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Neurotoxic implications of the interactions between Cu(I/II) and amyloid-ß (Aß) indicate a connection between amyloid cascade hypothesis and metal ion hypothesis with respect to the neurodegeneration associated with Alzheimer's disease (AD). Herein, we report a mechanistic strategy for modifying the first coordination sphere of Cu(II) bound to Aß utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)-Aß was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)-Aß was able to disrupt binding of Cu(II) to Aß and result in chemically modified Aß with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)-Aß could stem from the molecule's ability to 1) interact with Cu(II)-Aß and 2) foster copper-O2 chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)-Aß at a metal-binding amino acid residue and consequently alter Aß's coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity.
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Nowadays, cancers and dementia, such as Alzheimer's disease, are the most fatal causes of death. Many studies tried to understand the pathogenesis of those diseases clearly and develop a promising way to treat the diseases. Matrix metalloproteinases (MMPs) have been reported to be involved in the pathology of cancers and AD through tumor cell movement and amyloid degradation. Therefore, control of the levels and actions of MMPs, especially MMP-2 and MMP-9, is necessary to care for and/or cure cancer and AD. Various molecules have been examined for their potential application as regulators of MMPs expression and activity. Among the molecules, multiple metal complexes have shown advantages, including simple synthesis, less toxicity and specificity toward MMPs in cancer cells or in the brain. In this review, we summarize the recent studies and knowledge of metal complexes (e.g., Pt-, Ru-, Au-, Fe-, Cu-, Ni-, Zn-, and Sn-complexes) targeting MMPs and their potentials for treating and/or caring the most fatal human diseases, cancers and AD.
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Doença de Alzheimer , Complexos de Coordenação , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Metaloproteinases da Matriz/metabolismo , Encéfalo/metabolismoRESUMO
Fat-soluble vitamins (vitamin A, D, E, and K) assume a pivotal role in maintaining human homeostasis by virtue of their enzymatic functions. The daily inclusion of these vitamins is imperative to the upkeep of various physiological processes including vision, bone health, immunity, and protection against oxidative stress. Current research highlights fat-soluble vitamins as potential therapeutics for human diseases, especially cancer. Fat-soluble vitamins exert their therapeutic effects through multiple pathways, including regulation of matrix metalloproteinases' (MMPs) expression and enzymatic activity. As MMPs have been reported to be involved in the pathology of various diseases, such as cancers, cardiovascular diseases, and neurological disorders, regulating the expression and/or activity of MMPs could be considered as a potent therapeutic strategy. Here, we summarize the properties of fat-soluble vitamins and their potential as promising candidates capable of effectively modulating MMPs through multiple pathways to treat human diseases.
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Doenças Cardiovasculares , Vitamina A , Humanos , Vitamina A/farmacologia , Metaloproteinase 2 da Matriz , Vitaminas/uso terapêutico , Vitamina K , Doenças Cardiovasculares/tratamento farmacológico , Vitamina D/uso terapêutico , Vitamina ERESUMO
We use CeOx-TiO2hetero-interfaces generated on the surface of CeOx-TiO2hybrid oxide supporting powders to stabilize Au single-atoms (SAs) with excellent low-temperature activity toward CO oxidation. Based on intriguing density functional theory calculation results on the preferential formation of Au-SAs at the CeOx-TiO2interfaces and the high activity of Au-SAs toward the Mars-van Krevelen type CO oxidation, we synthesized a Au/CeOx-TiO2(ACT) catalyst with 0.05 wt.% of Au content. The Au-SAs stabilized at the CeOx-TiO2interfaces by electronic coupling between Au and Ce showed improved low-temperature CO oxidation activity than the conventional Au/TiO2control group catalyst. However, the light-off profile of ACT showed that the early activated Au-SAs are not vigorously participating in CO oxidation. The large portion of the positive effect on the overall catalytic activity from the low activation energy barrier of ACT was retarded by the negative impact from the decreasing active site density at high temperatures. We anticipate that the low-temperature activity and high-temperature stability of Au-SAs that stand against each other can be optimized by controlling the electronic coupling strength between Au-SAs and oxide clusters at the Au-oxide-TiO2interfaces. Our results show that atomic-precision interface modulation could fine-tune the catalytic activity and stability of Au-SAs.
