Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
Environ Res ; 200: 111450, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34102161

RESUMEN

BACKGROUND: Seasonal trends in suicide mortality are observed worldwide, potentially aligning with the seasonal release of aeroallergens. However, only a handful of studies have examined whether aeroallergens increase the risk of suicide, with inconclusive results thus far. The goal of this study was to use a time-stratified case-crossover design to test associations of speciated aeroallergens (evergreen, deciduous, grass, and ragweed) with suicide deaths in Ohio, USA (2007-2015). METHODS: Residential addresses for 12,646 persons who died by suicide were linked with environmental data at the 4-25 km grid scale including atmospheric aeroallergen concentrations, maximum temperature, sunlight, particulate matter <2.5 µm, and ozone. A case-crossover design was used to examine same-day and 7-day cumulative lag effects on suicide. Analyses were stratified by age group, gender, and educational level. RESULTS: In general, associations were null between aeroallergens and suicide. Stratified analyses revealed a relationship between grass pollen and same-day suicide for women (OR = 3.84; 95% CI = 1.44, 10.22) and those with a high school degree or less (OR = 2.03; 95% CI = 1.18, 3.49). CONCLUSIONS: While aeroallergens were generally not significantly related to suicide in this sample, these findings provide suggestive evidence for an acute relationship of grass pollen with suicide for women and those with lower education levels. Further research is warranted to determine whether susceptibility to speciated aeroallergens may be driven by underlying biological mechanisms or variation in exposure levels.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Suicidio , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Alérgenos , Ambrosia , Humanos , Ohio/epidemiología , Poaceae
2.
Int J Biol Macromol ; 74: 530-40, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25583021

RESUMEN

Herpes simplex virus type 1 (HSV1) induces the formation of the characteristic abnormal molecules of Alzheimer's disease (AD) brains, beta-amyloid, and abnormally phosphorylated, AD-like tau (P-tau). Formation of these molecules is inhibited by treatment with the antiviral agent acyclovir (ACV), which prevents viral DNA replication. A totally different mechanism of antiviral action against herpes simplex viruses is shown by sulfated fucans. The antiviral activity of sulfated fucans from five brown algae (Scytothamnus australis, Marginariella boryana, Papenfussiella lutea, Splachnidium rugosum and Undaria pinnatifida) was investigated in relation to the HSV1-induced formation of beta-amyloid, and AD-like tau. Antiviral activity was also related to specific structural features of these polysaccharides. Four sulfated fucan extracts each prevented the accumulation of HSV1-induced beta-amyloid and AD-like tau in HSV1-infected Vero cells. The structures of these extracts had some similarities but also key differences, indicating that a number of structural features can cause antiviral activity. The most active sulfated fucan combined with acyclovir was particularly effective, so may be particularly suitable for further experimental testing in order to develop treatment protocols for AD patients, with the aim of slowing or stopping disease progression.


Asunto(s)
Antivirales/farmacología , Herpesvirus Humano 1/efectos de los fármacos , Phaeophyceae/química , Polisacáridos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Animales , Antivirales/química , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Polisacáridos/química , Relación Estructura-Actividad , Células Vero , Proteínas tau
3.
Phys Rev Lett ; 112(18): 188101, 2014 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-24856725

RESUMEN

The two-dimensional fluidity of lipid bilayers enables the motion of membrane-bound macromolecules and is therefore crucial to biological function. Microrheological methods that measure fluid viscosity via the translational diffusion of tracer particles are challenging to apply and interpret for membranes, due to uncertainty about the local environment of the tracers. Here, we demonstrate a new technique in which determination of both the rotational and translational diffusion coefficients of membrane-linked particles enables quantification of viscosity, measurement of the effective radii of the tracers, and assessment of theoretical models of membrane hydrodynamics. Surprisingly, we find a wide distribution of effective tracer radii, presumably due to a variable number of lipids linked to each tracer particle. Furthermore, we show for the first time that a protein involved in generating membrane curvature, the vesicle trafficking protein Sar1p, dramatically increases membrane viscosity. Using the rheological method presented here, therefore, we are able to reveal a class of previously unknown couplings between protein activity and membrane mechanics.


