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1.
Brain Nerve ; 72(1): 23-34, 2020 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-31907330

RESUMO

There is an urgent need for Alzheimer's disease (AD) treatments because of the growing number of individuals with preclinical, prodromal, and dementia forms of AD. Unfortunately, there are few effective treatments for AD, and many drug development trials for AD ultimately have failed. Current AD clinical trials include disease-modifying therapies, symptomatic cognitive enhancers, and symptomatic agents addressing neuropsychiatric and behavioral changes. Disease modifying therapies include anti-amyloid agents and anti-tau agents, both of which contain small molecules, monoclonal antibodies, or biological therapies. Amyloid is the most common specific target in phase 3 and phase 2 disease modification trials. Recent drug development trials for AD include preclinical and prodromal populations. Although biomarkers are increasingly used in drug development for AD, they are not used uniformly for confirmation of AD diagnosis. Enrollment of earlier populations, new biomarkers (e.g., neurofilament light), novel outcomes (e.g., AD Composite Score [ADCOMS]), and innovative trial designs (e.g., futility analysis, Bayesian adaptive designs) are needed to develop effective drugs against AD.


Assuntos
Doença de Alzheimer , Amiloide , Proteínas Amiloidogênicas , Teorema de Bayes , Biomarcadores , Humanos
2.
J Chem Phys ; 152(3): 035104, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31968963

RESUMO

Nonthermal effects of the electromagnetic (EM) field in the radio and microwave frequency ranges on basic biological matter are difficult to detect and thus remain poorly understood. In this work, all-atom nonequilibrium molecular dynamics simulations were performed to investigate the molecular mechanisms of an amyloidogenic peptide response to nonionizing radiation of varying field characteristics. The results showed that the EM field induced peptide conformations dependent on the field frequency and strength. At the high field strength (0.7 V/nmrms), the peptide explored a wider conformational space as the frequency increased from 1.0 to 5.0 GHz. At the intermediate strength fields (0.07-0.0385 V/nmrms), the frequencies of 1.0 and 2.5 GHz resulted in the peptide being trapped in specific conformations, with 1.0 GHz enabling both fibril-forming and fibril-inhibiting conformations, while 2.5 GHz led to formation of mostly fibril-forming conformations. In contrast, the 5.0 GHz frequency caused increased peptide dynamics and more extended conformations with fibril-enabling aromatic side-chain arrangement akin to the structures formed under ambient conditions. All the simulated frequencies at low strength fields (0.007-0.0007 V/nmrms) resulted in the formation of amyloid-prone hairpin conformations similar to those formed under the weak static electric field and ambient conditions. These results suggest that specific ranges of EM field parameters produce peptide conformations unfavorable for formation of amyloid fibrils, a phenomenon that can be exploited in treatment and prevention of amyloid diseases. Alternatively, EM field parameters can be selected to modulate the formation of well-ordered peptide assemblies as a rational design strategy for engineering biocompatible materials.


Assuntos
Proteínas Amiloidogênicas/química , Campos Eletromagnéticos , Agregados Proteicos , Agregação Patológica de Proteínas , Simulação de Dinâmica Molecular , Conformação Proteica
3.
Mol Biol (Mosk) ; 53(6): 1020-1028, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31876280

RESUMO

Advances in the research of molecular factors involved in the onset and progression of Alzheimer's disease, have led to the creation of several pathogenesis concepts of the most common neurodegenerative disease in the world, and amyloid, cholinergic, and neuroinflammatory hypotheses became leading. Over past twenty years, based on these hypotheses, hundreds of drug prototypes were developed, but none of them were able to stop the development of Alzheimer's disease. In this review, based on the latest experimental data on structure-function properties of chemically modified amyloid-beta isoforms, the concept of the origin and the mechanism of action of amyloid-beta with isomerized Asp7 residue, as a molecular agent of Alzheimer's disease pathogenesis, is presented. This concept makes it possible not only to combine the most important aspects of existing hypotheses but also indicates ways of creating agents for fighting Alzheimer's disease with a principally new mechanism of action, "disease-modifying drugs."


