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1.
Int J Mol Sci ; 25(4)2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38396950

RESUMO

The complement is a component of the innate immune system designed to fight infections and tissue- or age-related damages. Complement activation creates an inflammatory microenvironment, which enhances cell death. Excessive complement inflammatory activity has been linked to alterations in the structure and functions of the blood-brain barrier, contributing to a poor prognosis for Alzheimer's disease (AD). In the AD preclinical phase, individuals are often clinically asymptomatic despite evidence of AD neuropathology coupled with heightened inflammation. Considering the involvement of the complement system in the risk of developing AD, we hypothesize that inhibiting complement activation could reduce this inflammatory period observed even before clinical signs, thereby slowing down the onset/progression of AD. To validate our hypothesis, we injected complement inhibitor factor H into the brain of APP/PS1 AD mice at early or late stages of this pathology. Our results showed that the injection of factor H had effects on both the onset and progression of AD by reducing proinflammatory IL6, TNF-α, IL1ß, MAC and amyloid beta levels. This reduction was associated with an increase in VGLUT1 and Psd95 synaptic transmission in the hippocampal region, leading to an improvement in cognitive functions. This study invites a reconsideration of factor H's therapeutic potential for AD treatment.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Fator H do Complemento , Camundongos Transgênicos , Ativação do Complemento , Modelos Animais de Doenças
2.
Cell Tissue Res ; 353(3): 483-91, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23700151

RESUMO

Neurogenic differentiation factor (NeuroD) is a transcription factor involved in the differentiation of neurons and in the control of energy balance and metabolism. It plays a key role in type 1 and type 2 diabetes. Melatonin is an important rhythmic endocrine signal within the circadian system of mammals and modulates insulin secretion and glucose metabolism. In the mouse pars tuberalis, NeuroD mRNA levels show day/night variation, which is independent of the molecular clock gene mPER1 but depends on the functional melatonin receptor 1 (MT1). So far, little is known about the effect of melatonin on NeuroD synthesis in the gastrointestinal tract. Thus, NeuroD protein levels and cellular localization were analyzed by immunohistochemistry in pancreatic islets and duodenal enteroendocrine cells of MT1- and mPER1-deficienct mice. In addition, the localization of NeuroD-positive cells was analyzed by double-immunofluorescence and confocal laser microscopy. In duodenal enteroendocrine cells and pancreatic islets of WT and PER1-deficient mice, NeuroD immunoreaction showed a peak during the early subjective night. In contrast, this peak was absent in MT1-deficent mice. These data suggest that melatonin, by acting on MT1 receptors, affects NeuroD expression in the gastrointestinal tract and thus might contribute to circadian regulation in metabolic functions.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Duodeno/metabolismo , Células Enteroendócrinas/metabolismo , Ilhotas Pancreáticas/metabolismo , Melatonina/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Receptor MT1 de Melatonina/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Duodeno/citologia , Células Enteroendócrinas/citologia , Ilhotas Pancreáticas/citologia , Melatonina/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Receptor MT1 de Melatonina/genética
3.
NPJ Prim Care Respir Med ; 31(1): 50, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34934070

RESUMO

The presence of acute infectious respiratory diseases (ARD) is one of the main reasons why recently arrived refugees seek medical help. This paper investigates the incidence rates of acute respiratory diseases in an adult refugee population as well as associated sociodemographic factors and drug treatments. We conducted a retrospective observational study of deidentified medical records. The data were collected between 2015 and 2019 in the health care centers of two large German initial reception centers for refugees. Multivariable analyses controlling for sociodemographics were carried out using generalized estimating equations. Out of 10,431 eligible residents, 6965 medical encounters of 2840 adult patients were recorded over 30 months. Of all the adult patients, 34.4% sought medical help for a respiratory symptom or diagnosis at least once. Older patients and patients from Sub-Saharan Africa sought help less often. The occurrence of ARD showed a typical distribution over the course of the year. Facility occupancy was not associated with ARD occurrence. Acute respiratory symptoms are a leading cause for adult refugee patients to seek medical care. The doctor contact rates due to ARD were consistently two to three times higher among refugees than among German residents.


Assuntos
Refugiados , Infecções Respiratórias , Adulto , Humanos , Infecções Respiratórias/epidemiologia , Estudos Retrospectivos
4.
Sci Rep ; 9(1): 13873, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554875

RESUMO

Age Related Macular Degeneration (AMD) is the first cause of social blindness in people aged over 65 leading to atrophy of retinal pigment epithelial cells (RPE), photoreceptors and choroids, eventually associated with choroidal neovascularization. Accumulation of undigested cellular debris within RPE cells or under the RPE (Drusen), oxidative stress and inflammatory mediators contribute to the RPE cell death. The major risk to develop AMD is the Y402H polymorphism of complement factor H (CFH). CFH interacting with oxidized phospholipids on the RPE membrane modulates the functions of these cells, but the exact role of CFH in RPE cell death and survival remain poorly understood. The aim of this study was to analyze the potential protective mechanism of CFH on RPE cells submitted to oxidative stress. Upon exposure to oxidized lipids 4-HNE (4-hydroxy-2-nonenal) derived from photoreceptors, both the human RPE cell line ARPE-19 and RPE cells derived from human induced pluripotent stem cells were protected from death only in the presence of the full length human recombinant CFH in the culture medium. This protective effect was independent from the membrane attack complex (MAC) formation. CFH maintained RPE cells tight junctions' structure and regulated the caspase dependent apoptosis process. These results demonstrated the CFH anti-oxidative stress functions independently of its capacity to inhibit MAC formation.


Assuntos
Fator H do Complemento/farmacologia , Complexo de Ataque à Membrana do Sistema Complemento/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Aldeídos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Microscopia Eletrônica de Transmissão , Estresse Oxidativo/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes , Epitélio Pigmentado da Retina/metabolismo , Junções Íntimas/efeitos dos fármacos
5.
J Biol Chem ; 279(2): 1040-9, 2004 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-14583617

RESUMO

Venoms from 14 snakes and four scorpions were screened for inhibitory activities toward store-operated Ca2+ entry (SOCE) in human embryonic kidney-293 cells. An inhibitory activity was found in venom from the African scorpion Pandinus imperator. The active agent of this venom was purified by gel filtration and reverse-phase high pressure liquid chromatography methods. Sequence information on the purified fraction, by automatic Edman degradation and mass spectrometry analysis, identified the activity as being contained in two tetrapeptides, which we have named tetrapandins. We demonstrate that synthesized tetrapandins have inhibitory activity for SOCE in human embryonic kidney-293 cells while having no effect on either thapsigargin- or carbachol-stimulated release of Ca2+ stores. These toxins should be extremely useful in future studies to determine downstream events regulated by SOCE as well as to determine whether multiple pathways exist for thapsigargin-stimulated Ca2+ entry.


Assuntos
Venenos de Escorpião/química , Venenos de Escorpião/classificação , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Linhagem Celular , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Humanos , Ionóforos/farmacologia , Espectrometria de Massas , Peptídeos/química , Escorpiões , Tapsigargina/farmacologia , Fatores de Tempo , Toxinas Biológicas/química , Valinomicina/farmacologia
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