Asunto(s)
Lípidos de la Membrana/química , Modelos Químicos , Avidina/química , Biotina/química , Colorantes Fluorescentes/química , Membrana Dobles de Lípidos/química , Fluidez de la Membrana , Microscopía Fluorescente/métodos , Reología/métodos , Viscosidad
4.
J Neuroimmunol ; 257(1-2): 7-12, 2013 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-23385080

RESUMEN

Intravenous immunoglobulin (IVIG) treatment of Alzheimer's disease (AD) has been encouraging. Its mechanism of action might be via anti-ß-amyloid (Aß) antibodies which facilitate Aß clearance. However, IVIG's benefits might result from its antiviral activity, particularly against herpes simplex virus type 1 (HSV1), a virus implicated in AD. We investigated IVIG's effect on HSV1, specifically on the accumulation of Aß and abnormally phosphorylated tau which it causes. We show that IVIG is effective at reducing the accumulation of these abnormal molecules and that it acts synergistically with the antiviral acyclovir, suggesting that their combined use would be beneficial for treating AD.


Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Herpesvirus Humano 1/patogenicidad , Inmunoglobulinas Intravenosas/administración & dosificación , Proteínas tau/antagonistas & inhibidores , Péptidos beta-Amiloides/efectos adversos , Animales , Chlorocebus aethiops , Células Vero , Proteínas Estructurales Virales/antagonistas & inhibidores , Proteínas Estructurales Virales/biosíntesis , Proteínas tau/efectos adversos , Proteínas tau/biosíntesis
6.
PLoS One ; 6(10): e25152, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22003387

RESUMEN

Alzheimer's disease (AD) afflicts around 20 million people worldwide and so there is an urgent need for effective treatment. Our research showing that herpes simplex virus type 1 (HSV1) is a risk factor for AD for the brains of people who possess a specific genetic factor and that the virus causes accumulation of key AD proteins (ß-amyloid (Aß) and abnormally phosphorylated tau (P-tau)), suggests that anti-HSV1 antiviral agents might slow AD progression. However, currently available antiviral agents target HSV1 DNA replication and so might be successful in AD only if Aß and P-tau accumulation depend on viral DNA replication. Therefore, we investigated firstly the stage(s) of the virus replication cycle required for Aß and P-tau accumulation, and secondly whether antiviral agents prevent these changes using recombinant strains of HSV1 that progress only partly through the replication cycle and antiviral agents that inhibit HSV1 DNA replication. By quantitative immunocytochemistry we demonstrated that entry, fusion and uncoating of HSV1, are insufficient to induce Aß and P-tau production. We showed also that none of the "immediate early" viral proteins is directly responsible, and that Aß and P-tau are produced at a subsequent stage of the HSV1 replication cycle. Importantly, the anti-HSV1 antiviral agents acyclovir, penciclovir and foscarnet reduced Aß and P-tau accumulation, as well as HSV1, with foscarnet being less effective in each case. P-tau accumulation was found to depend on HSV1 DNA replication, whereas Aß accumulation was not. The antiviral-induced decrease in Aß is attributable to the reduced number of new viruses, and hence the reduction in viral spread. Since antiviral agents reduce greatly Aß and P-tau accumulation in HSV1-infected cells, they would be suitable for treating AD with great advantage unlike current AD therapies, only the virus, not the host cell, would be targeted.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/biosíntesis , Antivirales/farmacología , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/fisiología , Proteínas tau/biosíntesis , Aciclovir/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Línea Celular , Células Cultivadas , Cricetinae , Replicación del ADN/efectos de los fármacos , ADN Viral/biosíntesis , Herpesvirus Humano 1/genética , Humanos , Biosíntesis de Proteínas/efectos de los fármacos , Factores de Tiempo , Replicación Viral/efectos de los fármacos , Proteínas tau/metabolismo
7.
PLoS One ; 6(6): e21456, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21738672

