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Cancela, M. Leonor

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  • Intranasal drug delivery for treatment of Alzheimer's disease
    Publication . Fonseca, Leonor Cancela; Lopes, Joao; Vieira, Joao; Viegas, Claudia; Oliveira, Claudia S.; Hartmann, Rafael P.; Fonte, Pedro
    The Alzheimer's disease is a neurodegenerative condition with severe consequences interfering with patient quality of life. It is characterized as a progressive and irreversible brain disorder hampering memory and thinking, affecting the capacity to perform daily tasks leading to physical and cognitive incapacitation. The conventional treatment occurs by the oral route, but it presents relevant drawbacks such as low bioavailability, fast metabolism, limited brain exposure, and undesirable side effects. The intranasal route has been proposed as a promising alternative to deliver drugs and improve the Alzheimer's disease treatment. Still, there is not a clear alternative delivery system available in the market with advantageous bioavailability and safety. The aim of this review is to perform an overview on the strategies for drug intranasal delivery for Alzheimer's disease treatment. The advantages and disadvantages of this delivery route and the delivery systems developed so far are discussed. A special focus is given on the use of permeation enhancers, the types of intranasal drug delivery devices, as well as possible toxicity concerns.
  • Central role of betaine-homocysteine S-methyltransferase 3 in chondral ossification and evidence for sub-functionalization in neoteleost fish
    Publication . Rosa, Joana; Tiago, Daniel; Marques, Cátia L.; Vijayakumar, Parameswaran; Fonseca, Luís; Cancela, Leonor; Laizé, Vincent
    Background: To better understand the complex mechanisms of bone formation it is fundamental that genes central to signaling/regulatory pathways and matrix formation are identified. Cell systems were used to analyze genes differentially expressed during extracellular matrix mineralization and bhmt3, coding for a betaine-homocysteine S-methyltransferase, was shown to be down-regulated in mineralizing gilthead seabream cells.Methods: Levels and sites of bhmt3 expression were determined by qPCR and in situ hybridization throughout seabream development and in adult tissues. Transcriptional regulation of bhmt3 was assessed from the activity of promoter constructs controlling luciferase gene expression. Molecular phylogeny of vertebrate BHMT was determined from maximum likelihood analysis of available sequences.Results: bhmt3 transcript is abundant in calcified tissues and localized in cartilaginous structures undergoing endo/perichondral ossification. Promoter activity is regulated by transcription factors involved in bone and cartilage development, further demonstrating the central role of Bhmt3 in chondrogenesis and/or osteogenesis. Molecular phylogeny revealed the explosive diversity of bhmt genes in neoteleost fish, while tissue distribution of bhmt genes in seabream suggested that neoteleostean Bhmt may have undergone several steps of sub-functionalization.Conclusions: Data on bhmt3 gene expression and promoter activity evidences a novel function for betaine-homocysteine S-methyltransferase in bone and cartilage development, while phylogenetic analysis provides new insights into the evolution of vertebrate BHMTs and suggests that multiple gene duplication events occurred in neoteleost fish lineage.General significance: High and specific expression of Bhmt3 in gilthead seabream calcified tissues suggests that bone-specific betaine-homocysteine S-methyltransferases could represent a suitable marker of chondral ossification.
  • Comparative analysis of gene expression profiles among distantly related fish species. Insight into skeletal and immunological systems
    Publication . Mariani, Valentina; Viegas, C. A.; Gavaia, Paulo J.; Cancela, Leonor; Giuffra, Elisabetta
    The aim of this project is to identify and characterize the polymorphism of genes relevant for the physiology of skeletal and immunological tissues, and highly conserved across fish species. To achieve this goal, the expression profiles of an ancient species relevant for caviar and fillet production(A. transmontanus) are compared to available and in progress information (Marine Genomics network of Excellence, UE) of modern Teleosts.
  • A revision of the status of Lepadogaster lepadogaster (Teleostei : Gobiesocidae): sympatric subspecies or a long misunderstood blend of species?
    Publication . Henriques, M.; Lourenço, R.; Almada, F.; Calado, G.; Gonçalves, D.; Guillemaud, Thomas; Cancela, M. Leonor; Almada, V. C.