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Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as potential drug candidates for these disorders with emphasis on multifunctionality. In addition, underrepresented areas of research are discussed to indicate new directions.
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Doença de Alzheimer/tratamento farmacológico , Esclerose Lateral Amiotrófica/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Doença de Alzheimer/patologia , Esclerose Lateral Amiotrófica/patologia , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , Descoberta de Drogas , Humanos , Metais/química , Metais/metabolismo , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo , Doença de Parkinson/patologia , Pró-Fármacos/químicaRESUMO
Redox-active metal ions, Cu(I/II) and Fe(II/III), are essential biological molecules for the normal functioning of the brain, including oxidative metabolism, synaptic plasticity, myelination, and generation of neurotransmitters. Dyshomeostasis of these redox-active metal ions in the brain could cause Alzheimer's disease (AD). Thus, regulating the levels of Cu(I/II) and Fe(II/III) is necessary for normal brain function. To control the amounts of metal ions in the brain and understand the involvement of Cu(I/II) and Fe(II/III) in the pathogenesis of AD, many chemical agents have been developed. In addition, since toxic aggregates of amyloid-ß (Aß) have been proposed as one of the major causes of the disease, the mechanism of clearing Aß is also required to be investigated to reveal the etiology of AD clearly. Multiple metalloenzymes (e.g., neprilysin, insulin-degrading enzyme, and ADAM10) have been reported to have an important role in the degradation of Aß in the brain. These amyloid degrading enzymes (ADE) could interact with redox-active metal ions and affect the pathogenesis of AD. In this review, we introduce and summarize the roles, distributions, and transportations of Cu(I/II) and Fe(II/III), along with previously invented chelators, and the structures and functions of ADE in the brain, as well as their interrelationships.
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Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Encéfalo/metabolismo , Proteína ADAM10/metabolismo , Doença de Alzheimer/etiologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Quelantes/metabolismo , Cobre/metabolismo , Humanos , Insulisina/metabolismo , Ferro/metabolismo , Proteínas de Membrana/metabolismo , Metais/metabolismo , Neprilisina/metabolismo , Oxirredução , ProteóliseRESUMO
Multiple pathogenic elements, including reactive oxygen species, amyloidogenic proteins, and metal ions, are associated with the development of neurodegenerative disorders. We report minimalistic redox-based principles for preparing compact aromatic compounds by derivatizing the phenylene moiety with various functional groups. These molecular agents display enhanced reactivities against multiple targets such as free radicals, metal-free amyloid-ß (Aß), and metal-bound Aß that are implicated in the most common form of dementia, Alzheimer's disease (AD). Mechanistic studies reveal that the redox properties of these reagents are essential for their function. Specifically, they engage in oxidative reactions with metal-free and metal-bound Aß, leading to chemical modifications of the Aß peptides to form covalent adducts that alter the aggregation of Aß. Moreover, the administration of the most promising candidate significantly attenuates the amyloid pathology in the brains of AD transgenic mice and improves their cognitive defects. Our studies demonstrate an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents.
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Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Hidrocarbonetos Aromáticos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Radicais Livres/antagonistas & inibidores , Hidrocarbonetos Aromáticos/química , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Oxirredução , Agregados Proteicos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/químicaRESUMO
The Lewis acid-base adduct approach has been widely used to form uniform perovskite films, which has provided a methodological base for the development of high-performance perovskite solar cells. However, its incompatibility with formamidinium (FA)-based perovskites has impeded further enhancement of photovoltaic performance and stability. Here, we report an efficient and reproducible method to fabricate highly uniform FAPbI3 films via the adduct approach. Replacement of the typical Lewis base dimethyl sulfoxide (DMSO) with N-methyl-2-pyrrolidone (NMP) enabled the formation of a stable intermediate adduct phase, which can be converted into a uniform and pinhole-free FAPbI3 film. Infrared and computational analyses revealed a stronger interaction between NMP with the FA cation than DMSO, which facilitates the formation of a stable FAI·PbI2·NMP adduct. On the basis of the molecular interactions with different Lewis bases, we proposed criteria for selecting the Lewis bases. Owed to the high film quality, perovskite solar cells with the highest PCE over 20% (stabilized PCE of 19.34%) and average PCE of 18.83 ± 0.73% were demonstrated.