RESUMEN

BACE1 is a key enzyme involved in the production of amyloid ß-peptide (Aß) in Alzheimer's disease (AD) brains. Normally, its expression is constitutively inhibited due to the presence of the 5'untranslated region (5'UTR) in the BACE1 promoter. BACE1 expression is activated by phosphorylation of the eukaryotic initiation factor (eIF)2-alpha, which reverses the inhibitory effect exerted by BACE1 5'UTR. There are four kinases associated with different types of stress that could phosphorylate eIF2-alpha. Here we focus on the double-stranded (ds) RNA-activated protein kinase (PKR). PKR is activated during viral infection, including that of herpes simplex virus type 1 (HSV1), a virus suggested to be implicated in the development of AD, acting when present in brains of carriers of the type 4 allele of the apolipoprotein E gene. HSV1 is a dsDNA virus but it has genes on both strands of the genome, and from these genes complementary RNA molecules are transcribed. These could activate BACE1 expression by the PKR pathway. Here we demonstrate in HSV1-infected neuroblastoma cells, and in peripheral nervous tissue from HSV1-infected mice, that HSV1 activates PKR. Cloning BACE1 5'UTR upstream of a luciferase (luc) gene confirmed its inhibitory effect, which can be prevented by salubrinal, an inhibitor of the eIF2-alpha phosphatase PP1c. Treatment with the dsRNA analog poly (I∶C) mimicked the stimulatory effect exerted by salubrinal over BACE1 translation in the 5'UTR-luc construct and increased Aß production in HEK-APPsw cells. Summarizing, our data suggest that PKR activated in brain by HSV1 could play an important role in the development of AD.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Herpesvirus Humano 1/fisiología , eIF-2 Quinasa/metabolismo , Anciano , Secretasas de la Proteína Precursora del Amiloide/genética , Animales , Western Blotting , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/genética , Supervivencia Celular/fisiología , Femenino , Células HeLa , Humanos , Inmunohistoquímica , Técnicas In Vitro , Ratones , Ratones Endogámicos BALB C , eIF-2 Quinasa/genética
8.
11.
J Alzheimers Dis ; 16(2): 341-50, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19221424

RESUMEN

Neurofibrillary tangles are one of the main neuropathological features of Alzheimer's disease (AD) and are composed of abnormally phosphorylated forms of a microtubule-associated protein called tau. What causes this abnormal phosphorylation is unknown. Our previous studies have implicated herpes simplex virus type 1 (HSV1) as an etiological agent in AD, and so we investigated whether infection with this virus induces AD-like tau phosphorylation. Here we demonstrate that HSV1 causes tau phosphorylation at several sites, including serine 202, threonine 212, serine 214, serine 396 and serine 404. In addition, we have elucidated the mechanism involved by showing that the virus induces glycogen synthase kinase 3beta and protein kinase A, the enzymes that cause phosphorylation at these sites. Our data clearly reveal the importance of HSV1 in AD-type tau phosphorylation, and support the case that the virus is a cause of the disease. Together with our previous data, our results point to the use of antiviral agents to slow the progression of the disease.


Asunto(s)
Herpesvirus Humano 1/fisiología , Proteínas tau/metabolismo , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática/métodos , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Infecciones , Neuroblastoma/metabolismo , Neuroblastoma/virología , Fosforilación , Serina/metabolismo , Treonina/metabolismo
13.
J Alzheimers Dis ; 13(4): 393-405, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18487848

RESUMEN

Alzheimer's disease is a modern scourge and is likely to become increasingly so in the future, with increasing longevity. The disease has been investigated for over one hundred years yet its causes and that of the neuropathological characteristics seen in AD brain are still completely unknown. Evidence for a major causative role of a common virus, herpes simplex virus type 1 (HSV1), acting in combination with a genetic factor - the type 4 allele of the apolipoprotein gene, a known susceptibility factor - is presented here. The characteristics of the virus, some of which make it an especially likely candidate for this role, are described, as are the many precedents for the action of a genetic factor modulating outcome of infection. Various possible ways in which HSV1 might lead to development of AD, such as its up-regulation of various enzymes and in particular certain kinases, its effect on the cell cycle, on autophagy, and its inflammatory and oxidative effects are also discussed. It is concluded that there is strong evidence that the virus is indeed a major factor in AD and therefore there is a strong case for appropriate treatment, and possibly for prevention in the future.


Asunto(s)
Enfermedad de Alzheimer/epidemiología , Herpes Simple/epidemiología , Herpes Simple/virología , Anciano , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Apolipoproteínas E/metabolismo , Encefalitis por Herpes Simple/epidemiología , Encefalitis por Herpes Simple/virología , Herpes Simple/genética , Herpesvirus Humano 1/genética , Humanos , Fosforilación , Proteínas tau/metabolismo
15.
J Neurovirol ; 14(1): 1-4, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18300070

