Peripheral Inflammatory Parameters in Late-Life Depression: A Systematic Review

Depressive disorders appear relatively frequently in older patients, and therefore represent an important disease burden worldwide. Given the high levels of inflammatory parameters found in depressed elderly patients, the "inflammaging" hypothesis is gaining strength. In this systematic review, we summarize current evidence regarding the relationship between inflammatory parameters and late-life depression, with a unique focus on longitudinal studies to guarantee temporality. According to the data summarized in this review, the levels of some proinflammatory parameters-especially interleukin (IL)-8, IL-6, and tumor necrosis factor (TNF)-α-could serve as biomarkers for the future development of depressive symptoms in elderly patients. Proinflammatory cytokines seem to be associated with the future development of clinically significant depression, irrespective of baseline scores, thus indicating that inflammation temporally precedes and increases depression risk. As insufficient research has been conducted in this field, further prospective studies are clearly warranted.This study was funded by grants from Research Network Center of Mental Health-CIBERSAM (2010-P-02); the Government of Spain “Health Research Fund” FEDER (PI08-1213, PI11-01977, PI14-01900, PI08-0873; PI10-01746; PS09/02002; PI12/02077; PI15-00789; PI13/00451); Ministry of Health and Social Equality (20111064) Policy; Local funding from the Department of Education, Language Policy and Culture of the Basque Government (200911147, 2013111162, 2010111170, SAIO10-PC10BF01); European Comission funds (UE/2012/FI-STAR). We appreciate the support of the University of the Basque Country (GIC10/80, GIC12/84) and the Basque Foundation for Health Innovation and Research-BIOEF. The Psychiatry Research Unit of the University Hospital of Álava-Santiago is supported by the “Stanley Research Foundation” (03-RC-003). John O’Brien is supported by the NIHR Cambridge Biomedical Research Centre awarded to the University of Cambridge, Cambridge University Hospitals NHS Trust and Cambridgeshire and Peterborough NHS Trust

MIANN models in medicinal, physical and organic chemistry

[Abstract] Reducing costs in terms of time, animal sacrifice, and material resources with computational methods has become a promising goal in Medicinal, Biological, Physical and Organic Chemistry. There are many computational techniques that can be used in this sense. In any case, almost all these methods focus on few fundamental aspects including: type (1) methods to quantify the molecular structure, type (2) methods to link the structure with the biological activity, and others. In particular, MARCH-INSIDE (MI), acronym for Markov Chain Invariants for Networks Simulation and Design, is a well-known method for QSAR analysis useful in step (1). In addition, the bio-inspired Artificial-Intelligence (AI) algorithms called Artificial Neural Networks (ANNs) are among the most powerful type (2) methods. We can combine MI with ANNs in order to seek QSAR models, a strategy which is called herein MIANN (MI & ANN models). One of the first applications of the MIANN strategy was in the development of new QSAR models for drug discovery. MIANN strategy has been expanded to the QSAR study of proteins, protein-drug interactions, and protein-protein interaction networks. In this paper, we review for the first time many interesting aspects of the MIANN strategy including theoretical basis, implementation in web servers, and examples of applications in Medicinal and Biological chemistry. We also report new applications of the MIANN strategy in Medicinal chemistry and the first examples in Physical and Organic Chemistry, as well. In so doing, we developed new MIANN models for several self-assembly physicochemical properties of surfactants and large reaction networks in organic synthesis. In some of the new examples we also present experimental results which were not published up to date.Ministerio de Ciencia e Innovación; CTQ2009-07733Universidad del Pais Vasco; UFI11/22Universidad del Pais Vasco; GIU 094

Fused 3-Hydroxy-3-trifluoromethylpyrazoles Inhibit Mutant Huntingtin Toxicity

[Image: see text] Here, we describe the selection and optimization of a chemical series active in both a full-length and a fragment-based Huntington’s disease (HD) assay. Twenty-four thousand small molecules were screened in a phenotypic HD assay, identifying a series of compounds bearing a 3-hydroxy-3-trifluoromethylpyrazole moiety as able to revert the toxicity induced by full-length mutant Htt by up to 50%. A chemical exploration around the series led to the identification of compound 4f, which demonstrated to be active in a Htt171–82Q rat primary striatal neuron assay and a PC12-Exon-1 based assay. This compound was selected for testing in R6/2 mice, in which it was well-tolerated and showed a positive effect on body weight and a positive trend in preventing ventricular volume enlargment. These studies provide strong rationale for further testing the potential benefits of 3-hydroxy-3-trifluoromethylpyrazoles in treating HD

IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species

Post-Collision-Interaction Effects in HCl Following Photofragmentation Near the Chlorine K Edge

Ion time-of-flight mass spectroscopy was used to study the relaxation dynamics of HCl following photoexcitation in the vicinity of the Cl K threshold (~2.8 keV). Detailed observations of molecular fragmentation mediated by postcollision interaction between a photoelectron and an Auger electron are presented, evidenced by the recapture of Cl K photoelectrons by either Cln+ or H+ dissociation fragments. [S1050-2947(98)51206-1

Photofragmentation of Third-Row Hydrides Following Photoexcitation at Deep-Core Levels

The relaxation dynamics of HCl, DCl, H2S, and D2S following photoexcitation in the vicinities of the Cl and S K-shell thresholds (∼2.8keV for Cl, ∼2.5 keV for S) were studied by means of ion time-of-flight mass spectroscopy. In all cases, the onset of pre-edge core-shell photoionization precedes the formation on resonance of a significant amount of neutral hydrogen as well as postcollision-interaction effects above threshold. Examination of the width of the H+ peak in spectra taken with the analyzer parallel and perpendicular to the polarization vector of the incident light indicates that on resonance, the photofragmentation asymmetry parameter, β, is approximately two for HCl, and is clearly positive for H2S

?2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of ?2-microglobulin (?2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which ?2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of ?2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that ?2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between ?2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of ?2m amyloid-associated osteoarticular tissue destruction in DRA

Longitudinal Imaging and Analysis of Neurons Expressing Polyglutamine-Expanded Proteins

Misfolded proteins have been implicated in most of the major neurodegenerative diseases, and identifying drugs and pathways that protect neurons from the toxicity of misfolded proteins is of paramount importance. We invented a form of automated imaging and analysis called robotic microscopy that is well suited to the study of neurodegeneration. It enables the monitoring of large cohorts of individual neurons over their lifetimes as they undergo neurodegeneration. With automated analysis, multiple endpoints in neurons can be measured, including survival. Statistical approaches, typically reserved for engineering and clinical medicine, can be applied to these data in an unbiased fashion to discover whether factors contribute positively or negatively to neuronal fate and to quantify the importance of their contribution. Ultimately, multivariate dynamic models can be constructed from these data, which can provide a systems-level understanding of the neurodegenerative disease process and guide the rationale for the development of therapies

Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a polyglutamine expansion in huntingtin. There are no treatments that are known to slow the neurodegeneration caused by this mutation. Mutant huntingtin causes disease via a toxic gain-of-function mechanism and has the propensity to aggregate and form intraneuronal inclusions. One therapeutic approach for HD is to enhance the degradation of the mutant protein. We have shown that this can be achieved by upregulating autophagy, using the drug rapamycin. In order to find safer ways of inducing autophagy for clinical purposes, we previously screened United States Food and Drug Administration-approved drugs for their autophagy-stimulating potential. This screen suggested that rilmenidine, a well tolerated, safe, centrally acting anti-hypertensive drug, could induce autophagy in cell culture via a pathway that was independent of the mammalian target of rapamycin. Here we have shown that rilmenidine induces autophagy in mice and in primary neuronal culture. Rilmenidine administration attenuated the signs of disease in a HD mouse model and reduced levels of the mutant huntingtin fragment. As rilmenidine has a long safety record and is designed for chronic use, our data suggests that it should be considered for the treatment of HD and related conditions

Comment on "Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells"

Egawa et al. recently showed the value of patient-specific induced pluripotent stem cells (iPSCs) for modeling amyotrophic lateral sclerosis in vitro. Their study and our work highlight the need for complementary assays to detect small, but potentially important, phenotypic differences between control iPSC lines and those carrying disease mutations