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1.
Chem Commun (Camb) ; 54(29): 3629-3631, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29577161

RESUMO

Calcium dysregulation, membrane leakage and Aß amyloid growth are hallmarks of Alzheimer's disease. Here we show that Ca2+ ions inhibit membrane damage due to amyloid channels but enhance membrane disruption associated with fibers growing on the lipid surface. The similarities with IAPP suggest that this may represent a mechanism common to all proteinopathies.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Cálcio/metabolismo , Membrana Celular/metabolismo , Fragmentos de Peptídeos/metabolismo , Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Animais , Membrana Celular/efeitos dos fármacos , Fluoresceínas/farmacologia , Corantes Fluorescentes/farmacologia , Fura-2/farmacologia , Cinética , Camundongos , Fragmentos de Peptídeos/química , Porosidade/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos
2.
Aging Cell ; 17(1)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29094448

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of ß-amyloid (Aß), and neuronal loss. The self-association of Aß monomers into soluble oligomers seems to be crucial for the development of neurotoxicity (J. Neurochem., 00, 2007 and 1172). Aß oligomers have been suggested to compromise neuronal functions in AD by reducing the expression levels of the CREB target gene and brain-derived neurotrophic factor (BDNF) (J. Neurosci., 27, 2007 and 2628; Neurobiol. Aging, 36, 2015 and 20406 Mol. Neurodegener., 6, 2011 and 60). We previously reported a broad neuroprotective activity of physiological Aß monomers, involving the activation of type-1 insulin-like growth factor receptors (IGF-IRs) (J. Neurosci., 29, 2009 and 10582, Front Cell Neurosci., 9, 2015 and 297). We now provide evidence that Aß monomers, by activating the IGF-IR-stimulated PI3-K/AKT pathway, induce the activation of CREB in neurons and sustain BDNF transcription and release.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptor IGF Tipo 1/efeitos dos fármacos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Humanos , Neurônios/metabolismo , Fragmentos de Peptídeos/metabolismo , Ratos , Receptor IGF Tipo 1/genética , Receptores de Somatomedina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
3.
ACS Chem Neurosci ; 8(8): 1767-1778, 2017 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-28562008

RESUMO

The self-assembling of the amyloid ß (Aß) peptide into neurotoxic aggregates is considered a central event in the pathogenesis of Alzheimer's disease (AD). Based on the "amyloid hypothesis", many efforts have been devoted to designing molecules able to halt disease progression by inhibiting Aß self-assembly. Here, we combine biophysical (ThT assays, TEM and AFM imaging), biochemical (WB and ESI-MS), and computational (all-atom molecular dynamics) techniques to investigate the capacity of four optically pure components of the natural product silymarin (silybin A, silybin B, 2,3-dehydrosilybin A, 2,3-dehydrosilybin B) to inhibit Aß aggregation. Despite TEM analysis demonstrated that all the four investigated flavonoids prevent the formation of mature fibrils, ThT assays, WB and AFM investigations showed that only silybin B was able to halt the growth of small-sized protofibrils thus promoting the formation of large, amorphous aggregates. Molecular dynamics (MD) simulations indicated that silybin B interacts mainly with the C-terminal hydrophobic segment 35MVGGVV40 of Aß40. Consequently to silybin B binding, the peptide conformation remains predominantly unstructured along all the simulations. By contrast, silybin A interacts preferentially with the segments 17LVFF20 and 27NKGAII32 of Aß40 which shows a high tendency to form bend, turn, and ß-sheet conformation in and around these two domains. Both 2,3-dehydrosilybin enantiomers bind preferentially the segment 17LVFF20 but lead to the formation of different small-sized, ThT-positive Aß aggregates. Finally, in vivo studies in a transgenic Caenorhabditis elegans strain expressing human Aß indicated that silybin B is the most effective of the four compounds in counteracting Aß proteotoxicity. This study underscores the pivotal role of stereochemistry in determining the neuroprotective potential of silybins and points to silybin B as a promising lead compound for further development in anti-AD therapeutics.


Assuntos
Peptídeos beta-Amiloides/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/efeitos dos fármacos , Silimarina/farmacologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Animais Geneticamente Modificados , Western Blotting , Caenorhabditis elegans , Relação Dose-Resposta a Droga , Microscopia de Força Atômica , Microscopia Eletrônica de Transmissão , Simulação de Dinâmica Molecular , Estrutura Molecular , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Agregação Patológica de Proteínas/tratamento farmacológico , Conformação Proteica , Silibina , Silimarina/química
4.
Sci Rep ; 6: 33444, 2016 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-27633879

RESUMO

Due to their altered metabolism cancer cells are more sensitive to proteasome inhibition or changes of copper levels than normal cells. Thus, the development of copper complexes endowed with proteasome inhibition features has emerged as a promising anticancer strategy. However, limited information is available about the exact mechanism by which copper inhibits proteasome. Here we show that Cu(II) ions simultaneously inhibit the three peptidase activities of isolated 20S proteasomes with potencies (IC50) in the micromolar range. Cu(II) ions, in cell-free conditions, neither catalyze red-ox reactions nor disrupt the assembly of the 20S proteasome but, rather, promote conformational changes associated to impaired channel gating. Notably, HeLa cells grown in a Cu(II)-supplemented medium exhibit decreased proteasome activity. This effect, however, was attenuated in the presence of an antioxidant. Our results suggest that if, on one hand, Cu(II)-inhibited 20S activities may be associated to conformational changes that favor the closed state of the core particle, on the other hand the complex effect induced by Cu(II) ions in cancer cells is the result of several concurring events including ROS-mediated proteasome flooding, and disassembly of the 26S proteasome into its 20S and 19S components.


Assuntos
Cobre/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Células HeLa , Humanos , Concentração Inibidora 50 , Íons , Mutação/genética , Inibidores de Proteassoma/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Fluorescência , Triptofano/metabolismo , Zinco/farmacologia
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