Research Institute for Medicines and Pharmaceutical science

Lisbon, Portugal

Research Institute for Medicines and Pharmaceutical science

Lisbon, Portugal

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Colaco R.,University of Lisbon | Goncalves M.C.,University of Lisbon | Goncalves L.M.D.,Research Institute for Medicines and Pharmaceutical science | Almeida A.J.,Research Institute for Medicines and Pharmaceutical science | Martins M.B.,Research Institute for Medicines and Pharmaceutical science
1st Portuguese Meeting in Biomedical Engineering, ENBENG 2011 | Year: 2011

Nanomedicine is an emerging new field combining nanotechnology and medicine. Silica nanoparticles are chemical and biologically inert, optically transparent and can be doped with imaging agents and/or functionalized to promote its conjugation with different therapeutic molecules. Silica nanoparticles can be engineered to improve diagnosis, treatment and follow-up of diseases. A combination of diagnosis devices and therapeutics (theranostics) would be beneficial for patients. In this work, ORMOSIL nanoparticles as non-viral vectors for gene delivery were prepared via a modified Stober sol-gel process directly with 3-aminopropyltriethoxysilane and tetraethylorthosilicate as precursors. Dynamic light scattering, transmission electron microscopy and Fourier transformed infrared spectroscopy were used to characterizing the hybrid nanospheres. Synthesis has been optimized and monodisperse spherical nanoparticles with desired size have been obtained. Nanoparticle-DNA complexes were successfully obtained at different ratios (nanoparticle/pDNA) and confirmed by agarose gel electrophoresis and ethidium bromide exclusion test. © 2011 IEEE.


Ventura F.V.,Research Institute for Medicines and Pharmaceutical science | Ventura F.V.,University of Lisbon | Leandro P.,Research Institute for Medicines and Pharmaceutical science | Leandro P.,University of Lisbon | And 17 more authors.
Clinical Genetics | Year: 2014

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the commonest genetic defect of mitochondrial fatty acid β-oxidation. About 60% of MCADD patients are homozygous for the c.985A>G (p.Lys329Glu) mutation in the ACADM gene (G985 allele). Herein, we present the first report on the molecular and biochemical spectrum of Portuguese MCADD population. From the 109 patients studied, 83 were diagnosed after inclusion of MCADD in the national newborn screening, 8 following the onset of symptoms and 18 through segregation studies. Gypsy ancestry was identified in 85/109 patients. The G985 allele was found in homozygosity in 102/109 patients, in compound heterozygosity in 6/109 and was absent in one patient. Segregation studies in the Gypsy families showed that 93/123 relatives were carriers of the G985 allele, suggesting its high prevalence in this ethnic group. Additionally, three new substitutions-c.218A>G (p.Tyr73Cys), c.503A>T (p.Asp168Val) and c.1205G>T (p.Gly402Val)-were identified. Despite the particularity of the MCADD population investigated, the G985 allele was found in linkage disequilibrium with H1(112) haplotype. Furthermore, two novel haplotypes, H5(212) and H6(122) were revealed. © 2013 John Wiley & Sons A/S.


Houten S.M.,Mount Sinai School of Medicine | Violante S.,Mount Sinai School of Medicine | Ventura F.V.,Research Institute for Medicines and Pharmaceutical science | Ventura F.V.,University of Lisbon | Wanders R.J.A.,University of Amsterdam
Annual Review of Physiology | Year: 2016

Mitochondrial fatty acid β-oxidation (FAO) is the major pathway for the degradation of fatty acids and is essential for maintaining energy homeostasis in the human body. Fatty acids are a crucial energy source in the postabsorptive and fasted states when glucose supply is limiting. But even when glucose is abundantly available, FAO is a main energy source for the heart, skeletal muscle, and kidney. A series of enzymes, transporters, and other facilitating proteins are involved in FAO. Recessively inherited defects are known for most of the genes encoding these proteins. The clinical presentation of these disorders may include hypoketotic hypoglycemia, (cardio)myopathy, arrhythmia, and rhabdomyolysis and illustrates the importance of FAO during fasting and in hepatic and (cardio)muscular function. In this review, we present the current state of knowledge on the biochemistry and physiological functions of FAO and discuss the pathophysiological processes associated with FAO disorders. Copyright © 2016 by Annual Reviews. All rights reserved.