RESUMEN

The causes of Alzheimer's disease (AD) and of the characteristic pathological features - amyloid plaques and neurofibrillary tangles - of AD brain are unknown, despite the enormous resources provided over the years for their investigation. Indeed, the only generally accepted risk factors are age, Down syndrome, carriage of the type 4 allele of the apolipoprotein E gene (APOE-epsilon 4), and possibly brain injury. Following the authors' previous studies implicating herpes simplex virus type 1 (HSV1) in brain of APOE-epsilon 4 carriers as a major cause of AD, the authors propose here, on the basis of their and others' recent studies, that not only does HSV1 generate the main components of amyloid plaques and neurofibrillary tangles (NFTs) - beta-amyloid (A beta) and abnormally phosphorylated tau but also, by disrupting autophagy, it prevents degradation of these aberrant proteins, leading to their accumulation and deposition, and eventually to AD.


Asunto(s)
Enfermedad de Alzheimer/virología , Autofagia , Herpesvirus Humano 1/patogenicidad , Factores de Edad , Anciano , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Encéfalo/virología , Encefalitis por Herpes Simple/complicaciones , Encefalitis por Herpes Simple/virología , Factor 2 Eucariótico de Iniciación/metabolismo , Predisposición Genética a la Enfermedad , Herpesvirus Humano 1/aislamiento & purificación , Humanos , Lisosomas/fisiología , Proteínas del Tejido Nervioso/metabolismo , Fosforilación , Placa Amiloide/metabolismo , Placa Amiloide/patología , Biosíntesis de Proteínas , Procesamiento Proteico-Postraduccional , Proteínas Virales/fisiología , eIF-2 Quinasa/metabolismo , Proteínas tau/metabolismo
16.
Neurosci Lett ; 429(2-3): 95-100, 2007 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-17980964

RESUMEN

It is uncertain whether environmental factors contribute to the formation of senile plaques and neurofibrillary tangles, the abnormal features that define the Alzheimer's disease (AD) brain. We previously proposed that herpes simplex virus type 1 (HSV1) is a strong risk factor for AD when it is present in the brains of people who possess the type 4 allele of the apolipoprotein E gene (APOE-epsilon4); however a direct biochemical link between viral infection and the development of the AD pathological features has never previously been examined. Here we show that infection of cultured neuronal and glial cells with HSV1 leads to a dramatic increase in the intracellular levels of beta-amyloid (Abeta) 1-40 and 1-42, whilst levels of amyloid precursor protein (APP) in cells decrease. Similarly, Abeta1-42 deposits are present in mouse brain after HSV1 infection. In the cultured cells the mechanism involves increased Abeta production, rather than merely greater retention of cellular Abeta, as levels of beta-site APP-cleaving enzyme (BACE-1) and of nicastrin, a component of gamma-secretase, both increase in HSV1-infected cells. These novel data show that HSV1 can directly contribute to the development of senile plaques.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encefalitis por Herpes Simple/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/virología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/virología , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/virología , Células Cultivadas , Chlorocebus aethiops , Encefalitis por Herpes Simple/virología , Herpesvirus Humano 1/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Neuroglía/metabolismo , Neuroglía/virología , Neuronas/metabolismo , Neuronas/virología , Fragmentos de Péptidos/metabolismo , Estrés Fisiológico/metabolismo , Estrés Fisiológico/virología , Regulación hacia Arriba , Células Vero , Activación Viral
17.
Eur J Hum Genet ; 15(6): 672-8, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17356546

RESUMEN

Over 90% of the population are infected with varicella zoster virus (VZV) but only some develop shingles - caused when the virus reactivates from latency, and only some shingles patients develop post-herpetic neuralgia (PHN), defined as pain continuing for more than about 4 months. Epstein Barr virus (EBV) similarly infects over 90% of the population; some of those infected during teenage or young adult years develop infectious mononucleosis (IM). The reason for these disparities between numbers infected and numbers affected by illness is unknown, but presumably reflects host factor(s). Our previous results showed that apolipoprotein E (APOE) genotype determines susceptibility to, or outcome of, infection in the case of several diseases of known infectious cause. Therefore, we investigated APOE genotypes of shingles, PHN, and IM patients. Our rationale for the previous studies and for investigating VZV was that these micro-organisms use for cell binding and entry the same sites in the cell surface as does the protein apoE, and that consequently, competition with apoE could affect the pathogen's extent of entry and hence extent of the damage caused. The APOE genotypes of shingles and PHN sufferers, and of IM sufferers were determined using restriction fragment length polymorphism. In females, epsilon4 homozygosity confers a risk of shingles and also of IM, and the APOE-epsilon4 allele is protective against PHN whereas APOE-epsilon3 allele is a risk. Our results showing that a host genetic factor influences the development of shingles and PHN in females have clinical significance: they could lead to identification of those (female) patients at greater risk of PHN, thus enabling these people to be targeted for treatment with the most effective drugs.


