Influência da farmacogenòmica na terapêutica antidislipidémica

Dissertação de mest., Ciências Farmacêuticas, Faculdade de Ciências e Tecnologia, Univ. do Algarve, 2010As doenças cardiovasculares apresentam-se como uma das principais causas de óbito na maioria das sociedades modernas actuais. Factores como a idade, antecedentes familiares, sedentarismo, dietas ricas em gorduras e sal, hipertensão arterial, tabagismo, excesso de bebidas alcoólicas e as dislipidémias aumentam o risco de desenvolver este tipo de doenças. As dislipidémias são distúrbios metabólicos associados a alterações dos níveis de lipoproteínas no sangue e pertencem ao grupo de factores que, através da adopção de estilos de vida saudáveis ou, se necessário, de terapêutica farmacológica, são possíveis de manter dentro dos valores considerados ideais. No entanto, quando se recorre à terapêutica farmacológica, os resultados têm demonstrado que a resposta à terapêutica está sujeita a uma grande variabilidade interindividual. Esta pode estar relacionada com factores como a idade, o sexo, doenças concomitantes e determinantes genéticos. A farmacogenómica tem demonstrado ser fundamental no estudo da terapêutica antidislipidémica, uma vez que permite uma melhor compreensão de como os diferentes polimorfismos, existentes nos genes que codificam enzimas envolvidas no metabolismo, alvos terapêuticos e transportadores dos fármacos antidislipidémicos, entre outros, podem influenciar e dar origem à grande variabilidade interindividual na resposta a esta terapêutica. Deste modo, o conhecimento destes polimorfismos que influenciam as variações interindividuais da terapêutica, permitirá que no futuro se possa individualizar, de acordo com o paciente, os tratamentos administrados e aumentar assim a sua eficácia e segurança

From PEF to PBF: what difference does the longer alkyl chain make a computational spectroscopy study of poly (butylene 2,5-furandicarboxylate)

This work explores the conformational preferences and the structureproperty correlations of poly(butylene 2,5-furandicarboxylate) (PBF), a longer chain analogue of the most well-known biobased polyester from the furan family, poly(ethylene 2,5-furandicarboxylate) (PEF). A thorough computational spectroscopic study–including infrared, Raman and inelastic neutron scattering spectroscopy, combined with discrete and periodic density functional theory calculations–allowed the identification of dominant structural motifs in the amorphous and crystalline regions. Discrete calculations and vibrational spectroscopy of semi-crystalline and amorphous samples strongly support the predominance of gauche, trans, gauche conformations of the butylene glycol fragment in both the crystalline and amorphous domains. In what concerns the furandicarboxylate fragment, amorphous domains are dominated by syn,syn conformations, while in the crystalline domains the anti,anti forms prevail. A possible crystalline structure–built from these conformational preferences and including a network of C-H···O hydrogen bond contacts—was optimized using periodic density functional theory. This proposed crystal structure avoids the unrealistic structural features of the previously proposed X-ray structure, provides an excellent description of the inelastic neutron scattering spectrum of the semi-crystalline form, and allows the correlation between microscopic structure and macroscopic properties of the polymer.publishe

The impact of IL-10 dynamic modulation on host immune response against visceral leishmaniasis

Leishmaniasis is a vector-borne disease caused by protozoan parasites from the genus Leishmania. The most severe form of disease is visceral leishmaniasis (VL), which is fatal if left untreated. It has been demonstrated that interleukin (IL)-10, is associated with disease progression and susceptibility. In this work, we took advantage of a transgenic mouse model that expresses high levels of IL-10 upon zinc sulfate administration (pMT-10). We addressed the role of IL-10 during the initial stages of L. donovani infection by analyzing the parasite burden in the spleen and liver of the infected pMT-10 and WT mice as well as the histopathological alterations upon IL-10 induction. Furthermore, the profile of cytokines expressed by T cells was assessed. Our results demonstrate that an increase in IL-10 production has an impact early but not later after infection. This specific temporal role for IL-10-mediated susceptibility to VL is of interest.Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013) and the Fundação para a Ciência e Tecnologia (FCT) (contracts SFRH/BD/120127/2016 to IM, PD/BDE/127830/2016 to CF, SFRH/BD/120371/2016 to AMB, IF/01147/2013 to RDO, IF/01390/2014 to ET, IF/00735/2014 to AC, SFRH/BPD/96176/2013 to CC and IF/00021/2014 to RS), and Infect-Era (project INLEISH). JE also thanks the Canada Research Chair program for financial assistanceinfo:eu-repo/semantics/publishedVersio

IL-10 Overexpression After BCG Vaccination Does Not Impair Control of Mycobacterium tuberculosis Infection

Control of tuberculosis depends on the rapid expression of protective CD4+ T-cell responses in the Mycobacterium tuberculosis (Mtb)-infected lungs. We have recently shown that the immunomodulatory cytokine IL-10 acts intrinsically in CD4+ T cells and impairs their parenchymal migratory capacity, thereby preventing control of Mtb infection. Herein, we show that IL-10 overexpression does not impact the protection conferred by the established memory CD4+ T-cell response, as BCG-vaccinated mice overexpressing IL-10 only during Mtb infection display an accelerated, BCG-induced, Ag85b-specific CD4+ T-cell response and control Mtb infection. However, IL-10 inhibits the migration of recently activated ESAT-6-specific CD4+ T cells into the lung parenchyma and impairs the development of ectopic lymphoid structures associated with reduced expression of the chemokine receptors CXCR5 and CCR7. Together, our data support a role for BCG vaccination in preventing the immunosuppressive effects of IL-10 in the fast progression of Mtb infection and may provide valuable insights on the mechanisms contributing to the variable efficacy of BCG vaccination