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Proteínas Amiloidogênicas/metabolismo , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico
4.
Adv Exp Med Biol ; 1174: 223-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31713201

RESUMO

Nanofibrillar forms of amyloidogenic proteins were initially discovered in the context of protein misfolding and disease but have more recently been found at the origin of key biological functionality in many naturally occurring functional materials, such as adhesives and biofilm coatings. Their physiological roles in nature reflect their great strength and stability, which has led to the exploration of their use as the basis of artificial protein-based functional materials. Particularly for biomedical applications, they represent attractive building blocks for the development of, for instance, drug carrier agents due to their inherent biocompatibility and biodegradability. Furthermore, the propensity of proteins to self-assemble into amyloid fibrils can be exploited under microconfinement, afforded by droplet microfluidic techniques. This approach allows the generation of multi-scale functional microgels that can host biological additives and can be designed to incorporate additional functionality, such as to aid targeted drug delivery.


Assuntos
Proteínas Amiloidogênicas , Géis , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/metabolismo , Tecnologia Biomédica/tendências , Géis/química , Microfluídica
5.
Phys Chem Chem Phys ; 21(41): 22679-22694, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31595905

RESUMO

Peptide misfolding and aberrant assembly in membranous micro-environments have been associated with numerous neurodegenerative diseases. The biomolecular mechanisms and biophysical implications of these amyloid membrane interactions have been under extensive research and can assist in understanding disease pathogenesis and potential development of rational therapeutics. But, the complex nature and diversity of biomolecular interactions, structural transitions, and dependence on local environmental conditions have made accurate microscopic characterization challenging. In this review, using cases of Alzheimer's disease (amyloid-beta peptide), Parkinson's disease (alpha-synuclein peptide) and Huntington's disease (huntingtin protein), we illustrate existing challenges in experimental investigations and summarize recent relevant numerical simulation studies into amyloidogenic peptide-membrane interactions. In addition we project directions for future in silico studies and discuss shortcomings of current computational approaches.


Assuntos
Biologia Computacional , Lipídeos/química , Doenças Neurodegenerativas , Dobramento de Proteína , Proteínas Amiloidogênicas/metabolismo , Membrana Celular/metabolismo , Simulação por Computador , Humanos , Metabolismo dos Lipídeos , Doenças Neurodegenerativas/fisiopatologia , Peptídeos/metabolismo
6.
Anal Chim Acta ; 1087: 121-130, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31585560

RESUMO

Protein misfolding and aggregation are the common mechanisms in a variety of aggregation-dependent diseases. The compromised proteins often assemble into toxic, accumulating amyloid-like structures of various lengths and their toxicity can also be transferred both in vivo and in vitro a prion-like behavior. The characterization of protein interactions, degradation and conformational dynamics in biological systems still represents an analytical challenge in the prion-like protein comprehension. In our work, we investigated the nature of a transferable cytotoxic agent, presumably a misfolded protein, through the coupling of a multi-detector, non-destructive separation platform based on hollow-fiber flow field-flow fractionation with imaging and downstream in vitro tests. After purification with ion exchange chromatography, the transferable cytotoxic agentwas analyzed with Atomic Force Microscopy and statistical analysis, showing that the concentration of protein dimers and low n-oligomer forms was higher in the cytotoxic sample than in the control preparation. To assess whether the presence of these species was the actual toxic and/or self-propagating factor, we employed HF5 fractionation, with UV and Multi-Angle Light Scattering detection, to define proteins molar mass distribution and abundance, and fractionate the sample into size-homogeneous fractions. These fractions were then tested individually in vitro to investigate the direct correlation with cytotoxicity. Only the later-eluted fraction, which contains high-molar mass aggregates, proved to be toxic onto cell cultures. Moreover, it was observed that the selective transfer of toxicity also occurs for one lower-mass fraction, suggesting that two different mechanisms, acute and later induced toxicity, are in place. These results strongly encourage the efficacy of this platform to enable the identification of protein toxicants.


