Glutathione-sensitive nanoplatform for monitored intracellular delivery and controlled release of Camptothecin

[EN] We report the design, synthesis, characterization and in vitro testing of a novel nanodrug based on a covalent linking model that allows intracellular controlled release of the pharmaceutical payload. A new synthetic strategy is implemented by direct coupling of as-synthesized (pyridin-2-yldisulfanyl)alkyl carbonate derivatives of camptothecin (CPT) with thiol groups of silica hybrid nanoparticles containing a non-porous core and a mesoporous shell. Upon reaction with thiols in physiological conditions, disulfide bridge cleavage occurs, releasing the naked drug after an intramolecular cyclization mechanism. Additional incorporation of a fluorophore into particles core facilitates imaging at the subcellular level for the monitoring of uptake and delivery. Confocal microscopy experiments in HeLa cervix cancer cells confirms that nanoparticles enter the cells by endocytosis but are able to escape from endo-lysosomes and enter the cytosolic compartment to release their cargo. The incorporation to cells of L-buthionine-sulfoximine, a glutathione inhibitor allows concluding that the intracellular releasing mechanism is mainly driven by the reducing activity of this tripeptide. This camptothecin nanoplatform shows the same cytotoxic activity than the free drug and is clearly superior to those release systems depending on enzymatic hydrolysis (as determined by calculation of the IC50 ratios).This work was financially supported by "Comision Interministerial de Ciencia y Tecnologia" of Spain (projects CSD2009-00050 and MAT2012-39290-C02-02), and grants from CIBER-BBN (NanoMets Intramural Grant) "Fondo de Investigaciones Sanitarias - Instituto de Salud Carlos III" (PI080771) y "Universidad Catolica de Valencia San Vicente Martir" (PI2011-011-010). CM thanks the Spanish "Ministerio de Economia y Competitividad" for a FPU Ph.D. studentship (AP2008-02851). SSA thanks the "Universidad Catolica de Valencia San Vicente Martir" for a Ph.D. studentship.Muniesa Lajara, C.; Vicente Vilas, V.; Quesada Vilar, M.; Saez-Atienzar, S.; Blesa-Blesa, JR.; Abasolo, I.; Fernández, Y.... (2013). Glutathione-sensitive nanoplatform for monitored intracellular delivery and controlled release of Camptothecin. RSC Advances. 3(35):15121-15131. https://doi.org/10.1039/c3ra41404cS151211513133

Strategies for Continued Successful Treatment in Patients with Alzheimer's Disease : An Overview of Switching Between Pharmacological Agents

Altres ajuts: This review article is sponsored by Novartis Pharma K.K., Tokyo, Japan. The publication processing fees were funded by Novartis Pharma K.K., Tokyo, Japan.Alzheimer's disease (AD) is the most common cause of dementia, characterized by a progressive decline in cognition and function. Current treatment options for AD include the cholines-terase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine, as well as the N-methyl-D-aspartate receptor antagonist memantine. Treatment guidelines recommend the use of ChEIs as the standard of care first-line therapy. Several randomized clinical studies have demonstrated the benefits of ChEIs on cogni-tion, global function, behavior and activities of daily living. However, patients may fail to achieve sus-tained clinical benefits from ChEIs due to lack/loss of efficacy and/or safety, tolerability issues, and poor adherence to the treatment. The purpose of this review is to explore the strategies for continued successful treatment in patients with AD. Literature search was performed for articles published in PubMed and MEDLINE, using pre-specified search terms. Articles were critically evaluated for inclusion based on their titles, abstracts, and full text of the publication. The findings of this review indicate that dose up-titration and switching between ChEIs may help to improve response to ChEI treatment and also address issues such as lack/loss of effica-cy or safety/tolerability in patients with AD. However, well-designed studies are needed to provide robust evidence

Chronic intestinal pseudoobstruction and ophthalmoplegia in a patient with mitochondrial myopathy