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Aluminum nanoparticles are considered promising as alternatives to conventional ink materials, replacing silver and copper nanoparticles, due to their extremely low cost and low melting temperature. However, a serious obstacle to realizing their use as conductive ink materials is the oxidation of aluminum. In this research, we synthesized the oxide-free aluminum nanoparticles using catalytic decomposition and an oleic acid coating method, and these materials were applied to conductive ink for the first time. The injection time of oleic acid determines the size of the aluminum nanoparticles by forming a self-assembled monolayer on the nanoparticles instead of allowing the formation of an oxide phase. Fabricated nanoparticles were analyzed by transmission electron microscopy and x-ray photoelectron spectroscopy to verify their structural and chemical composition. In addition, conductive inks made of these nanoparticles exhibit electrical properties when they are sintered at over 300 °C in a reducing atmosphere. This result shows that aluminum nanoparticles can be used as an alternative conductive material in printed electronics and can solve the cost issues associated with noble metals.
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The polarizable charge equilibration (PQEq) method was developed to provide a simple but accurate description of the electrostatic interactions and polarization effects in materials. Previously, we optimized four parameters per element for the main group elements. Here, we extend this optimization to the 24 d-block transition-metal (TM) elements, columns 4-11 of the periodic table including Ti-Cu, Zr-Ag, and Hf-Au. We validate the PQEq description for these elements by comparing to interaction energies computed by quantum mechanics (QM). Because many materials applications involving TM are for oxides and other compounds that formally oxidize the metal, we consider a variety of oxidation states in 24 different molecular clusters. In each case, we compare interaction energies and induced fields from QM and PQEq along various directions. We find that the original χ and J parameters (electronegativity and hardness) related to the ionization of the atom remain valid; however, we find that the atomic radius parameter needs to be close to the experimental ionic radii of the transition metals. This leads to a much higher spring constant to describe the atomic polarizability. We find that these optimized parameters for PQEq provide accurate interaction energies compared to QM with charge distributions that depend in a reasonable way on the coordination number and oxidation states of the transition metals. We expect that this description of the electrostatic interactions for TM will be useful in molecular dynamics simulations of inorganic and organometallic materials.
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Alzheimer's disease (AD) is characterized by an imbalance between production and clearance of amyloid-ß (Aß) species. Aß peptides can transform structurally from monomers into ß-stranded fibrils via multiple oligomeric states. Among the various Aß species, structured oligomers are proposed to be more toxic than fibrils; however, the identification of Aß oligomers has been challenging due to their heterogeneous and metastable nature. Multiple techniques have recently helped us gain a better understanding of oligomers' assembly details and structural properties. Moreover, some progress on elucidating the mechanisms of oligomer-triggered toxicity has been made. Based on the collection of current findings, there is growing consensus that control of toxic Aß oligomers could be a valid approach to regulate Aß-associated toxicity, which could advance development of new diagnostics and therapeutics for amyloid-related diseases. In this review, we summarize the recent understanding of Aß oligomers' assembly, structural properties, and toxicity, along with inhibitors against Aß aggregation, including oligomerization.
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Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , HumanosRESUMO
Regulation of amyloid-ß (Aß) aggregation by metal ions and proteins is essential for understanding the pathology of Alzheimer's disease (AD). Human serum albumin (HSA), a regulator of metal and protein transportation, can modulate metal-Aß interactions and Aß aggregation in human fluid; however, the molecular mechanisms for such activities remain unclear. Herein, we report the molecular-level complexation between Zn(II), Cu(II), Aß, and HSA, which is able to alter the aggregation and cytotoxicity of Aß peptides and induce their cellular transportation. In addition, a single Aß monomer-bound HSA is observed with the structural change of Aß from a random coil to an α-helix. Small-angle X-ray scattering (SAXS) studies indicate that Aß-HSA complexation causes no structural variation of HSA in solution. Conversely, ion mobility mass spectrometry (IM-MS) results present that Aß prevents the shrinkage of the V-shaped groove of HSA in the gas phase. Consequently, for the first time, HSA is demonstrated to predominantly capture a single Aß monomer at the groove using the phase transfer of a protein heterodimer from solution to the gas phase. Moreover, HSA sequesters Zn(II) and Cu(II) from Aß while maintaining Aß-HSA interaction. Therefore, HSA is capable of controlling metal-free and metal-bound Aß aggregation and aiding the cellular transportation of Aß via Aß-HSA complexation. The overall results and observations regarding HSA, Aß, and metal ions advance our knowledge of how protein-protein interactions associated with Aß and metal ions could be linked to AD pathogenesis.