PubMed | Mount Sinai School of Medicine, Research Institute for Medicines and Pharmaceutical science and Metabolic
Type: | Journal: Annual review of physiology | Year: 2016

Mitochondrial fatty acid -oxidation (FAO) is the major pathway for the degradation of fatty acids and is essential for maintaining energy homeostasis in the human body. Fatty acids are a crucial energy source in the postabsorptive and fasted states when glucose supply is limiting. But even when glucose is abundantly available, FAO is a main energy source for the heart, skeletal muscle, and kidney. A series of enzymes, transporters, and other facilitating proteins are involved in FAO. Recessively inherited defects are known for most of the genes encoding these proteins. The clinical presentation of these disorders may include hypoketotic hypoglycemia, (cardio)myopathy, arrhythmia, and rhabdomyolysis and illustrates the importance of FAO during fasting and in hepatic and (cardio)muscular function. In this review, we present the current state of knowledge on the biochemistry and physiological functions of FAO and discuss the pathophysiological processes associated with FAO disorders.


Da Silva D.,CSIC - Institute of Polymer Science and Technology | Da Silva D.,Research Institute for Medicines and Pharmaceutical science | Samadi A.,CSIC - Institute of Polymer Science and Technology | Chioua M.,CSIC - Institute of Polymer Science and Technology | And 2 more authors.
Synthesis | Year: 2010

The Sandmeyer reaction on some selected heterocycles bearing the 2-amino-3-carbonitrile structural moiety has been investigated in order to prepare the corresponding 2-chloro-3-carbonitrile derivatives as synthetic useful intermediates for further development. © Georg Thieme Verlag Stuttgart.


Esteves M.A.,National Institute of Engineering, Technology and Innovation | Fragiadaki I.,University of Crete | Lopes R.,New University of Lisbon | Lopes R.,Research Institute for Medicines and Pharmaceutical science | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

A series of new analogues of trifluralin (TFL) were synthesized and characterized in view of changing the unfavorable properties that limits its use as antileishmanial agent. Some of the TFL analogues display more activity than a standard drug (miltefosine) against the promastigote forms of Leishmania infantum and Leishmania donovani and the intracellular form (THP-1 infected with L. infantum). All analogues showed a clear advantage over miltefosine, as they are not hemolytic. Some analogues can conjugate these characteristics with reduced cell toxicity and improved intracellular activity. © 2009 Elsevier Ltd. All rights reserved.


PubMed | Research Institute for Medicines and Pharmaceutical science
Type: Journal Article | Journal: PloS one | Year: 2012

Human PDHA2 is a testis-specific gene that codes for the E(1) subunit of Pyruvate Dehydrogenase Complex (PDC), a crucial enzyme system in cell energy metabolism. Since activation of the PDHA2 gene in somatic cells could be a new therapeutic approach for PDC deficiency, we aimed to identify the regulatory mechanisms underlying the human PDHA2 gene expression. Functional deletion studies revealed that the -122 to -6 promoter region is indispensable for basal expression of this TATA-less promoter, and suggested a role of an epigenetic program in the control of PDHA2 gene expression. Indeed, treatment of SH-SY5Y cells with the hypomethylating agent 5-Aza-2-deoxycytidine (DAC) promoted the reactivation of the PDHA2 gene, by inducing the recruitment of the RNA polymerase II to the proximal promoter region and the consequent increase in PDHA2 mRNA levels. Bisulfite sequencing analysis revealed that DAC treatment induced a significant demethylation of the CpG island II (nucleotides +197 to +460) in PDHA2 coding region, while the promoter region remained highly methylated. Taken together with our previous results that show an in vivo correlation between PDHA2 expression and the demethylation of the CpG island II in testis germ cells, the present results show that internal methylation of the PDHA2 gene plays a part in its repression in somatic cells. In conclusion, our data support the novel finding that methylation of the PDHA2 coding region can inhibit gene transcription. This represents a key mechanism for absence of PDHA2 expression in somatic cells and a target for PDC therapy.


PubMed | Research Institute for Medicines and Pharmaceutical science
Type: Journal Article | Journal: Biochimica et biophysica acta | Year: 2012

Stem cell therapy is a strategy far from being satisfactory and applied in the clinic. Poor survival and differentiation levels of stem cells after transplantation or neural injury have been major problems. Recently, it has been recognized that cell death-relevant proteins, notably those that operate in the core of the executioner apoptosis machinery are functionally involved in differentiation of a wide range of cell types, including neural cells.This article will review recent studies on the mechanisms underlying the non-apoptotic function of mitochondrial and death receptor signaling pathways during neural differentiation. In addition, we will discuss how these major apoptosis-regulatory pathways control the decision between differentiation, self-renewal and cell death in neural stem cells and how levels of activity are restrained to prevent cell loss as final outcome.Emerging evidence suggests that, much like p53, caspases and Bcl-2 family members, the two prime triggers of cell death pathways, death receptors and mitochondria, may influence proliferation and differentiation potential of stem cells, neuronal plasticity, and astrocytic versus neuronal stem cell fate decision.A better understanding of the molecular mechanisms underlying key checkpoints responsible for neural differentiation as an alternative to cell death will surely contribute to improve neuro-replacement strategies.

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