A 38 year old woman having chronic intestinal pseudoobstruction associated with mitochondrial myopathy is reported. The clinical and radiographic features suggested the diagnosis of chronic intestinal pseudoobstruction. Muscular atrophy and ophthalmoplegia led to muscle biopsy, which disclosed accumulation of normal and abnormal mitochondria ('ragged red fibres'), characteristic of mitochondrial myopathy

Feasibility of lumbar puncture in the study of cerebrospinal fluid biomarkers for Alzheimer disease in subjects with Down syndrome

Background: Alzheimer's disease (AD) is the main medical problem in older adults with Down syndrome (DS). Studies of cerebrospinal fluid (CSF) AD biomarkers are limited and the feasibility of lumbar puncture (LP) is controversial in this population. Objective: to analyze the frequency of complications after a LP in DS. Methods: we collected data from 80 adults with DS that underwent a LP within the Down Alzheimer Barcelona Neuroimaging Initiative. Demographics, cognitive status, headache history, and presence of complications after the LP were recorded in every subject. In 53 of them (active group), this information was collected following a semi-structured and validated protocol that actively looks for complications. Other variables related to the LP procedure were also recorded. A telephone interview to the caregiver was performed 5-7 days after the procedure to ask about complications. Data from 27 subjects (clinical practice group), from whom the presence of complications was obtained in a medical follow-up visit within the three months after the LP, were also included. Results: there were no adverse events in 90% of our participants. The most frequent complication was headache (6.25%); only one subject reported a typical post-lumbar puncture headache with moderate severity that required analgesic treatment. Dizziness (3.75%) and back pain (1.25%) were also reported. All the participants that reported complications belonged to the active group. Conclusion: LP can be safely performed to study CSF biomarkers in DS. The reported complications are qualitatively similar to the general population, but are less frequently reported, even when actively searched for

Different Impacts of Cardiovascular Risk Factors on Oxidative Stress

The objective of the study was to evaluate oxidative stress (OS) status in subjects with different cardiovascular risk factors. With this in mind, we have studied three models of high cardiovascular risk: hypertension (HT) with and without metabolic syndrome, familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) with and without insulin resistance. Oxidative stress markers (oxidized/reduced glutathione ratio, 8-oxo-deoxyguanosine and malondialdehide) together with the activity of antioxidant enzyme triad (superoxide dismutase, catalase, glutathione peroxidase) and activation of both pro-oxidant enzyme (NAPDH oxidase components) and AGTR1 genes, as well as antioxidant enzyme genes (CuZn-SOD, CAT, GPX1, GSR, GSS and TXN) were measured in mononuclear cells of controls (n = 20) and patients (n = 90) by assessing mRNA levels. Activity of some of these antioxidant enzymes was also tested. An increase in OS and pro-oxidant gene mRNA values was observed in patients compared to controls. The hypertensive group showed not only the highest OS values, but also the highest pro-oxidant activation compared to those observed in the other groups. In addition, in HT a significantly reduced antioxidant activity and mRNA induction of antioxidant genes were found when compared to controls and the other groups. In FH and FCH, the activation of pro-oxidant enzymes was also higher and antioxidant ones lower than in the control group, although it did not reach the values obtained in hypertensives. The thioredoxin system was more activated in patients as compared to controls, and the highest levels were in hypertensives. The increased oxidative status in the presence of cardiovascular risk factors is a consequence of both the activation of pro-oxidant mechanisms and the reduction of the antioxidant ones. The altered response of the main cytoplasmic antioxidant systems largely contributes to OS despite the apparent attempt of the thioredoxin system to control it

Nerve growth factor (NGF) pathway biomarkers in Down syndrome prior to and after the onset of clinical Alzheimer's disease : A paired CSF and plasma study