    Molecular (partial mitochondrial 12S ribosomal DNA sequences), morphological and meristic analysis of Lepadogaster lepadogaster lepadogaster, L. l. purpurea and L. zebrina were performed to investigate the relationships between these taxa. On the western shore of mainland Portugal, where the two subspecies of L. lepadogaster occur sympatrically, they differ in microhabitat preferences and their breeding seasons are largely out of phase. This information, combined with data on distribution patterns, led to the following conclusions: Lepadogaster l. purpurea is considered to be a valid species, L. purpurea (Bonnaterre, 1788), different from L. l. lepadogaster, now designated L. lepadogaster (Bonnaterre, 1788). L. zebrina was found to be a synonym of L. lepadogaster. The two newly defined species were found to be in sympatry at Madeira and the Canary islands, the Atlantic coast of the Iberian Peninsula, and the Mediterranean at least as far as Genoa (Italy). Diagnostic characters and a list of synonyms are provided. (C) 2002 The Linnean Society of London, Biological Journal of the Linnean Society, 2002, 76, 327-338.
  • Osteological development and abnormalities of the vertebral column and caudal skeleton in larval and juvenile stages of hatchery reared solea senegalensis (kaup)
    Publication . Gavaia, Paulo J.; Dinis, Maria Teresa; Cancela, Leonor
    The Senegal sole is a species recently adapted to aquaculture for which little information on larval development is available. This study was designed to describe normal skeletal development and the occurrence of skeletal malformations in Senegal sole reared in captivity. Eggs were collected from natural spawning, incubated until hatching and larvae reared to the juvenile stage in a closed recirculating system. Samples were collected throughout development at regular intervals from hatching to fully formed juveniles. Specimens were stained with alcian blue and alizarin red and observed for skeletal development and detection of anomalies. A high number of malformations were detected, both in the caudal complex and the vertebral column. About 44% of the individuals observed showed at least one malformation and the highest occurrence of deformities was observed in the caudal region and in the vertebral column. Accordingly, 28% of the total deformities identified in this study were detected at those sites and in adjacent arches and spines. The causes were not identified in this study, but the high incidence of malformations may reflect culture problems due to rearing and/or feeding conditions that affect skeletal development.
  • Detection and localization of osteocalcin (BGP or Bone Gla Protein) in teleosts by in situ hybridization and immunohistochemistry
    Publication . Gavaia, Paulo J.; Viegas, C. A.; Pinto, Jorge; Sarasquete, C.; Cancela, Leonor
    Although the presence of osteocalcin (BGP) has been known for a number years, little knowledge on the regulation of expression and tissue localization of this protein in lower vertebrate organisms. In this site we have investigated the site of BGP mRNA expression by in situ hybridization using radiolabeled riboprobes and the tissue localization of the mature protein by immunohistochemistry in the Senegal sole (Solea senegalensis), zebrafish (Danio rerio), and gilthead sea bream (Sparus aurata) using fish BGP polyclonal antibodies.
  • Endogenous calcification inhibitors in the prevention of vascular calcification: a consensus statement from the COST action EuroSoftCalcNet
    Publication . Bäck, Magnus; Aranyi, Tamas; Cancela, M. Leonor; Carracedo, Miguel; Conceição, Natércia; Leftheriotis, Georges; Macrae, Vicky; Martin, Ludovic; Nitschke, Yvonne; Pasch, Andreas; Quaglino, Daniela; Rutsch, Frank; Shanahan, Catherine; Sorribas, Victor; Szeri, Flora; Valdivielso, Pedro; Vanakker, Olivier; Kempf, Hervé
    The physicochemical deposition of calcium-phosphate in the arterial wall is prevented by calcification inhibitors. Studies in cohorts of patients with rare genetic diseases have shed light on the consequences of loss-of-function mutations for different calcification inhibitors, and genetic targeting of these pathways in mice have generated a clearer picture on the mechanisms involved. For example, generalized arterial calcification of infancy (GACI) is caused by mutations in the enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (eNPP1), preventing the hydrolysis of ATP into pyrophosphate (PPi). The importance of PPi for inhibiting arterial calcification has been reinforced by the protective effects of PPi in various mouse models displaying ectopic calcifications. Besides PPi, Matrix Gla Protein (MGP) has been shown to be another potent calcification inhibitor as Keutel patients carrying a mutation in the encoding gene or Mgp-deficient mice develop spontaneous calcification of the arterial media. Whereas PPi and MGP represent locally produced calcification inhibitors, also systemic factors contribute to protection against arterial calcification. One such example is Fetuin-A, which is mainly produced in the liver and which forms calciprotein particles (CPPs), inhibiting growth of calcium-phosphate crystals in the blood and thereby preventing their soft tissue deposition. Other calcification inhibitors with potential importance for arterial calcification include osteoprotegerin, osteopontin, and klotho. The aim of the present review is to outline the latest insights into how different calcification inhibitors prevent arterial calcification both under physiological conditions and in the case of disturbed calcium-phosphate balance, and to provide a consensus statement on their potential therapeutic role for arterial calcification.
