Departamento de Ciências Médicas
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- 10ß,17ß-Dihidroxiestra-1,4-dien-3-ona e compostos análogos: revisão das suas potenciais utilidades farmacológicasPublication . Letras, Teresa Isabel Vermelho; Silvestre, Samuel Martins; Monteiro, CristinaA presente dissertação está integrada na unidade curricular “Estágio”, do Mestrado Integrado em Ciências Farmacêuticas. Este trabalho é composto por duas componentes: a componente de investigação (Capítulo I) e a componente profissional em farmácia comunitária (Capítulo II). O primeiro capítulo corresponde à revisão da literatura sobre os efeitos farmacológicos em ensaios pré-clínicos do 10ß,17ß-dihidroxiestra-1,4-dien-3-ona, 10ß,17adihidroxiestra-1,4-dien-3-ona e 10ß-hidroxiestra-1,4-dieno-3,17-diona, que são prófármacos do estradiol, 17a-estradiol e estrona, respetivamente. O 10ß,17ßdihidroxiestra-1,4-dien-3-ona originou um melhor desempenho no teste comportamental RAWN e uma redução dos níveis de Aß, no contexto da doença de Alzheimer; atenuou o aumento da temperatura da pele da cauda, em afrontamentos; e, foi metabolizado em estradiol na retina, no contexto do glaucoma. O 10ß,17adihidroxiestra-1,4-dien-3-ona reduziu os tempos de imobilidade no teste de natação de Porsolt, apresentado, assim, atividade antidepressiva. O 10ß,17ß-dihidroxiestra-1,4- dien-3-ona e o 10ß,17a-dihidroxiestra-1,4-dien-3-ona não apresentaram os efeitos secundários periféricos associados aos estrogénios, sendo, assim, potenciais candidatos a terapêuticas estrogénicas seguras e eficazes nas doenças acima referidas. O 10ßhidroxiestra-1,4-dieno-3,17-diona apresentou efeitos anti-proliferativos em seis linhas celulares (MCF-7, T47-D, LNCaP, HepaRG, Caco-2 e NHDF), principalmente contra as células cancerígenas hormono-dependentes (MCF-7, T47-D e LNCaP). O segundo capítulo é referente ao estágio curricular em farmácia comunitária, na Farmácia Queija Ferreira, no Porto. Durante o estágio, tive a oportunidade de colocar em prática os conhecimentos técnico-científicos adquiridos no mestrado integrado e, de melhorar as minhas competências interpessoais.
- 2019 ARIA Care pathways for allergen immunotherapyPublication . Bousquet, Jean; Pfaar, Oliver; Togias, Alkis; Schünemann, Holger J; Ansotegui, Ignacio; Papadopoulos, Nikolaos G; Tsiligianni, Ioanna; Agache, Ioana; Anto, Josep M.; Bachert, Claus; Bedbrook, Anna; Bergmann, Karl-Christian; Bosnic-Anticevich, Sinthia; Bosse, Isabelle; Brozek, Jan; Calderon, Moises A; Canonica, Giorgio W; Caraballo, Luigi; Cardona, Victoria; Casale, Thomas; Cecchi, Lorenzo; Chu, Derek; Costa, Elísio; Cruz, Alvaro A; Czarlewski, Wienczyslawa; Durham, Stephen R; Du Toit, George; Dykewicz, Mark; Ebisawa, Motohiro; Fauquert, Jean Luc; Fernandez-Rivas, Montserrat; Fokkens, Wytske J; Fonseca, João; Fontaine, Jean-François; Gerth van Wijk, Roy; Haahtela, Tari; Halken, Susanne; Hellings, Peter; Ierodiakonou, Despo; Iinuma, Tomohisa; Ivancevich, Juan Carlos; Jacobsen, Lars; Jutel, Marek; Kaidashev, Igor; Khaitov, Musa; Kalayci, Omer; Kleine Tebbe, Jörg; Klimek, Ludger; Kowalski, Marek L; Kuna, Piotr; Kvedarienė, Violeta; La Grutta, Stefania; Larenas Linnemann, Désirée; Lau, Susanne; Laune, Daniel; Le Thi Tuyet, Lan; Lodrup Carlsen, Karin; Lourenço, Olga; Malling, Hans-Jørgen; Marien, Gert; Menditto, Enrica; Mercier, Gregoire; Mullol, Joaquim; Muraro, Antonella; O'Hehir, Robyn; Okamoto, Yoshitaka; Pajno, Giovanni