Assuntos
Proteínas Amiloidogênicas/análise , Príons/análise , Agregados Proteicos , Proteínas Amiloidogênicas/isolamento & purificação , Proteínas Amiloidogênicas/toxicidade , Linhagem Celular Tumoral , Cromatografia por Troca Iônica , Fracionamento por Campo e Fluxo , Humanos , Luz , Microscopia de Força Atômica , Tamanho da Partícula , Príons/isolamento & purificação , Príons/toxicidade , Espalhamento de Radiação
7.
Folia Neuropathol ; 57(3): 220-226, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588708

RESUMO

As the population is aging all over the world, the economic burden of ischemic brain injuries is constantly increasing. Human brain ischemia is one of the leading causes of premature death, significant morbidity and physical and mental disabilities, resulting in a lower quality of life and unusually high costs of health and social care. One of the most difficult problems associated with the pathology of the brain after ischemia is progressive dementia observed in people who survived the stroke. More recently, brain ischemia has been shown to elicit Alzheimer's disease neuropathologic change, possibly facilitating the development of dementia due to the amyloidogenic processing of Alzheimer's disease-related amyloid protein precursor into amyloid. The main purpose of this review is to present the development of Alzheimer's disease neuropathologic change in the brain after human and experimental ischemia, with a particular emphasis on proteins and genes involved in the amyloidogenic processing of the amyloid protein precursor to amyloid.


Assuntos
Proteínas Amiloidogênicas , Isquemia Encefálica/patologia , Encéfalo/patologia , Acidente Vascular Cerebral/patologia , Animais , Humanos
8.
Phys Chem Chem Phys ; 21(43): 23931-23942, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31661536

RESUMO

There is a growing body of experimental work showing that protein aggregates associated with amyloid fibrils feature intrinsic fluorescence. In order to understand the microscopic origin of this behavior observed in non-aromatic aggregates of peptides and proteins, we conducted a combined experimental and computational study on the optical properties of amyloid-derived oligopeptides in the near-UV region. We have focused on a few model systems having charged termini (zwitterionic) or acetylated termini. For the zwitterionic system, we were able to simulate the longer tail absorption in the near UV (250-350 nm), supporting the experimental results in terms of excitation spectra. We analyzed the optical excitations responsible for the low-energy absorption and found a large role played by charge-transfer states around the termini. These charge-transfer excitations are very sensitive to the conformation of the peptide and in realistic fibrils may involve inter and intra chain charge reorganization.


Assuntos
Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/metabolismo , Teoria da Densidade Funcional , Microscopia de Força Atômica , Espectrofotometria , Termodinâmica
9.
Int J Mol Sci ; 20(21)2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31661810

RESUMO

The adsorption of amyloidogenic peptides, amyloid beta 1-40 (Aß1-40), alpha-synuclein (α-syn), and beta 2 microglobulin (ß2m), was attempted over the surface of nano-gold colloidal particles, ranging from d = 10 to 100 nm in diameter (d). The spectroscopic inspection between pH 2 and pH 12 successfully extracted the critical pH point (pHo) at which the color change of the amyloidogenic peptide-coated nano-gold colloids occurred due to aggregation of the nano-gold colloids. The change in surface property caused by the degree of peptide coverage was hypothesized to reflect the ΔpHo, which is the difference in pHo between bare gold colloids and peptide coated gold colloids. The coverage ratio (Θ) for all amyloidogenic peptides over gold colloid of different sizes was extracted by assuming Θ = 0 at ΔpHo = 0. Remarkably, Θ was found to have a nano-gold colloidal size dependence, however, this nano-size dependence was not simply correlated with d. The geometric analysis and simulation of reproducing Θ was conducted by assuming a prolate shape of all amyloidogenic peptides. The simulation concluded that a spiking-out orientation of a prolate was required in order to reproduce the extracted Θ. The involvement of a secondary layer was suggested; this secondary layer was considered to be due to the networking of the peptides. An extracted average distance of networking between adjacent gold colloids supports the binding of peptides as if they are "entangled" and enclosed in an interfacial distance that was found to be approximately 2 nm. The complex nano-size dependence of Θ was explained by available spacing between adjacent prolates. When the secondary layer was formed, Aß1-40 and α-syn possessed a higher affinity to a partially negative nano-gold colloidal surface. However, ß2m peptides tend to interact with each other. This difference was explained by the difference in partial charge distribution over a monomer. Both Aß1-40 and α-syn are considered to have a partial charge (especially δ+) distribution centering around the prolate axis. The ß2m, however, possesses a distorted charge distribution. For a lower Θ (i.e., Θ <0.5), a prolate was assumed to conduct a gyration motion, maintaining the spiking-out orientation to fill in the unoccupied space with a tilting angle ranging between 5° and 58° depending on the nano-scale and peptide coated to the gold colloid.


Assuntos
Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/ultraestrutura , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/ultraestrutura , Coloide de Ouro/química , Adsorção , Coloides/química , Ouro/química , Concentração de Íons de Hidrogênio , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Microscopia Eletrônica de Transmissão , Simulação de Dinâmica Molecular , Nanogéis/química , Nanogéis/ultraestrutura , Tamanho da Partícula , Análise Espectral , Propriedades de Superfície , alfa-Sinucleína/química , alfa-Sinucleína/ultraestrutura , Microglobulina beta-2/química , Microglobulina beta-2/ultraestrutura
11.
Neurology ; 93(16): e1514-e1525, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31511349

RESUMO

OBJECTIVE: To examine the effects of baseline Alzheimer disease and cerebrovascular disease markers on longitudinal default mode network (DMN) and executive control network (ECN) functional connectivity (FC) changes in mild cognitive impairment (MCI). METHODS: We studied 30 patients with amnestic MCI (aMCI) and 55 patients with subcortical vascular MCI (svMCI) with baseline Pittsburgh Compound B (PiB)-PET scans and longitudinal MRI scans. Participants were followed up clinically with annual MRI for up to 4 years (aMCI: 26 with 2 timepoints, 4 with 3 timepoints; svMCI: 13 with 2 timepoints, 16 with 3 timepoints, 26 with 4 timepoints). RESULTS: ß-Amyloid (Aß) burden was associated with longitudinal DMN FC declines, while cerebrovascular burden was associated with longitudinal ECN FC changes. When patients were divided into PiB+ and PiB- groups, PiB+ patients showed longitudinal DMN FC declines, while patients with svMCI showed longitudinal ECN FC increases. Direct comparisons between the 2 groups without mixed pathology (aMCI PiB+ and svMCI PiB-) recapitulated this divergent pattern: aMCI PiB+ patients showed steeper longitudinal DMN FC declines, while svMCI PiB- patients showed steeper longitudinal ECN FC increases. Finally, using baseline PiB uptake and lacune numbers as continuous variables, baseline PiB uptake showed inverse U-shape associations with longitudinal DMN FC changes in both MCI subtypes, while baseline lacune numbers showed mainly inverse U-shape relationships with longitudinal ECN FC changes in patients with svMCI. CONCLUSIONS: Our findings underscore the divergent effects of Aß and cerebrovascular burden on longitudinal FC changes in the DMN and ECN in the predementia stage, which reflect the underlying pathology and may be used to track early changes in Alzheimer disease and cerebrovascular disease.


Assuntos
Doença de Alzheimer/patologia , Amiloide/metabolismo , Encéfalo/patologia , Rede Nervosa/patologia , Idoso , Doença de Alzheimer/metabolismo , Proteínas Amiloidogênicas/metabolismo , Amiloidose/metabolismo , Amiloidose/patologia , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/metabolismo , Testes Neuropsicológicos
12.
Molecules ; 24(18)2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527516

RESUMO

Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer's disease (AD), Parkinson's disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways-including protein synthesis, quality control, and clearance-which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed.


Assuntos
Proteínas Amiloidogênicas/química , Autofagia/efeitos dos fármacos , Amiloide/química , Amiloide/metabolismo , Proteínas Amiloidogênicas/antagonistas & inibidores , Proteínas Amiloidogênicas/metabolismo , Animais , Apoptose , Biomarcadores , Suscetibilidade a Doenças , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Agregados Proteicos , Agregação Patológica de Proteínas/tratamento farmacológico , Transdução de Sinais
13.
Molecules ; 24(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491967

RESUMO

Alzheimer's disease (AD) is a widespread dynamic neurodegenerative malady. Its etiology is still not clear. One of the foremost pathological features is the extracellular deposits of Amyloid-beta (Aß) peptides in senile plaques. The interaction of Aß and the receptor for advanced glycation end products at the blood-brain barrier is also observed in AD, which not only causes the neurovascular anxiety and articulation of proinflammatory cytokines, but also directs reduction of cerebral bloodstream by upgrading the emission of endothelin-1 to induce vasoconstriction. In this process, RAGE is deemed responsible for the influx of Aß into the brain through BBB. In the current study, we predicted the interaction potential of the natural compounds vincamine, ajmalicine and emetine with the Aß peptide concerned in the treatment of AD against the standard control, curcumin, to validate the Aß peptide-compounds results. Protein-protein interaction studies have also been carried out to see their potential to inhibit the binding process of Aß and RAGE. Moreover, the current study verifies that ligands are more capable inhibitors of a selected target compared to positive control with reference to ΔG values. The inhibition of Aß and its interaction with RAGE may be valuable in proposing the next round of lead compounds for effective Alzheimer's disease treatment.