Empowerment-based nutrition interventions on blood pressure: a randomized comparative effectiveness trial

IntroductionEmpowerment lifestyle programs are needed to reduce the risk of hypertension. Our study compared the effectiveness of two empowerment-based approaches toward blood pressure (BP) reduction: salt reduction-specific program vs. healthy lifestyle general program.MethodsThree hundred and eleven adults (median age of 44 years, IQR 34–54 years) were randomly assigned to a salt reduction (n = 147) or a healthy lifestyle program (n = 164). The outcome measures were urinary sodium (Na+) and potassium (K+) excretion, systolic (SBP) and diastolic (DBP) blood pressure, weight, and waist circumference.ResultsThere were no significant differences in primary and secondary outcomes between the two program groups. When comparing each program to baseline, the program focused on salt reduction was effective in lowering BP following a 12-week intervention with a mean change of −2.5 mm Hg in SBP (95% CI, −4.1 to −0.8) and − 2.7 mm Hg in DBP (95% CI, −3.8 to −1.5) in the intention-to-treat (ITT) analysis. In the complete-case (CC) analysis, the mean change was −2.1 mm Hg in SBP (95% CI, −3.7 to −0.5) and − 2.3 mm Hg in DBP (95% CI, −3.4 to −1.1). This effect increases in subjects with high-normal BP or hypertension [SBP − 7.9 mm Hg (95% CI, −12.5 to −3.3); DBP − 7.3 mm Hg (95% CI, −10.2 to −4.4)]. The healthy lifestyle group also exhibited BP improvements after 12 weeks; however, the changes were less pronounced compared to the salt reduction group and were observed only for DBP [mean change of −1.5 mm Hg (95% CI, −2.6 to −0.4) in ITT analysis and − 1.4 mm Hg (95% CI, −2.4 to −0.3) in CC analysis, relative to baseline]. Overall, improvements in Na+/K+ ratio, weight, and Mediterranean diet adherence resulted in clinically significant SBP decreases. Importantly, BP reduction is attributed to improved dietary quality, rather than being solely linked to changes in the Na+/K+ ratio.ConclusionSalt-focused programs are effective public health tools mainly in managing individuals at high risk of hypertension. Nevertheless, in general, empowerment-based approaches are important strategies for lowering BP, by promoting health literacy that culminates in adherence to the Mediterranean diet and weight reduction

Phagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity

Acknowledgements This work was supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01- 0145-FEDER-000013), the Fundação para a Ciência e Tecnologia (FCT) (SFRH/BD/136814/2018 to S.M.G., SFRH/BD/141127/2018 to C.D.O., PD/BD/137680/2018 to D.A., IF/00474/2014 to N.S.O., IF/01390/2014 to E.T., IF/00959/2014 to S.C., IF/00021/2014 to R.S., PTDC/SAU-SER/29635/2017 and CEECIND/04601/2017 to C.C., and CEECIND/03628/2017 to A.C.), the Institut Mérieux (Mérieux Research Grant 2017 to C.C.), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID Research Grant 2017 to A.C.). M.G.N. was supported by a Spinoza grant of the Netherlands Organization for Scientific Research. A.A.B. was supported by the Deutsche Forschungsgemeinschaft Collaborative Research Center/Transregio TR124 FungiNet (project A1). G.D.B. was funded by the Wellcome Trust (102705), the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).Peer reviewedPublisher PD

Proceedings - CBiOS Science Sessions - 2012

CBiOS Science Sessions Proceedings - 2012 - Study of the potential applicability of the by-products of the Prunus cerasus in promoting health and skin care; Contribution to a biologic and legal framework of the M. sylvestris in skin repair; Nanotechnology and drug delivery systems; Bacterial cellulose membranes applied in topical and transdermal delivery; New treatment strategies with plant extract teas for Alzheimer´s disease

Bacterial cellulose membranes as transdermal delivery systems for diclofenac: In vitro dissolution and permeation studies

Bacterial cellulose (BC) membranes were explored as novel nanostructured transdermal delivery systems for diclofenac sodium salt (a typical non-steroidal anti-inflammatory drug). Diclofenac sodium salt loaded BC membranes were prepared through a simple methodology, using glycerol as plasticizer, and characterized in terms of structure, morphology and swelling behavior. The membranes were very homogeneous, quite flexible and presented a considerably higher swelling behavior when compared with pure BC. In vitro diffusion studies with Franz cells, were conducted using human epidermal membranes, and showed that the incorporation of diclofenac in BC membranes provided similar permeation rates to those obtained with commercial patches and substantially lower than those observed with a commercial gel. This release profile together with the ease of application and the simple preparation and assembly of the drug-loaded membranes clearly indicates the enormous potentialities of using BC membranes for transdermal administration of diclofenac. (C) 2014 Elsevier Ltd. All rights reserved

Phagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity

In response to infection, macrophages adapt their metabolism rapidly to enhance glycolysis and fuel specialized antimicrobial effector functions. Here we show that fungal melanin is an essential molecule required for the metabolic rewiring of macrophages during infection with the fungal pathogen Aspergillus fumigatus. Using pharmacological and genetic tools, we reveal a molecular link between calcium sequestration by melanin inside the phagosome and induction of glycolysis required for efficient innate immune responses. By remodeling the intracellular calcium machinery and impairing signaling via calmodulin, melanin drives an immunometabolic signaling axis towards glycolysis with activation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) and phagosomal recruitment of mammalian target of rapamycin (mTOR). These data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during fungal infection and highlight the metabolic repurposing of immune cells as a potential therapeutic strategy.status: publishe