B; Park, Hae-Sim; Panzner, Petr; Passalacqua, Giovanni; Pham-Thi, Nhan; Roberts, Graham; Pawankar, Ruby; Rolland, Christine; Rosario, Nelson; Ryan, Dermot; Samolinski, Boleslaw; Sanchez-Borges, Mario; Scadding, Glenis; Shamji, Mohamed H; Sheikh, Aziz; Sturm, Gunter J; Todo-Bom, Ana; Toppila-Salmi, Sanna; Valentin Rostan, Marylin; Valiulis, Arunas; Valovirta, Erkka; Ventura, Maria Teresa; Wahn, Ulrich; Walker, Samantha; Wallace, Dana; Waserman, Susan; Yorgancioglu, Arzu; Zuberbier, TorstenAllergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence-based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including healthcare professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow-up of patients.
- 2023 UPDATE: Luso-Brazilian evidence-based guideline for the management of antidiabetic therapy in type 2 diabetesPublication . Bertoluci, Marcello Casaccia; Júnior, Wellington S. Silva; Valente, Fernando; Araujo, Levimar Rocha; Lyra, Ruy; Castro, João Jácome de; Raposo, João; Miranda, Paulo Augusto Carvalho; Boguszewski, Cesar Luiz; Hohl, Alexandre; Duarte, Rui; Salles, Joao Eduardo Nunes; Silva-Nunes, José; Dores, Jorge; Melo, Miguel; Sá, João Roberto de; Neves, João Sérgio; Moreira, Rodrigo Oliveira; Malachias, Marcus Vinicius Bolivar; Lamounier, Rodrigo Nunes; Malerbi, Domingos Augusto; Calliari, Luís Eduardo; Cardoso, Luis Miguel; Carvalho, Maria Raquel; Ferreira, Hélder José; Nortadas, Rita; Trujilho, Fábio Rogério; Leitão, Cristiane Bauermann; Simões, José Augusto Rodrigues; Reis, Mónica Isabel Natal dos; Melo, Pedro; Marcelino, Mafalda; Carvalho, DavideBackground The management of antidiabetic therapy in people with type 2 diabetes (T2D) has evolved beyond gly‑ cemic control. In this context, Brazil and Portugal defned a joint panel of four leading diabetes societies to update the guideline published in 2020. Methods The panelists searched MEDLINE (via PubMed) for the best evidence from clinical studies on treating T2D and its cardiorenal complications. The panel searched for evidence on antidiabetic therapy in people with T2D with‑ out cardiorenal disease and in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or diabetic kidney disease (DKD). The degree of recommendation and the level of evidence were determined using predefned criteria. Results and conclusions All people with T2D need to have their cardiovascular (CV) risk status stratifed and HbA1c, BMI, and eGFR assessed before defning therapy. An HbA1c target of less than 7% is adequate for most adults, and a more fexible target (up to 8%) should be considered in frail older people. Non-pharmacological approaches are recommended during all phases of treatment. In treatment naïve T2D individuals without cardiorenal complications, metformin is the agent of choice when HbA1c is 7.5% or below. When HbA1c is above 7.5% to 9%, starting with dual therapy is recommended, and triple therapy may be considered. When HbA1c is above 9%, starting with dual therapyt is recommended, and triple therapy should be considered. Antidiabetic drugs with proven CV beneft (AD1) are recommended to reduce CV events if the patient is at high or very high CV risk, and antidiabetic agents with proven efcacy in weight reduction should be considered when obesity is present. If HbA1c remains above tar‑ get, intensifcation is recommended with triple, quadruple therapy, or even insulin-based therapy. In people with T2D.
