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- Dual-crosslinked injectable in situ forming Alginate/CaCl2/Pluronic F127/ α-Cyclodextrin hydrogels incorporating Doxorubicin and graphene-based nanomaterials for cancer chemo-photothermal therapyPublication . Gonçalves, Joaquim; Melo, Bruna Daniela Lopes ; Pouso, Manuel António do Rosário ; Correia, Ilídio Joaquim Sobreira ; de Melo-Diogo, DuarteInjectable in situ forming hydrogels have been emerging due to their capacity to perform the direct delivery of therapeutics into the tumor site with minimal off-target leakage. Particularly, physical crosslinked injectable in situ forming hydrogels are appealing due to their straightforward preparation that exploits the native jointing capabilities of specific polymers/materials. However, the features of these hydrogels (e.g., injectability, degradation, swelling) are strongly pre-determined by the physical interactions available on the selected polymers/ materials, occasionally yielding undesired outcomes. Thus, the combination of multiple physical crosslinking cues may allow the preparation of hydrogels with enhanced properties. In this work, a dual-crosslinked injectable in situ forming hydrogel was engineered by combining Pluronic F127/α-Cyclodextrin and Alginate/CaCl2 (i.e., combination of host-guest and electrostatic interactions), being loaded with Doxorubicin (chemotherapeutic drug) and Dopamine-reduced Graphene Oxide (photothermal nano-agent) for application in cancer chemophotothermal therapy. When compared to the single-crosslinked hydrogels, the dual-crosslinking contributed to the assembly of formulations with suitable injectability and improved degradation and water absorption behaviors. Moreover, the dual-crosslinked hydrogels presented a good photothermal capacity (ΔT ≈ 14 ◦C), leading to a 1.18-times enhanced Doxorubicin release. In in vitro cell-based studies, the dual-crosslinked hydrogels exhibited an excellent cytocompatibility towards healthy (normal human dermal fibroblasts) and breast cancer (MCF-7) cells. As importantly, the dual-crosslinked hydrogels were able to mediate a chemophotothermal effect that diminished the cancer cells’ viability to just 23 %. Overall, the developed dualcrosslinked injectable in situ forming hydrogels incorporating Doxorubicin and Dopamine-reduced Graphene Oxide are a promising macroscale system for breast cancer chemo-photothermal therapy.
- Beeswax-enriched tricalcium phosphate/hydroxyapatite/sodium alginate/ thymol 3D-printed scaffolds for application in bone tissue engineeringPublication . Francisco, Martinho Jorge ; Cabral, Cátia Solange Duarte; Calvinho, Paula Cristina Nunes Ferreira ; Correia, Ilídio Joaquim Sobreira ; Moreira, André FerreiraTissue engineering, particularly bone tissue engineering (BTE), continues to pose significant challenges to modern medicine. In this work, a rapid prototyping technique was explored to create 3D scaffolds using a Fab@Home 3D-Plotter extruder. For that purpose, a novel composite mixture containing tricalcium phosphate (TCP), hydroxyapatite (HAp), sodium alginate (SA), beeswax (BW), and thymol (TM) was formulated. BW and TM resulted in 3D scaffolds with rougher surfaces and moderate hydrophilic profiles, properties crucial for mediating cell adhesion and proliferation. Moreover, the 3D scaffolds containing BW displayed a significant increase in compressive strength and Young modulus, being comparable to those exhibited by trabecular bone. TM loading prevented the establishment of Staphylococcus aureus and Escherichia coli infections, inhibiting bacterial adhesion and proliferation at the scaffolds' surface. Additionally, the cytocompatibility of the scaffolds was confirmed over 21 days, with the adhesion and proliferation of Human osteoblasts (hOB) at the scaffold's surfaces. Simultaneously, calcium and phosphate ions accumulated at the scaffolds' surface, forming apatite crystals. Therefore, this improved composite mixture showed promising results for being applied in BTE, not only facilitating hOB cell adhesion and proliferation but also avoiding bacterial infection, addressing a critical challenge in implant-based therapies.
- Injectable and implantable hydrogels for localized delivery of drugs and nanomaterials for cancer chemotherapy: A reviewPublication . Pouso, Manuel António do Rosário ; Melo, Bruna Daniela Lopes ; Gonçalves, Joaquim; Louro, Ricardo; Mendonça, António; Correia, Ilídio Joaquim Sobreira ; de Melo-Diogo, DuarteMultiple chemotherapeutic strategies have been developed to tackle the complexity of cancer. Still, the outcome of chemotherapeutic regimens remains impaired by the drugs’ weak solubility, unspecific biodistribution and poor tumor accumulation after systemic administration. Such constraints triggered the development of nanomaterials to encapsulate and deliver anticancer drugs. In fact, the loading of drugs into nanoparticles can overcome most of the solubility concerns. However, the ability of systemically administered drug-loaded nanomaterials to reach the tumor site has been vastly overestimated, limiting their clinical translation. The drugs’ and drug-loaded nanomaterials’ systemic administration issues have propelled the development of hydrogels capable of performing their direct/local delivery into the tumor site. The use of these macroscale systems to mediate a tumor-confined delivery of the drugs/drugs-loaded nanomaterials grants an improved therapeutic efficacy and, simultaneously, a reduction of the side effects. The manufacture of these hydrogels requires the careful selection and tailoring of specific polymers/materials as well as the choice of appropriate physical and/or chemical crosslinking interactions. Depending on their administration route and assembling process, these matrices can be classified as injectable in situ forming hydrogels, injectable shear-thinning/selfhealing hydrogels, and implantable hydrogels, each type bringing a plethora of advantages for the intended biomedical application. This review provides the reader with an insight into the application of injectable and implantable hydrogels for performing the tumor-confined delivery of drugs and drug-loaded nanomaterials.
