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The role of Fbxo42 in Ataxin-2-mediated regulation of Xbp1 signalling
Publication . Dias Santos, Cristiana Catarina; Domingos, Pedro
"The accumulation of misfolded/unfolded proteins in the
endoplasmic reticulum (ER) leads to a cellular condition known as
“ER stress”. To alleviate this stress and restore cellular
homeostasis, cells activate a signalling pathway collectively referred
to as the Unfolded Protein Response (UPR). As a result, the ER
sensor protein IRE1 is activated and mediates the splicing of XBP1
mRNA. Xbp1 spliced (Xbp1s) is an effective transcription factor and
promotes the transcription of UPR-target genes, helping to reduce
ER stress levels. However, when stress is prolonged or severe, it
can lead to cell death by apoptosis.(...)"
Catalytic peptide-based coacervates for enhanced function through structural organization and substrate specificity
Publication . Reis, David Q.P.; Pereira, Sara; Ramos, Ana P.; Pereira, Pedro M.; Morgado, Leonor; Calvário, Joana; Henriques, Adriano O.; Serrano, Mónica; Pina, Ana S.; Instituto de Tecnologia Química e Biológica António Xavier (ITQB); UCIBIO - Applied Molecular Biosciences Unit; Faculdade de Ciências e Tecnologia (FCT); Nature Portfolio
Liquid-liquid phase separation (LLPS) in living cells provides innovative pathways for synthetic compartmentalized catalytic systems. While LLPS has been explored for enhancing enzyme catalysis, its potential application to catalytic peptides remains unexplored. Here, we demonstrate the use of coacervation, a key LLPS feature, to constrain the conformational flexibility of catalytic peptides, resulting in structured domains that enhance peptide catalysis. Using the flexible catalytic peptide P7 as a model, we induce reversible biomolecular coacervates with structured peptide domains proficient in hydrolyzing phosphate ester molecules and selectively sequestering phosphorylated proteins. Remarkably, these coacervate-based microreactors exhibit a 15,000-fold increase in catalytic efficiency compared to soluble peptides. Our findings highlight the potential of a single peptide to induce coacervate formation, selectively recruit substrates, and mediate catalysis, enabling a simple design for low-complexity, single peptide-based compartments with broad implications. Moreover, LLPS emerges as a fundamental mechanism in the evolution of chemical functions, effectively managing conformational heterogeneity in short peptides and providing valuable insights into the evolution of enzyme activity and catalysis in prebiotic chemistry.
Genomic signatures and phenotypic traits of Staphylococcus aureus from atopic dermatitis patients in Portugal
Publication . Pinho, Diana Luísa Caieiro; Miragaia, Maria
A dermatite atópica (DA) é uma doença inflamatória crónica da pele que é exacerbada pela colonização por Staphylococcus aureus. Apesar da elevada prevalência de DA em Portugal, a epidemiologia molecular de S. aureus permanece pouco caracterizada. Também não estão totalmente esclarecidos os efeitos do dupilumab nos padrões de colonização, a associação entre linhagens bacterianas e DA, nem os mecanismos de colonização das lesões e adaptação intra-hospedeiro. Para responder a estas questões, recolheram-se zaragatoas das narinas, lesões e pele saudável de 57 doentes adultos com DA (2024–2025) num hospital português. Determinámos prevalência e carga de S. aureus em doentes com e sem dupilumab. Os isolados foram caracterizados quanto à resistência a antibióticos e produção de biofilme, urease e hemolisinas. Um subconjunto pertencente ao sequence-type (ST) dominante foi analisado por WGS para avaliar relação filogenética, perfis de genes de resistência/virulência e sinais de adaptação cutânea. No total, 82% dos doentes estavam colonizados com S. aureus. O dupilumab reduziu a carga bacteriana em lesões, pele saudável e narinas. O clone mais prevalente foi ST398 S. aureus suscetível à meticilina (ST398-MSSA) (47%). A comparação genómica com coleção internacional mostrou que a maioria dos isolados portugueses ST398-MSSA (84%) agrupou-se num cluster distinto, sugerindo estruturação regional. Os dados de WGS revelaram que estirpes de diferentes locais do mesmo doente eram geneticamente próximas (2–46 SNPs), mas variavam na presença de genes de resistência (blaZ), virulência (clfA, cna), exibindo mutações recorrentes em IS21 (n=4/6 doentes). Estes resultados sugerem que doentes portugueses com DA são reservatórios de ST398- MSSA, clone associado a infeções hospitalares. A população de S. aureus em DA reflete a população local de MSSA e os constrangimentos do ambiente da lesão. Os dados indicam que a colonização das lesões é endógena e que S. aureus sofre alterações genéticas para se adaptar a diferentes nichos.
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.
Mechanistic insights into Staphylococcus aureus IsdG-Ferrochelatase interactions
Publication . Almeida, Mafalda R.; Videira, Marco A. M.; Lima, João C.; Saraiva, Lígia; Instituto de Tecnologia Química e Biológica António Xavier (ITQB); LAQV@REQUIMTE; DQ - Departamento de Química; Elsevier
In this study, we explore the molecular interactions between two Staphylococcus aureus enzymes, the haem oxygenase IsdG and ferrochelatase CpfC. Based on our previous research showing that IsdG interacts specifically with ferrochelatase, we constructed several mutants of IsdG and determined by fluorescence anisotropy the kinetic and affinity parameters of the interaction between CpfC and IsdG mutants. Our data indicate that the interacting residues on CpfC are located on a surface region distant from the porphyrin binding pocket. The identified interactions suggest that the inhibition of CpfC's iron-coproporphyrin chelatase activity by IsdG arises from long-range interactions, rather than direct blocking of the active site. Altogether, the experimental data allowed defining the regions involved in the interaction between the two proteins. These findings illuminate the interplay between haem acquisition and biosynthesis in pathogens, emphasizing the importance of specific protein interactions in mitigating intracellular haem toxicity. By elucidating these molecular mechanisms, we advance our understanding of bacterial haem homeostasis and contribute to development of potential therapeutic targets for combating haem-dependent pathogenesis.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
Concurso de avaliação no âmbito do Programa Plurianual de Financiamento de Unidades de I&D (2017/2018) - Financiamento Programático
Número da atribuição
UIDP/04612/2020