- 3D Printed scaffolds with bactericidal activity aimed for bone tissue regenerationPublication . Correia, Tiago R.; Figueira, Daniela Sofia Rodrigues; Sá, Kevin; Miguel, Sónia P.; Fradique, Ricardo Gil; Mendonça, António; Correia, I.J.Nowadays, the incidence of bone disorders has steeply ascended and it is expected to double in the next decade, especially due to the ageing of the worldwide population. Bone defects and fractures lead to reduced patient’s quality of life. Autografts, allografts and xenografts have been used to overcome different types of bone injuries, although limited availability, immune rejection or implant failure demand the development of new bone replacements. Moreover, the bacterial colonization of bone substitutes is the main cause of implant rejection. To vanquish these drawbacks, researchers from tissue engineering area are currently using computer-aided design models or medical data to produce 3D scaffolds by Rapid Prototyping (RP). Herein, Tricalcium phosphate (TCP)/Sodium Alginate (SA) scaffolds were produced using RP and subsequently functionalized with silver nanoparticles (AgNPs) through two different incorporation methods. The obtained results revealed that the composite scaffolds produced by direct incorporation of AgNPs are the most suitable for being used in bone tissue regeneration since they present appropriate mechanical properties, biocompatibility and bactericidal activity.
- 3D printing of β-TCP/Alginate Scaffolds for Bone RegenerationPublication . Carlos, Gabriela Soares Diogo; Correia, I.J.The rise of bone defects in the last decades has become a worldwide problem. They can arise from several causes such as tumors, trauma, infection, nutrition and bone diseases. This may compromise the mechanical and biological functions of bone tissue. Autografts, allografts and xenografts are some attractive alternatives used for bone tissue regeneration, however, several factors such as high risk of infection, immunogenic response and lack of donor has limited their use. Tissue Engineering is an interdisciplinary area that combines biomaterials and bioactive molecules to promote the repair and regeneration of bone. Scaffolds are 3D matrices that act as temporary templates, allowing cell adhesion and proliferation providing mechanical support until new bone tissue formation. Rapid prototyping technologies allow the production of 3D structures with controlled architecture from models created by computer-aided design, through a layer-by-layer process. The present work describes the production and characterization of βeta-Tricalcium phosphate/Alginate 3D scaffolds. Higher concentrations of βeta-Tricalcium phosphate provide structures with better mechanical and biological properties.
- 3D scaffolds coated with nanofibers displaying bactericidal activity for bone tissue applicationsPublication . Sá, Kevin; Figueira, Daniela Sofia Rodrigues; Miguel, Sónia P.; Correia, Tiago R.; Silva, Abílio Manuel Pereira da; Correia, I.J.Bone-limited capacity to fully repair large defects requires the development of new implants. In this context, new approaches have been used to promote bone regeneration and also to avoid the side effects associated with the therapeutics currently used in the clinic. Herein, 3D tricalcium phosphate/alginic acid scaffolds were produced and then coated with an electrospun mesh loaded with two different antibacterial agents, silver nanoparticles, and salicylic acid. The obtained results showed that the produced scaffolds have suitable mechanical properties, swelling, biodegradation, biomineralization activity, enhanced cellular adhesion/proliferation and bactericidal activity, and features essential for bone regeneration.
- 3D tumor spheroids as in vitro models to mimic in vivo human solid tumors resistance to therapeutic drugsPublication . Nunes, Ana S.; Barros, Andreia; Costa, Elisabete; Moreira, André; Correia, I.J.Three-dimensional cell culture models, such as spheroids, can be used in the process of the development of new anticancer agents because they are able to closely mimic the main features of human solid tumors, namely their structural organization, cellular layered assembling, hypoxia, and nutrient gradients. These properties imprint to the spheroids an anticancer therapeutics resistance profile, which is similar to that displayed by human solid tumors. In this review, an overview of the drug resistance mechanisms observed in 3D tumor spheroids is provided. Furthermore, comparisons between the therapeutics resistance profile exhibited by spheroids, and 2D cell cultures are presented. Finally, examples of the therapeutic approaches that have been developed to surpass the drug resistance mechanisms exhibited by spheroids are described.
- 3D tumor spheroids: an overview on the tools and techniques used for their analysisPublication . Costa, Elisabete C.; Moreira, André; Diogo, Duarte Miguel de Melo; Gaspar, V. M.; Carvalho, Marco António Paulo de; Correia, I.J.In comparison with 2D cell culture models, 3D spheroids are able to accurately mimic some features of solid tumors, such as their spatial architecture, physiological responses, secretion of soluble mediators, gene expression patterns and drug resistance mechanisms. These unique characteristics highlight the potential of 3D cellular aggregates to be used as in vitro models for screening new anticancer therapeutics, both at a small and large scale. Nevertheless, few reports have focused on describing the tools and techniques currently available to extract significant biological data from these models. Such information will be fundamental to drug and therapeutic discovery process using 3D cell culture models. The present review provides an overview of the techniques that can be employed to characterize and evaluate the efficacy of anticancer therapeutics in 3D tumor spheroids.
- 5-HT2 antagonist activity of 3-aminomethyltetralonesPublication . Verde, Ignacio; Loza, M.; Castro, Maria Elena; Orallo, Francisco; Fontenla, José Angel; Calleja, José Maria; Ravina, Enrique; Cortizo, L.; Deceballos, M. L.The affinity of four 3-aminomethyltetralones for 5-HT2 receptors is reported, together with their inhibitory activity against serotonin-induced contractions in rat aorta rings stripped of endothelium. Compound 4, which has a p-fluorobenzoyl-piperidine fragment, exhibited activity similar to that of methysergyde.
- 5α-Dihydrotestosterone regulates the expression of L-type calcium channels and calcium-binding protein regucalcin in human breast cancer cells with suppression of cell growthPublication . Marques, Ricardo; Peres, Carina; Vaz, Cátia; Gomes, Inês; Figueira, Marília I; Cairrão, Elisa; Verde, Ignacio; Baptista, Cláudio; Socorro, SílviaAndrogens have been associated with the development of normal breast, and their role in mammary gland carcinogenesis has also been described. Several studies reported that androgens inhibit breast cancer cell growth, whereas others linked their action with the modulation of calcium (Ca(2+)) pumps, Ca(2+) channels and Ca(2+)-binding proteins. Also, it is known that deregulated Ca(2+) homeostasis has been implicated in the pathophysiology of breast. The L-type Ca(2+) channels (LTCCs) were found to be up-regulated in colon, colorectal and prostate cancer, but their presence in breast tissues remains uncharacterized. On the other hand, regucalcin (RGN) is a Ca(2+)-binding protein involved in the control of mammary gland cell proliferation, which has been identified as an androgen target gene in distinct tissues except breast. This study aimed to confirm the expression and activity of LTCCs in human breast cancer cells and investigate the effect of androgens in regulating the expression of α1C subunit (Cav1.2) of LTCCs and Ca(2+)-binding protein RGN. PCR, Western blot, immunofluorescence and electrophysiological experiments demonstrated the expression and activity of Cav1.2 subunit in MCF-7 cells. The MCF-7 cells were treated with 1, 10 or 100 nM of 5α-dihydrotestosterone (DHT) for 24-72 h. The obtained results showed that 1 nM DHT up-regulated the expression of Cav1.2 subunit while diminishing RGN protein levels, which was underpinned by reduced cell viability. These findings first confirmed the presence of LTCCs in breast cancer cells and opened new perspectives for the development of therapeutic approaches targeting Ca(2+) signaling.