- Renewable Photo-Cross-Linkable Polyester-Based Biomaterials: Synthesis, Characterization, and Cytocompatibility AssessmentPublication . Cernadas, Maria Teresa; Pereira, João; Melo, Bruna Daniela Lopes ; de Melo-Diogo, Duarte; Correia, Ilídio Joaquim Sobreira ; Alves, Patrícia; Calvinho, Paula Cristina Nunes FerreiraTThe present work consist of the synthesis of photo-crosslinkable materials, based on unsaturated polyesters (UPs), synthesized from biobased monomers from renewable sources such as itaconic acid and 1,4- butanediol. The UPs were characterized to assess the influence of polycondensation reaction temperature and cross-linking time on their final properties. For this purpose, different UV irradiation exposure periods were tested. Homogeneous, uniform, and transparent films were obtained after 1, 3, and 5 min of UV exposure. These cross-linked films were then characterized. All materials presented high gel content, which was dependent on the reaction’s temperature. The thermal behaviors of the UPs were shown to be similar. In vitro hydrolytic degradation tests showed that the materials can undergo degradation in phosphate-buffered saline (PBS) at pH 7.4 and 37 °C, ensuring their biodegradability over time. Finally, to assess the applicability of the polyesters as biomaterials, their cytocompatibility was determined by using human dermal fibroblasts.
- ARIA-Italy managing allergic rhinitis and asthma in a changing world: The role of the PharmacistPublication . Paoletti, Giovanni; Giua, Corrado; Marti, Alessandro; Baio, Matteo Alberto; Valli, Nicolò; Ridolo, Erminia; Ventura, Maria Teresa; Passalacqua, Giovanni; Puggioni, Francesca; Lourenço, Olga ; Bousquet, Jean; Canonica, Giogio Walter; Heffler, Enrico; Lombardi, CarloAllergic rhinitis (AR) and asthma are common respiratory disorders that often occur together, affecting quality of life and increasing healthcare expenses of patients. These chronic illnesses are often managed without medical supervision, creating distinct challenges. A lack of resources can limit regular follow-up, which in turn promotes disease mismanagement and an increased reliance on self-medication, including the inappropriate use of corticosteroids and nasal decongestants. Community pharmacies could serve as critical primary healthcare providers, facilitating AR and asthma management by promoting therapy adherence, minimizing drug misuse, and improving symptom monitoring using digital tools. The evolving role of pharmacists as vital healthcare team members is highlighted by their involvement in screening, prevention, and patient education, particularly in underserved communities. Strengthening the partnerships between pharmacists, physicians, and patients may lead to more tailored and effective management strategies. This collaborative approach has demonstrated promise in enhancing disease outcomes and reducing healthcare costs.
- Computational Resources and Infrastructures for a Novel Bioinformatics Laboratory: A Case StudyPublication . Maldonado, Emanuel Filipe Escaleira ; Lemos, Manuel; Manoj, Gupta; Dennis, DouroumisIntroduction: Bioinformatics is a relatively recent multidisciplinary research field continuously offering novel opportunities. Although many researchers are actively working in/with bioinformatics, some research centers still face difficulties in hiring bioinformaticians and establishing the appropriate (first) bioinformatics infrastructures and computational resources. In our research center, we started from scratch and established initial bioinformatics infrastructures for common use and also for the specific case of precision/personalized medicine. Case description: Here, we report a case study reflecting our specific needs and circumstances during the implementation of a novel bioinformatics laboratory. This involved the preparation of rooms, computer networks, computational resources novel designs, and upgrades to existing designs. Moreover, this work involved people from diverse areas and institutions, such as companies, institutional projects, informatics, and technical infrastructures services. Discussion and evaluation: The work resulted in the implementation of four novel designs dedicated to genomic medicine and in the adaptation of two existing designs dedicated to common use located in the dry-lab room. This is not an accurate and objective work, as it often depends on the available computer hardware and the target bioinformatics field(s). The four novel designs offered substantial improvements when compared to the upgraded designs, additionally corroborated by performance evaluations, which resulted in an overall highest performance of the novel designs. Conclusions: We present work that was developed over two years until completion with functioning infrastructure. This project enabled us to learn many novel aspects not only related to redundant disk technologies, but also related to computer networks, hardware, storage-management operating systems, file systems, performance evaluation, and also in the management of services. Moreover, additional equipment will be important to maintain and expand the potential and reliability of the bioinformatics laboratory. We hope that this work can be helpful for other researchers seeking to design their bioinformatics equipment or laboratories.