Asunto(s)
Apolipoproteínas E/fisiología , Herpes Zóster/genética , Mononucleosis Infecciosa/genética , Neuralgia Posherpética/genética , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteínas E/genética , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad
19.
Prog Lipid Res ; 45(1): 73-90, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16406033

RESUMEN

Almost a hundred years ago, the main neuropathological features of Alzheimer's disease (AD) brain were discovered, yet the underlying cause(s) are still unknown, and the disease is basically untreatable. Despite the very numerous studies on the neuropathological features, the cause(s) of their production and whether they have an aetiological role in the disease or are merely end-products ("tombstones") are still unknown. Indeed, until fairly recently, the only known risk factors were age, Down's syndrome and head injury. A susceptibility factor, the type 4 allele of the apolipoprotein E gene was identified, but it is neither essential nor sufficient to cause AD, so other factors must be involved also. We investigated the possibility of a viral role and discovered that HSV1 DNA is present in brain of a high proportion of elderly people and that in combination with APOE-epsilon4 it confers a high risk of AD. Subsequently, we found that APOE determines outcome of infection in several diseases caused by diverse infectious agents. Here we describe our studies, and the few others carried out elsewhere, on the mechanism of action of HSV1 and the dependence of the damage on APOE. We discuss, in relation to HSV1 action on lipids and to the spread of the virus via lipid rafts in brain, the possible involvement in AD of cholesterol, a vital and major component of the human brain, and the dispute over whether statins, drugs used for lowering cholesterol levels, are protective against the disease. We also link the damage due to two major consequences of HSV1 infection--inflammatory and oxidative processes--to lipid peroxidation in brain, and consider the influence of the different apoE isoforms in this process.


Asunto(s)
Enfermedad de Alzheimer/etiología , Apolipoproteínas E/fisiología , Colesterol/fisiología , Herpes Simple/complicaciones , Herpesvirus Humano 1/fisiología , Anciano , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/virología , Apolipoproteínas E/genética , Encéfalo/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Peroxidación de Lípido , Microdominios de Membrana/virología , Latencia del Virus
20.
J Infect Dis ; 193(3): 442-50, 2006 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-16388493

RESUMEN

BACKGROUND: The APOE genotype has a uniquely strong influence on the outcome of viral infection. The mechanism is unknown, although one possibility is direct inhibition of viral entry into cells. METHODS: We have examined the direct anti-infective activity of a peptide analogue of the receptor-binding region of apolipoprotein E (apoE) that is known as "apoE dimer tandem repeat peptide" (apoEdp) and has previously been shown to mimic some of the biological effects of apoE and that recently was shown to bind low-density lipoprotein receptor-related protein. RESULTS: apoEdp has activity against herpes simplex virus types 1 and 2, human immunodeficiency virus, Pseudomonas aeruginosa, and Staphylococcus aureus; concentrations in the range of 1-20 micromol/L inhibit infection by 50%. These biological actions depend on adoption of an alpha -helical structure, as has been found for other biological effects of apoE peptides. The peptide interferes with the earliest stages of viral infection, preventing viral attachment and exerting a mild virucidal action. In addition, an N-terminal fragment of apoE that also contains this binding domain has antiviral activity. CONCLUSIONS: These data suggest that human apoE or fragments containing the receptor-binding domain may contribute to innate immunity to viral infection by direct disruption of viral particles and/or inhibition of viral attachment, thus reducing viral entry.


Asunto(s)
Antiinfecciosos/farmacología , Apolipoproteínas E/química , Apolipoproteínas E/farmacología , Fragmentos de Péptidos/farmacología , Receptores de Lipoproteína/metabolismo , Animales , Apolipoproteínas E/metabolismo , Línea Celular , Chlorocebus aethiops , VIH-1/efectos de los fármacos , VIH-1/patogenicidad , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/patogenicidad , Herpesvirus Humano 2/efectos de los fármacos , Herpesvirus Humano 2/patogenicidad , Humanos , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Células Vero
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA