RESUMO
Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-ß peptide (Aß42) are key pathogenic agents in Alzheimer's disease (AD). To investigate the relationship between Aß42 aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly reduces the toxicity of the resulting oligomers to neuroblastoma cells by inhibiting their binding to the cellular membranes. When administered to a C. elegans model of AD, we again observe an increase in aggregate formation alongside the suppression of Aß42-induced toxicity. In addition to oligomer displacement, the reduced toxicity could also point towards an increased rate of conversion of oligomers to less toxic fibrils. The ability of a small molecule to reduce the toxicity of oligomeric species represents a potential therapeutic strategy against AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Colestanos/uso terapêutico , Fragmentos de Peptídeos/metabolismo , Espermina/análogos & derivados , Peptídeos beta-Amiloides/efeitos dos fármacos , Animais , Caenorhabditis elegans , Linhagem Celular Tumoral , Colestanos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Fragmentos de Peptídeos/efeitos dos fármacos , Espermina/farmacologia , Espermina/uso terapêuticoAssuntos
Pólen , Polinização , Animais , Flores , Humanos , Hipersensibilidade , Insetos , Microbiota , ReproduçãoAssuntos
Óleo de Fígado de Bacalhau/efeitos adversos , Surtos de Doenças/estatística & dados numéricos , Infecções Respiratórias/epidemiologia , Vitamina A/efeitos adversos , Deficiência de Vitamina D/epidemiologia , Óleo de Fígado de Bacalhau/uso terapêutico , Humanos , Países Baixos/epidemiologia , Infecções Respiratórias/tratamento farmacológico , Fatores de Risco , Vitamina A/uso terapêutico , Deficiência de Vitamina D/tratamento farmacológico , Vitaminas/efeitos adversos , Vitaminas/uso terapêuticoRESUMO
Considering the anatomical location of the urethral meatus, it is surprising that urine is normally sterile. The defensive properties of uroepithelia help maintain this sterility as strategically necessary for long-term survival. Epithelia lining the urinary tract prevent adhesion of bacteria by release of Tamm-Horsfall protein, lactoferrin, lipocalin, and constitutive and inducible bactericidal antimicrobial peptides such as alpha- and beta-defensins and cathelicidin. Microbes that overwhelm these early defenses contact uroepithelia and activate an innate immune response through Toll-like receptor 4. With persistence of increasing numbers of microbes, chemokines (IL-8) and cytokines (IL-1 and TNFalpha) attract and activate large numbers of neutrophils and macrophages that damage tubulointerstitial parenchyma. The risk of serious infection in humans seems quite variable. Cathelicidin, for example, is a vitamin D-dependent gene, and vitamin D stores may influence susceptibility to urinary tract infection in selected individuals. As more knowledge accrues, vitamin D supplementation may someday be useful as adjuvant therapy in this setting.