  • Expression of osteonectin correlates with levels of fin regeneration in zebrafish (Danio rerio
    Publication . Brito, A. B.; Cancela, Leonor; Gavaia, Paulo J.
    Mammals have the ability to regenerate some tissues such as blood and liver, but the majority of organs fail to regenerate. In contrast, zebrafish is capable of regenerating complex organs/tissues such as optic nerve, scales, heart and fins, and is presently one of the most used metazoan in regeneration research. Zebrafish fin is composed of multiple fin rays with bony parts (lepidotrichia) originated by intramembraneous ossification. Fin regeneration is an epimorphic process dependent on formation of a specialized structure (blastema), consisting of mesenchymal-like cells located between stump tissues and the wounded epidermis,
  • Transcriptional profiling of populations in the clam Ruditapes decussatus suggests genetically determined differentiation in gene expression along parallel temperature gradients and between races of the Atlantic ocean and west Mediterranean sea
    Publication . Saavedra, Carlos; Milan, Massimo; M. Leite, Ricardo; Cordero, David; Patarnello, Tomaso; Cancela, M. Leonor; Bargelloni, Luca
    Ongoing ocean warming due to climate change poses new challenges for marine life and its exploitation. We have used transcriptomics to find genetically based responses to increased temperature in natural populations of the marine clam Ruditapes decussatus, which lives along parallel thermal gradients in southern Europe. Clams of the Atlantic and West Mediterranean races were collected in northern (cool) and a southern (warm) localities. The animals were kept in running seawater in the warm, southern Atlantic locality for a 15-week period. During this period, water temperature was raised to typical southern European summer values. After this period, an expression profile was obtained for a total of 34 clams and 11,025 probes by means of an oligonucleotide microarray. We found distinct transcriptional patterns for each population based on a total of 552 differentially expressed genes (DEGs), indicating innate differences which probably have a genetic basis. Race and latitude contributed significantly to gene expression differences, with very different sets of DEGs. A gene ontology analysis showed that races differed mainly in the genes involved in ribosomal function and protein biosynthesis, while genes related to glutathione metabolism and ATP synthesis in the mitochondria were the most outstanding with respect to north/south transcriptional differences.
  • Phox2b function in the enteric nervous system is conserved in zebrafish and is sox10-dependent
    Publication . Elworthy, S.; P Pinto, Jorge; Pettifer, A.; Leonor Cancela, M.; Kelsh, R. N.
    Zebrafish lacking functional sox10 have defects in non-ectomesenchymal neural crest derivatives including the enteric nervous system (ENS) and as such provide an animal model for human Waardenburg Syndrome IV. Here, we characterize zebrafish phox2b as a functionally conserved marker of the developing ENS. We show that morpholino-mediated knockdown of Phox2b generates fish modeling Hirschsprung disease. Using markers, including phox2b, we investigate the ontogeny of the sox10 ENS phenotype. As previously shown for melanophore development, ENS progenitor fate specification fails in these mutant fish. However, in addition, we trace back the sox10 mutant ENS defect to an even earlier time point, finding that most neural crest cells fail to migrate ventrally to the gut primordium. (c) 2005 Elsevier Ireland Ltd. All rights reserved.