Glycogen Synthase Kinase 3 Inhibitors in the Next Horizon for Alzheimer's Disease Treatment

Glycogen synthase kinase 3 (GSK-3), a proline/serine protein kinase ubiquitously expressed and involved in many cellular signaling pathways, plays a key role in the pathogenesis of Alzheimer's disease (AD) being probably the link between β-amyloid and tau pathology. A great effort has recently been done in the discovery and development of different new molecules, of synthetic and natural origin, able to inhibit this enzyme, and several kinetics mechanisms of binding have been described. The small molecule called tideglusib belonging to the thiadiazolidindione family is currently on phase IIb clinical trials for AD. The potential risks and benefits of this new kind of disease modifying drugs for the future therapy of AD are discussed in this paper

Germination ecology of the perennial Centaurium somedanum, a specialist species of mountain springs

To improve understanding of how a rare endemic species of Centaurium adapts to a specialized ecological niche, we studied the germination ecology of the mountain spring specialist, C. somedanum, a perennial species restricted to an unusual habitat for this genus. We conducted laboratory experiments with fresh seeds collected from two populations for three consecutive years, to investigate: (1) the effect of temperature and light ongermination; (2) the existence of seed dormancy; and (3) inter-population and inter-annual variation in germinability. Germination occurred only in the light and at relatively low temperatures (15?228C) with no differences between constant and alternating regimes, and a significant decrease at high temperatures (258C and 308C). We found non-deep simple morphophysiological dormancy and variation in seed germinability depending on the year of seed collection. C. somedanum diverged from the common germination characteristics of the genus in: (1) its germination at lower temperatures, which contrasts with what is generally expected in wetland species but could be adaptive in the spring habitat; and (2) its morphophysiological dormancy, which we report here for the first time in the genus and which could be an adaptation to its mountain habitat

1-(Benzo[d]thiazol-2-yl)-3-phenylureas as dual inhibitors of casein kinase 1 and ABAD enzymes for treatment of neurodegenerative disorders

This work was supported by the Ministry of Health of the Czech Republic [no. NV15-28967 A], Specific Research Project of Faculty of Science, University of Hradec Kralove [no. 2103-2017], National Institute of Mental Health [NIMH CZ; no. ED2.1.00/03.0078] from the European Regional Development Fund, COST CA15135, The Alzheimer’s Society (specifically The Barcopel Foundation), The Rosetrees trust and The Biotechnology and Biological Sciences Research Council (BBSRC) [no. BB/J01446X/1]. Funding from Ministry of Economy and competitiveness, Spain [no. SAF2012-37979-C03-01] is also acknowledged.Several neurodegenerative disorders including Alzheimer’s disease (AD) have been connected with deregulation of casein kinase 1 (CK1) activity. Inhibition of CK1 therefore presents a potential therapeutic strategy against such pathologies. Recently, novel class of CK1-specific inhibitors with N-(benzo[d]thiazol-2-yl)-2-phenylacetamide structural scaffold has been discovered. 1-(benzo[d]thiazol-2-yl)-3-phenylureas, on the other hand, are known inhibitors amyloid-beta binding alcohol dehydrogenase (ABAD), an enzyme also involved in pathophysiology of AD. Based on their tight structural similarity, we decided to evaluate series of previously published benzothiazolylphenylureas, originally designed as ABAD inhibitors, for their inhibitory activity towards CK1. Several compounds were found to be submicromolar CK1 inhibitors. Moreover, two compounds were found to inhibit both, ABAD and CK1. Such dual-activity could be of advantage for AD treatment, as it would simultaneously target two distinct pathological processes involved in disease’s progression. Based on PAMPA testing both compounds were suggested to permeate the blood-brain barrier, which makes them, together with their unique dual activity, interesting lead compounds for further development.Publisher PDFPeer reviewe

Assessing, quantifying and valuing the ecosystem services of coastal lagoons

The natural conservation of coastal lagoons is important not only for their ecological importance, but also because of the valuable ecosystem services they provide for human welfare and wellbeing. Coastal lagoons are shallow semi-enclosed systems that support important habitats such as wetlands, mangroves, salt-marshes and seagrass meadows, as well as a rich biodiversity. Coastal lagoons are also complex social-ecological systems with ecosystem services that provide livelihoods, wellbeing and welfare to humans. This study assessed, quantified and valued the ecosystem services of 32 coastal lagoons. The main findings of the study are: (i) the definitions of ecosystem services are still not generally accepted; (ii) the quantification of ecosystem services is made in many different ways, using different units; (iii) the evaluation in monetary terms of some ecosystem service is problematic, often relying on non-monetary evaluation methods; (iv) when ecosystem services are valued in monetary terms, this may represent very different human benefits; and, (v) different aspects of climate change, including increasing temperature, sea-level rise and changes in rainfall patterns threaten the valuable ecosystem services of coastal lagoons.DEVOTES project, from the European Union's Seventh Framework Programme for research, technological development and demonstration [308392]; networks and communities of Eurolag; Future Earth Coasts; SCOR; Fundacao para a Ciencia e a Tecnologia (FCT) Investigador Programme [IF/00331/2013]; Fundacao para a Ciencia e a Tecnologia [UID/MAR/04292/2013]; CESAM by FCT/MEC national funds (PIDDAC) [UID/AMB/50017/2013 - POCI-01-0145-FEDER-007638]; FEDER; European Commission, under the 7th Framework Programme through the collaborative research project LAGOONS [283157]; FCT [SFRH/BPD/107823/2015, SFRH/BPD/91494/2012

Marfan syndrome with a complex chromosomal rearrangement including deletion of the FBN1 gene

<p>Abstract</p> <p>Background</p> <p>The majority of Marfan syndrome (MFS) cases is caused by mutations in the fibrillin-1 gene (<it>FBN1</it>), mapped to chromosome 15q21.1. Only few reports on deletions including the whole <it>FBN1 </it>gene, detected by molecular cytogenetic techniques, were found in literature.</p> <p>Results</p> <p>We report here on a female patient with clinical symptoms of the MFS spectrum plus craniostenosis, hypothyroidism and intellectual deficiency who presents a 1.9 Mb deletion, including the <it>FBN1 </it>gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12 and 15.</p> <p>Discussion</p> <p>This is the first report of MFS with a complex chromosome rearrangement involving a deletion of <it>FBN1 </it>and contiguous genes. In addition to the typical clinical findings of the Marfan syndrome due to <it>FBN1 </it>gene haploinsufficiency, the patient presents features which may be due to the other gene deletions and possibly to the complex chromosome rearrangement.</p

Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease

Abstract BACKGROUND AND PURPOSE: Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimer's disease and on memory-related behaviour were investigated. EXPERIMENTAL APPROACH: Sildenafil was administered to the Tg2576 transgenic mouse model of Alzheimer's disease and to age-matched negative littermates (controls). Memory function was analysed using the Morris water maze test and fear conditioning tasks. Biochemical analyses were performed in brain lysates from animals treated with saline or with sildenafil. KEY RESULTS: Treatment of aged Tg2576 animals with sildenafil completely reversed their cognitive impairment. Such changes were accompanied in the hippocampus by a reduction of tau hyperphosphorylation and a decrease in the activity of glycogen synthase kinase 3β (GSK3β) and of cyclin-dependent kinase 5 (CDK5) (p25/p35 ratio). Moreover, sildenafil also increased levels of brain-derived neurotrophic factor (BDNF) and the activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus without any detectable modification of brain amyloid burden. CONCLUSIONS AND IMPLICATIONS: Sildenafil improved cognitive functions in Tg2576 mice and the effect was not related to changes in the amyloid burden. These data further strengthen the potential of sildenafil as a therapeutic agent for Alzheimer's disease

Case Report Buttock Necrosis after Uterine Artery Embolization for Delayed Hysterectomy in Placenta Percreta

Background. Morbidly adherent placenta (MAP) is increasing in incidence and is commonly associated with maternal hemorrhage and cesarean hysterectomy. Uterine artery embolization (UAE) may be utilized in the conservative management of placenta percreta to potentially reduce blood loss. The incidence of complications from UAE in the conservative management of placenta percreta is poorly described. To our knowledge, we present the first reported case of buttock necrosis in this setting. Case. A 39-year-old gravida nine para two with placenta percreta who underwent conservative management with UAE complicated by right buttock necrosis. Conclusion. While UAE may potentially decrease blood loss, it is not without risk. More studies must be performed in order to quantify those risks and determine the clinical utility of UAE