Altres ajuts: This work was also supported by the National Institutes of Health (R21AG056974 and R01AG061566 to JF); Departament de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca i Innovació en Salut (SLT002/16/00408 to AL); Fundació La Marató de TV3 (20141210 to JF, 044412 to RB). Fundació Catalana Síndrome de Down and Fundació Víctor Grífols i Lucas partially supported this work. This work was also supported by Generalitat de Catalunya (SLT006/17/00119 to JF) and a grant from the Fundació Bancaria La Caixa to RB.The discovery that nerve growth factor (NGF) metabolism is altered in Down syndrome (DS) and Alzheimer's disease (AD) brains offered a framework for the identification of novel biomarkers signalling NGF deregulation in AD pathology. We examined levels of NGF pathway proteins (proNGF, neuroserpin, tissue plasminogen activator [tPA], and metalloproteases [MMP]) in matched cerebrospinal fluid (CSF)/plasma samples from AD-symptomatic (DSAD) and AD-asymptomatic (aDS) individuals with DS, as well as controls (HC). ProNGF and MMP-3 were elevated while tPA was decreased in plasma from individuals with DS. CSF from individuals with DS showed elevated proNGF, neuroserpin, MMP-3, and MMP-9. ProNGF and MMP-9 in CSF differentiated DSAD from aDS (area under the curve = 0.86, 0.87). NGF pathway markers associated with CSF amyloid beta and tau and differed by sex. Brain NGF metabolism changes can be monitored in plasma and CSF, supporting relevance in AD pathology. These markers could assist staging, subtyping, or precision medicine for AD in DS

Control biológico en árboles ornamentales y cítricos

[ES] En este documento se detallan algunas de las plagas más importantes presentes en árboles ornamentales y en el cultivo de los cítricos en diferentes localidades de España. Las especies que se analizan son pulgones, psila, trips y pseudocóccidos en Ficus nitida, pulgones en Jacaranda mimosifolia y piojo rojo de California en Citrus sinensis. Se han detallado también los principales enemigos naturales encontrados en estas plagas, tanto parasitoides como depredadores, tratando de establecer con detalle las cadenas tróficas que se establecen entre la planta y los insectos.Laborda Cenjor, R.; Rodrigo Santamalia, ME.; Xamani Monserrat, P.; Galan Blesa, J.; Sanchez Domingo, A. (2013). Control biológico en árboles ornamentales y cítricos. Rafael Laborda Cenjor. http://hdl.handle.net/10251/54936

Challenges associated with biomarker-based classification systems for Alzheimer's disease

Altres ajuts: This work was also supported by research grants from the Carlos III Institute of Health, Spain and the CIBERNED program (Program 1, Alzheimer Disease to Alberto Lleó and SIGNAL study, www.signalstudy.es), partly funded by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, "Una manera de hacer Europa". This work has also been supported by a "Marató TV3" grant (20141210 to Juan Fortea and 044412 to Rafael Blesa) and by Generalitat de Catalunya and a grant from the Fundació Bancaria La Caixa to Rafael Blesa. I. Illán-Gala is supported by the i-PFIS grant from the FIS, Instituto de Salud Carlos III and the Rio Hortega grant (CM17/00074) from "Acción estratégica en Salud 2013-2016" and the European Social Fund. USPHS NIH grants awarded to M.J.d.L. include: AG13616, AG022374, AG12101, and AG057570.We aimed to evaluate the consistency of the A/T/N classification system. We included healthy controls, mild cognitive impairment, and dementia patients from Alzheimer's disease Neuroimaging Initiative. We assessed subject classification consistency with different biomarker combinations and the agreement and correlation between biomarkers. Subject classification discordance ranged from 12.2% to 44.5% in the whole sample; 17.3%-46.4% in healthy controls; 11.9%-46.5% in mild cognitive impairment, and 1%-35.7% in dementia patients. Amyloid, but not neurodegeneration biomarkers, showed good agreement both in the whole sample and in the clinical subgroups. Amyloid biomarkers were correlated in the whole sample, but not along the Alzheimer's disease continuum (as defined by a positive amyloid positron emission tomography). Neurodegeneration biomarkers were poorly correlated both in the whole sample and along the Alzheimer's disease continuum. The relationship between biomarkers was stage-dependent. Our findings suggest that the current A/T/N classification system does not achieve the required consistency to be used in the clinical setting

Monoaminergic impairment in Down syndrome with Alzheimer's disease compared to early-onset Alzheimer's disease

Introduction: People with Down syndrome (DS) are at high risk for Alzheimer's disease (AD). Defects in monoamine neurotransmitter systems are implicated in DS and AD but have not been comprehensively studied in DS. Methods: Noradrenaline, adrenaline, and their metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid; and serotonin and its metabolite 5-hydroxyindoleacetic acid were quantified in 15 brain regions of DS without AD (DS, n = 4), DS with AD (DS+AD, n = 17), early-onset AD (EOAD, n = 11) patients, and healthy non-DS controls (n = 10) in the general population. Moreover, monoaminergic concentrations were determined in cerebrospinal fluid (CSF)/plasma samples of DS (n = 37/149), DS with prodromal AD (DS+pAD, n = 13/36), and DS+AD (n = 18/40). Results: In brain, noradrenergic and serotonergic compounds were overall reduced in DS+AD versus EOAD, while the dopaminergic system showed a bidirectional change. For DS versus non-DS controls, significantly decreased MHPG levels were noted in various brain regions, though to a lesser extent than for DS+AD versus EOAD. Apart from DOPAC, CSF/plasma concentrations were not altered between groups. Discussion: Monoamine neurotransmitters and metabolites were evidently impacted in DS, DS+AD, and EOAD. DS and DS+AD presented a remarkably similar monoaminergic profile, possibly related to early deposition of amyloid pathology in DS. To confirm whether monoaminergic alterations are indeed due to early amyloid β accumulation, future avenues include positron emission tomography studies of monoaminergic neurotransmission in relation to amyloid deposition, as well as relating monoaminergic concentrations to CSF/plasma levels of amyloid β and tau within individuals

Cerebral changes and disrupted gray-matter cortical networks in asymptomatic older adults at risk for Alzheimer's disease

The diagnostic value of cerebrospinal fluid (CSF) biomarkers is well established in Alzheimer's disease, but our current knowledge about how abnormal CSF levels affect cerebral integrity, at local and network levels, is incomplete in asymptomatic older adults. Here, we have collected CSF samples and performed structural magnetic resonance imaging scans in cognitively normal elderly as part of a cross-sectional multicenter study (SIGNAL project). To identify group differences in cortical thickness, white matter volume, and properties of structural networks, participants were split into controls (N = 20), positive amyloid-? (A?1?42 +) (N = 19), and positive phosphorylated tau (N = 18). The A?1?42 + group exhibited thickening of middle temporal regions, while positive phosphorylated tau individuals showed thinning in the superior parietal and orbitofrontal cortices. Subjects with abnormal CSF biomarkers further showed regional white matter atrophy and more segregated cortical networks, the A?1?42 + group showing heightened isolation of cingulate and temporal cortices. Collectively, these findings highlight the relevance of combining structural brain imaging and connectomics for in vivo tracking of Alzheimer's disease lesions in asymptomatic stages.This work was supported by research grants from the Spanish Ministry of Economy and Competitiveness (SAF2011-25463 to J.L.C., PSI2014-55747-R to M.A.), the Carlos III Institute of Health, Spain (PI11/02425 and PI14/01126 to J.F.; PI11/3035 and PI14/1561 to A.L.; PI08/0139, PI12/02288 and PI16/01652 to P.S.J.), jointly funded by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, “Una manera de hacer Europa”, the Joint Programming in Neurodegenerative Disease Research (DEMTEST to P.S.J.), “Marató TV3” (project 20141210 to J.F. and 20142610 to A.L.), the Regional Ministry of Innovation, Science and Enterprise, Junta de Andalucia (P12- CTS-2327 to J.C.L.), and the CIBERNED program (Signal project)