Assuntos
Peptídeos beta-Amiloides/química , Produtos Biológicos/química , Modelos Moleculares , Doença de Alzheimer , Aminoácidos , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Proteínas Amiloidogênicas/antagonistas & inibidores , Proteínas Amiloidogênicas/química , Sítios de Ligação , Produtos Biológicos/farmacologia , Humanos , Ligação de Hidrogênio , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Relação Estrutura-Atividade
14.
Curr Pharm Biotechnol ; 20(14): 1223-1233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475895

RESUMO

BACKGROUND: Staphylococcus aureus nosocomial infections with a high mortality rate in human and animals have been reported to associate with bacterial biofilm formation, along with the secretion of numerous virulence factors. Therefore, the inhibition of biofilm formation and attenuation of virulence determinants are considered as a promising solution to combat the spread of S. aureus infections. Modern trends in antibiofilm therapies have opted for the active agents that are biocompatible, biodegradable, non-toxic and cost-effective. Owning the aforementioned properties, chitosan, a natural N-acetylated carbohydrate biopolymer derived from chitin, has been favorably employed. Recently, the chitosan structure has been chemically modified into Chitooligosaccharides (COS) to overcome its limited solubility in water, thus widening chitosan applications in modern antibiofilm research. In the present study, we have investigated the antibacterial, antibiofilm and anti-virulence activities against S. aureus of COS of different molecular weights dissolved in neutral water. METHODS: The study of bactericidal activity was performed using the micro-dilution method while the biofilm inhibition assay was performed using crystal-violet staining method and confirmed by scanning electron microscopic analysis. The inhibition of amyloid protein production was confirmed by Congo Red staining. RESULTS: Results showed that low molecular weight COS exhibited bactericidal activity and reduced the bacterial amylogenesis, hemolytic activity as well as H2O2 resistance properties, while slightly inhibiting biofilm formation. The present study provides a new insight for further applications of the water-soluble COS as a safe and cost-effective drug for the treatment of S. aureus biofilm-associated infections. CONCLUSION: Reducing the molecular weight of chitosan in the form of COS has become an effective strategy to maintain chitosan biological activity while improving its water solubility. The low molecular weight COS investigated in this study have effectively performed antibacterial, antibiofilm and antivirulence properties against S. aureus.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Quitina/análogos & derivados , Fatores de Hemolisina/antagonistas & inibidores , Staphylococcus aureus/efeitos dos fármacos , Xantofilas/antagonistas & inibidores , Proteínas Amiloidogênicas/antagonistas & inibidores , Animais , Células Cultivadas , Quitina/farmacologia , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Staphylococcus aureus/patogenicidade , Staphylococcus aureus/ultraestrutura , Virulência
15.
Biochim Biophys Acta Proteins Proteom ; 1867(11): 140263, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31421227

RESUMO

Pseudomonas species export the amyloid-forming protein FapC to strengthen bacterial biofilm. P. species also produce the biosurfactant rhamnolipid (Rhl) and its outer membrane contains lipopolysaccharide (LPS). Given the possible contacts between FapC, Rhl and LPS, we here investigate how Rhl and LPS affect FapC fibrillation compared with SDS, known to promote fibrillation of proteins at sub-micellar concentrations. Micelles of all three surfactants help FapC bypass the nucleation lag phase, leading to rapid fibrillation, which persists even at high concentrations of micelles and incorporates almost all available FapC monomers. Fibrils formed at high micellar concentrations of Rhl and SDS seed fibrillation at low surfactant concentrations while retaining the original fibril structure. FapC interacts strongly with SDS to form a dense network of narrow fibrils. Small angle X-ray scattering (SAXS) analyses reveal that surfactants reduce the population of intermediates in the fibrillation process and detect a fast aggregation step over the first 2-4 h which precedes the main fibrillation monitored by Thioflavin T. An additional SAXS-detected rearrangement of early aggregates occurs after 4-10 h. At high Rhl concentrations, the micelles are decorated with protein fibrils. SDS induces FapC fibrillation so efficiently that epigallocatechin-3-gallate (EGCG) is unable to inhibit this process. However, EGCG stimulates FapC oligomer formation and inhibits fibrillation both on its own and in the presence of Rhl and LPS. This oligomer could be modelled as a compact core with a flexible shell. This suggests that EGCG can override the natural amyloid-stimulatory properties of these biosurfactants and thus target biofilm.