- Supplemental Data - Genetics of Growth Hormone Deficiency: Insights from a Cohort of 203 PatientsPublication . Ribeiro, Ana Cláudia Batista JordãoSupplemental Table S1. Genes selected for variant analysis. Supplemental Table S2. Characteristics of 172 GH deficiency patients studied by exome sequencing of 184 genes (only P, LP and VUS variants are presented).
- Non-coding RNAs: Emerging from the discovery to therapeutic applicationsPublication . Baptista, Bruno; Riscado, Micaela; Queiroz, João; Pichon, Chantal; Sousa, F.The knowledge about non-coding RNAs (ncRNAs) is rapidly increasing with new data continuously emerging, regarding their diverse types, applications, and roles. Particular attention has been given to ncRNA with regulatory functions, which may have a critical role both in biological and pathological conditions. As a result of the diversity of ncRNAs and their ubiquitous involvement in several biologic processes, ncRNA started to be considered in the biomedical field, with immense potential to be exploited either as biomarkers or as therapeutic agents in certain pathologies. Indeed, ncRNA-based therapeutics have been proposed in many disorders and some even reached clinical trials. However, to prepare an RNA product suitable for pharmacological applications, certain criteria must be fulfilled, and it has to be guaranteed RNA purity, stability, and bioactivity. So, in this review, the different types of ncRNAs are identified and characterized, by describing their biogenesis, functions, and applications. A perspective on the main challenges and innovative approaches for the future and broad therapeutic application of RNA is also presented.
- The Pros and Cons of Estrogens in Prostate Cancer: An Update with a Focus on PhytoestrogensPublication . Figueira, Marília I; Carvalho, Tiago; Monteiro, Joana; Cardoso, Henrique J.; Correia, Sara; Vaz, CV; Duarte, Ana Paula; Socorro, SílviaThe role of estrogens in prostate cancer (PCa) is shrouded in mystery, with its actions going from angelic to devilish. The findings by Huggins and Hodges establishing PCa as a hormone-sensitive cancer have provided the basis for using estrogens in therapy. However, despite the clinical efficacy in suppressing tumor growth and the panoply of experimental evidence describing its anticarcinogenic effects, estrogens were abolished from PCa treatment because of the adverse secondary effects. Notwithstanding, research work over the years has continued investigating the effects of estrogens, reporting their pros and cons in prostate carcinogenesis. In contrast with the beneficial therapeutic effects, many reports have implicated estrogens in the disruption of prostate cell fate and tissue homeostasis. On the other hand, epidemiological data demonstrating the lower incidence of PCa in Eastern countries associated with a higher consumption of phytoestrogens support the beneficial role of estrogens in counteracting cancer development. Many studies have investigated the effects of phytoestrogens and the underlying mechanisms of action, which may contribute to developing safe estrogen-based anti-PCa therapies. This review compiles the existing data on the anti- and protumorigenic actions of estrogens and summarizes the anticancer effects of several phytoestrogens, highlighting their promising features in PCa treatment.
- Effect of Diosgenin in Suppressing Viability and Promoting Apoptosis of Human Prostate Cancer Cells: An Interplay with the G Protein-Coupled Oestrogen Receptor?Publication . Figueira, Marília I; Marques, Ricardo; Cardoso, Henrique J.; Fonseca, Lara R. S.; Duarte, Ana Paula; Silvestre, Samuel; Socorro, SílviaDiosgenin is a phytosteroid sapogenin with reported antitumoral activity. Despite the evidence indicating a lower incidence of prostate cancer (PCa) associated with a higher consumption of phytosteroids and the beneficial role of these compounds, only a few studies have investigated the effects of diosgenin in PCa, and its mechanisms of action remain to be disclosed. The present study investigated the effect of diosgenin in modulating PCa cell fate and glycolytic metabolism and explored its potential interplay with G protein-coupled oestrogen receptor (GPER). Non-neoplastic (PNT1A) and neoplastic (LNCaP, DU145, and PC3) human prostate cell lines were stimulated with diosgenin in the presence or absence of the GPER agonist G1 and upon GPER knockdown. Diosgenin decreased the cell viability, as indicated by the MTT assay results, which also demonstrated that castrate-resistant PCa cells were the most sensitive to treatment (PC3 > DU145 > LNCaP > PNT1A; IC50 values of 14.02, 23.21, 56.12, and 66.10 µM, respectively). Apoptosis was enhanced in diosgenin-treated cells, based on the increased caspase-3-like activity, underpinned by the altered expression of apoptosis regulators evaluated by Western blot analysis, which indicated the activation of the extrinsic pathway. Exposure to diosgenin also altered glucose metabolism. Overall, the effects of diosgenin were potentiated in the presence of G1. Moreover, diosgenin treatment augmented GPER expression, and the knockdown of the GPER gene suppressed the proapoptotic effects of diosgenin in PC3 cells. Our results support the antitumorigenic role of diosgenin and its interest in PCa therapy, alone or in combination with G1, mainly targeting the more aggressive stages of the disease.