolítico, manipulámos a produção de lactato utilizando 2-desoxi-D-glucose, galoflavina, oxamato de sódio e lactato exógeno. Em seguida, avaliámos a acumulação de lactato extracelular e os níveis de lactilação após exposição a três insultos tóxicos distintos: acetaminofeno, peróxido de hidrogénio e cloreto de cobalto. Estes compostos foram selecionados por recriarem danos celulares fisiologicamente relevantes que caracterizam ambientes danificados. Por fim, explorámos se estas condições afetavam a expressão de OCT4 em função do estado de lactilação. Os nossos resultados demonstram que a lactilação é regulada pela atividade glicolítica. A acumulação de lactato e a lactilação induzidas por toxicidade dependeram do tipo de insulto. Apesar da clara modulação da lactilação, a expressão de OCT4 manteve-se inalterada, sugerindo que a lactilação não regula diretamente a transcrição deste gene. Ao esclarecer a interligação entre metabolismo, modificação das histonas e regulação transcricional durante o dano celular, este estudo fornece novos contributos para a compreensão da biologia regenerativa humana. O conhecimento destes mecanismos poderá apoiar o desenvolvimento de estratégias terapêuticas baseadas na modulação metabólica para promover a reparação de tecidos, especialmente em órgãos com capacidade regenerativa limitada.
Unidades organizacionais
Descrição
Palavras-chave
Contribuidores
Financiadores
Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
Concurso para Atribuição do Estatuto e Financiamento de Laboratórios Associados (LA)
Número da atribuição
LA/P/0087/2020