Navegando por Palavras-chave "Amyloid"
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- ItemAcesso aberto (Open Access)Aggregation limiting cell-penetrating peptides derived from protein signal sequences(MDPI, 2023-02-16) da Silva, Emerson Rodrigo [UNIFESP]; Bicev, Renata Naporano [UNIFESP]; Porosk, Ly; Härk, Heleri; Armolik, Eger-Jasper; Langel, Ülo; Nebogatova, Jekaterina; Gaidutsik, Ilja; Arukuust, Piret; http://lattes.cnpq.br/7800589206457326Alzheimer’s disease (AD) is the most common neurodegenerative disease (ND) and the leading cause of dementia. It is characterized by non-linear, genetic-driven pathophysiological dynamics with high heterogeneity in the biological alterations and the causes of the disease. One of the hallmarks of the AD is the progression of plaques of aggregated amyloid-β (Aβ) or neurofibrillary tangles of Tau. Currently there is no efficient treatment for the AD. Nevertheless, several breakthroughs in revealing the mechanisms behind progression of the AD have led to the discovery of possible therapeutic targets. Some of these include the reduction in inflammation in the brain, and, although highly debated, limiting of the aggregation of the Aβ. In this work we show that similarly to the Neural cell adhesion molecule 1 (NCAM1) signal sequence, other Aβ interacting protein sequences, especially derived from Transthyretin, can be used successfully to reduce or target the amyloid aggregation/aggregates in vitro. The modified signal peptides with cell-penetrating properties reduce the Aβ aggregation and are predicted to have anti-inflammatory properties. Furthermore, we show that by expressing the Aβ-EGFP fusion protein, we can efficiently assess the potential for reduction in aggregation, and the CPP properties of peptides in mammalian cells.
- ItemAcesso aberto (Open Access)Amyloid formation by short peptides in the presence of dipalmitoylphosphatidylcholine membranes(American Chemical Society, 2020-11-19) da Silva, Emerson Rodrigo [UNIFESP]; Gerbelli, Barbara Bianca; Alves, Wendel Andrade; Oliveira, Cristiano Luis Pinto; Hamley, Ian; http://lattes.cnpq.br/7800589206457326The aggregation of two short peptides [RF] and [RF]4 (where R = arginine and F = phenylalanine) with dipalmitoylphosphatidylcholine (DPPC) model membranes was investigated at the air-water interface using the Langmuir technique and vesicles in aqueous solutions. The molar ratio of the peptide and lipid components was varied to provide insights into the peptide-membrane interactions, which might be related to their cytotoxicity.1 Both peptides exhibited affinity to the DPPC membrane interface and rapidly adopted β-sheet rich structures upon adsorption onto the surface of the zwitterionic membrane. Results from adsorption isotherm and small angle X-ray scattering (SAXS) experiments showed changes in the structural and thermodynamics parameters of the membrane with the increase in peptide concentration. Using atomic force microscopy (AFM), we showed the appearance of pores through the bilayer membranes and peptide aggregation at different interfaces, suggesting that the hydrophobic residues might have an effect on both pore size and layer structure, facilitating the membrane disruption and leading to different cytotoxicity effects.
- ItemAcesso aberto (Open Access)Amyloid-like self-assembly of a hydrophobic cell-penetrating peptide and its use as a carrier for nucleic acids(American Chemical Society, 2021-08-04) da Silva, Emerson Rodrigo [UNIFESP]; Mello, Lucas Rodrigues de [UNIFESP]; Porosk, Ly; Lourenço, Thiago da Costa [UNIFESP]; Garcia, Bianca Bonetto Moreno [UNIFESP]; Costa, Carlos Alberto Rodrigues; Han, Sang Won [UNIFESP]; Souza, Juliana dos Santos de; Langel, Ülo; http://lattes.cnpq.br/7800589206457326; http://lattes.cnpq.br/4209242593570615; http://lattes.cnpq.br/4726216622634724; http://lattes.cnpq.br/7341563736516694; http://lattes.cnpq.br/2833950143696339; http://lattes.cnpq.br/0069955147703693; http://lattes.cnpq.br/7929949468269206Cell-penetrating peptides (CPPs) are a topic subject potentially exploitable for creating new nanotherapeutics for the delivery of bioactive loads. These compounds are often classified into three major categories according to their physicochemical characteristics: cationic, amphiphilic, and hydrophobic. Among them, the group of hydrophobic CPPs has received increasing attention in recent years due to toxicity concerns posed by highly cationic CPPs. The hexapeptide PFVYLI (P: proline, F: phenylalanine, V: valine, Y: tyrosine, L: leucine and I: isoleucine), a fragment derived from the C-terminal portion of α1-antitrypsin, is a prototypal example of hydrophobic CPP. This sequence shows reduced cytotoxicity, capacity of nuclear localization, and its small size readily hints suitability as a building block to construct nanostructured materials. In this study, we examine the self-assembling properties of PFVYLI and investigate its ability to form non-covalent complexes with nucleic acids. By using a combination of biophysical tools including synchrotron small-angle X-ray scattering and atomic force microscopy-based infrared spectroscopy, we discovered that this CPP self-assembles into discrete nanofibrils with remarkable amyloidogenic features. Over the course of days, these fibrils coalesce into rod-like crystals that easily reach the micrometer range. Despite lacking cationic residues in the composition, PFVYLI forms non-covalent complexes with nucleic acids that retain -sheet pairing found in amyloid aggregates. In vitro vectorization experiments performed with double-stranded DNA fragments indicate that complexes promote the internalization of nucleic acids, revealing that tropism toward cell membranes is preserved upon complexation. On the other hand, transfection assays with splice-correction oligonucleotides (SCOs) for luciferase expression show limited bioactivity across a narrow concentration window, suggesting that propensity to form amyloidogenic aggregates may trigger endosomal entrapment. We anticipate that the findings presented here open perspectives for using this archetypical hydrophobic CPP in the fabrication of nanostructured scaffolds, which potentially integrate properties of amyloids and translocation capabilities of CPPs.
- ItemSomente MetadadadosThe theory of bipolar disorder as an illness of accelerated aging: Implications for clinical care and research(Elsevier B.V., 2014-05-01) Rizzo, Lucas Bortolotto [UNIFESP]; Costa, Leonardo Gazzi [UNIFESP]; Mansur, Rodrigo B. [UNIFESP]; Swardfager, Walter; Belangero, Sintia Iole [UNIFESP]; Grassi-Oliveira, Rodrigo; McIntyre, Roger S.; Bauer, Moises E.; Brietzke, Elisa [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Univ Hlth Network; Univ Toronto; Pontificia Univ Catolica Rio Grande do SulBipolar Disorder (BD) has been conceptualized as both a cyclic and a progressive disorder. Mechanisms involved in neuroprogression in BD remain largely unknown although several non-mutually exclusive models have been proposed as explanatory frameworks. in the present paper, we propose that the pathophysiological changes observed in BD (e.g. brain structural alterations, cognitive deficits, oxidative stress imbalance, amyloid metabolism, immunological deregulation, immunosenescence, neurotrophic deficiencies and telomere shortening) converge on a model of accelerated aging (AA). Aging can be understood as a multidimensional process involving physical, neuropsychological, and social changes, which can be highly variable between individuals. Determinants of successful aging (e.g environmental and genetic factors), may also confer differential vulnerability to components of BD pathophysiology and contribute to the clinical presentation of BD. Herein we discuss how the understanding of aging and senescence can contribute to the search for new and promising molecular targets to explain and ameliorate neuroprogression in BD. We also present the strengths and limitations of this concept. (c) 2014 Elsevier B.V. All rights reserved.