Assuntos
Proteínas Amiloidogênicas/química , Proteínas de Bactérias/química , Glicolipídeos/química , Lipopolissacarídeos/química , Agregados Proteicos , Pseudomonas aeruginosa/química
16.
Ageing Res Rev ; 56: 100937, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31430565

RESUMO

Hallmarks of most of the amyloid pathologies are surprisingly found to be heterocomponent entities such as inclusions and plaques which contain diverse essential proteins and metabolites. Experimental studies have already revealed the occurrence of coaggregation and cross-seeding during amyloid formation of several proteins and peptides, yielding multicomponent assemblies of amyloid nature. Further, research reports on the co-occurrence of more than one type of amyloid-linked pathologies in the same individual suggest the possible cross-talk among the disease related amyloidogenic protein species during their amyloid growth. In this review paper, we have tried to gain more insight into the process of coaggregation and cross-seeding during amyloid aggregation of proteins, particularly focusing on their relevance to the pathogenesis of the protein misfolding diseases. Revelation of amyloid cross-seeding and coaggregation seems to open new dimensions in our mechanistic understanding of amyloidogenesis and such knowledge may possibly inspire better designing of anti-amyloid therapeutics.


Assuntos
Amiloide/metabolismo , Amiloidose , Doenças Neurodegenerativas/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Proteínas Amiloidogênicas/metabolismo , Animais , Humanos , Doenças Neurodegenerativas/fisiopatologia , Placa Amiloide/metabolismo
17.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416122

RESUMO

Accumulation of α-synuclein (α-Syn) is a remarkable pathology for Parkinson's disease (PD), therefore clearing it is possibly a promising strategy for treating PD. Aberrant copper (Cu(II)) homeostasis and oxidative stress play critical roles in the abnormal aggregation of α-Syn in the progress of PD. It is reported that the polyphenol (-)-epi-gallocatechin gallate (EGCG) can inhibit α-Syn fibrillation and aggregation, disaggregate α-Syn mature fibrils, as well as protect α-Syn overexpressed-PC12 cells against damage. Also, previous studies have reported that EGCG can chelate many divalent metal ions. What we investigate here is whether EGCG can interfere with the Cu(II) induced fibrillation of α-Syn and protect the cell viability. In this work, on a molecular and cellulaire basis, we demonstrated that EGCG can form a Cu(II)/EGCG complex, leading to the inhibition of Cu(II)-induced conformation transition of α-Syn from random coil to ß-sheet, which is a dominant structure in α-Syn fibrils and aggregates. Moreover, we found that the mixture of Cu(II) and EGCG in a molar ratio from 0.5 to 2 can efficiently inhibit this process. Furthermore, we demonstrated that in the α-Syn transduced-PC12 cells, EGCG can inhibit the overexpression and fibrillation of α-Syn in the cells, and reduce Cu(II)-induced reactive oxygen species (ROS), protecting the cells against Cu(II)-mediated toxicity.


Assuntos
Proteínas Amiloidogênicas/metabolismo , Catequina/análogos & derivados , Cobre , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/metabolismo , alfa-Sinucleína/metabolismo , Proteínas Amiloidogênicas/química , Animais , Catequina/química , Catequina/farmacologia , Linhagem Celular , Cobre/química , Cobre/toxicidade , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ressonância Magnética Nuclear Biomolecular , Estresse Oxidativo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/tratamento farmacológico , Ratos , Espécies Reativas de Oxigênio/metabolismo , alfa-Sinucleína/química
18.
Chem Commun (Camb) ; 55(74): 11143-11146, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31463510

RESUMO

We develop a membrane technology based on amyloid fibrils to remove aluminium from water and minimize its exposure to humans. We study aluminium adsorption by amyloid fibrils by evaluating the binding isotherms, the thermodynamics and the effects of different parameters. Amyloid-based membranes demonstrate outstanding removal efficiencies beyond 98%.


Assuntos
Alumínio/metabolismo , Proteínas Amiloidogênicas/metabolismo , Lactoglobulinas/metabolismo , Membranas Artificiais , Poluentes Químicos da Água/metabolismo , Purificação da Água/métodos , Adsorção , Alumínio/química , Proteínas Amiloidogênicas/química , Bebidas , Concentração de Íons de Hidrogênio , Lactoglobulinas/química , Ligação Proteica , Temperatura , Termodinâmica , Águas Residuárias/química , Poluentes Químicos da Água/química
19.
Int J Mol Sci ; 20(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398866

RESUMO

A large number of low-resolution models have been proposed in the last decades to reduce the computational cost of molecular dynamics simulations for bio-nano systems, such as those involving the interactions of proteins with functionalized nanoparticles (NPs). For the proteins, "minimalist" models at the one-bead-per residue (Cα-based) level and with implicit solvent are well established. For the gold NPs, widely explored for biotechnological applications, mesoscale (MS) models treating the NP core with a single spheroidal object are commonly proposed. In this representation, the surface details (coating, roughness, etc.) are lost. These, however, and the specificity of the functionalization, have been shown to have fundamental roles for the interaction with proteins. We presented a mixed-resolution coarse-grained (CG) model for gold NPs in which the surface chemistry is reintroduced as superficial smaller beads. We compared molecular dynamics simulations of the amyloid ß2-microglobulin represented at the minimalist level interacting with NPs represented with this model or at the MS level. Our finding highlights the importance of describing the surface of the NP at a finer level as the chemical-physical properties of the surface of the NP are crucial to correctly understand the protein-nanoparticle association.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Microglobulina beta-2/química , Algoritmos , Proteínas Amiloidogênicas/química , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica
20.
Am J Hematol ; 94(11): 1214-1226, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31396978

RESUMO

Lower-respiratory-tract (LRT) amyloidosis has rarely been investigated. Our study presents characteristics, outcomes and survival of LRT amyloidosis. This multicenter retrospective study, from 1995 to 2017, included 73 patients with amyloidosis and LRT involvement. Respiratory patterns were: tracheobronchial (n = 17), nodular (n = 10), interstitial (n = 14) or composite (several respiratory involvements, n = 32). Interstitial and composite patterns were associated with multi-organ amyloidosis (n = 37, 80%) while tracheobronchial and nodular patterns were associated with organ-limited amyloidosis (n = 21, 78%). Amyloid light chain (AL) amyloidosis was diagnosed in 43 patients (59%), mainly of lambda type (n = 33, 77%). Smokers' proportion was higher in tracheobronchial (71%) and nodular (90%) patterns than in interstitial (14%) and composite (34%) patterns. The B-cell neoplasms involved 15 patients (21%), solid neoplasms 8 (11%), connective tissue diseases 8 (11%) and multiple myeloma 6 (8%). The B-cell and solid neoplasms were most prevalent in nodular pattern. Median follow-up was 4.4 years (2.2-8.9). Twenty-four patients died, mostly from respiratory infection. Survival at 1, 5, 10 years was respectively 88%, 70% and 54% for multi-organ amyloidosis, 96%, 89% and 69% for organ-limited amyloidosis (P = .125). Tracheobronchial and nodular patterns survival was better than in other respiratory patterns (P = .039). Death risk factors (multivariate analysis) were: cardiac localization (hazard-ratio [HR] 4.3 [95% confidence interval 1.6-11.5]; P = .004), age (HR 2.1 [1.2-3.7]; P = .008) and dyspnea at diagnosis (HR 4.0 [1.3-12.3]; P = .014). Various LRT amyloidosis patterns depend on smoking habits, organ-limited or multi-organ extension and comorbidities. They are associated with a different survival, which is also predicted by age, cardiac localization and dyspnea at presentation.


Assuntos
Amiloidose/epidemiologia , Sistema Respiratório/patologia , Adulto , Idoso , Proteínas Amiloidogênicas/análise , Amiloidose/diagnóstico por imagem , Amiloidose/patologia , Amiloidose/terapia , Comorbidade , Feminino , Seguimentos , Volume Expiratório Forçado , França/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Especificidade de Órgãos , Tomografia por Emissão de Pósitrons , Prognóstico , Modelos de Riscos Proporcionais , Sistema Respiratório/diagnóstico por imagem , Estudos Retrospectivos , Fumar/epidemiologia , Tomografia Computadorizada por Raios X
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