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Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Espaço Extracelular/química , Espaço Extracelular/metabolismo , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Líquidos Corporais/química , Líquidos Corporais/metabolismo , Cobre/química , Humanos , Ligação Proteica , Conformação Proteica em alfa-Hélice , Espalhamento a Baixo Ângulo , Difração de Raios X , Zinco/químicaRESUMO
Aggregates of amyloidogenic peptides are involved in the pathogenesis of several degenerative disorders. Herein, an iridium(III) complex, Ir-1, is reported as a chemical tool for oxidizing amyloidogenic peptides upon photoactivation and subsequently modulating their aggregation pathways. Ir-1 was rationally designed based on multiple characteristics, including 1)â photoproperties leading to excitation by low-energy radiation; 2)â generation of reactive oxygen species responsible for peptide oxidation upon photoactivation under mild conditions; and 3)â relatively easy incorporation of a ligand on the IrIII center for specific interactions with amyloidogenic peptides. Biochemical and biophysical investigations illuminate that the oxidation of representative amyloidogenic peptides (i.e., amyloid-ß, α-synuclein, and human islet amyloid polypeptide) is promoted by light-activated Ir-1, which alters the conformations and aggregation pathways of the peptides. Additionally, their potential oxidation sites are identified as methionine, histidine, or tyrosine residues. Overall, our studies on Ir-1 demonstrate the feasibility of devising metal complexes as chemical tools suitable for elucidating the nature of amyloidogenic peptides at the molecular level, as well as controlling their aggregation.
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Peptídeos beta-Amiloides/química , Complexos de Coordenação/química , Irídio/química , Sequência de Aminoácidos , Peptídeos beta-Amiloides/metabolismo , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Luz , Oxirredução , Agregados Proteicos/efeitos da radiação , Espectrometria de Massas por Ionização por Electrospray , alfa-Sinucleína/química , alfa-Sinucleína/metabolismoRESUMO
To elucidate the involvement of individual and inter-related pathological factors [i.e., amyloid-ß (Aß), metals, and oxidative stress] in the pathogenesis of Alzheimer's disease (AD), chemical tools have been developed. Characteristics required for such tool construction, however, have not been clearly identified; thus, the optimization of available tools or new design has been limited. Here, key structural properties and mechanisms that can determine tools' regulatory reactivities with multiple pathogenic features found in AD are reported. A series of small molecules was built up through rational structural selection and variations onto the framework of a tool useful for in vitro and in vivo metal-Aß investigation. Variations include: (i)â location and number of an Aß interacting moiety; (ii)â metal binding site; and (iii)â denticity and structural flexibility. Detailed biochemical, biophysical, and computational studies were able to provide a foundation of how to originate molecular formulas to devise chemical tools capable of controlling the reactivities of various pathological components through distinct mechanisms. Overall, this multidisciplinary investigation illustrates a structure-mechanism-based strategy of tool invention for such a complicated brain disease.
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Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Doença de Alzheimer/metabolismo , Sequência de Aminoácidos , Peptídeos beta-Amiloides/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cloretos/química , Cobre/química , Humanos , Metais/química , Metais/metabolismo , Estresse Oxidativo , Ligação Proteica , Estrutura Terciária de Proteína , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria , Compostos de Zinco/químicaRESUMO
PURPOSE: Various immunocompromised conditions increase the risk of meningitis caused by Listeria monocytogenes. However, the relative importance of these risk factors has not been well established. We determined the risk factors that predict meningitis due to L. monocytogenes compared to that caused by Streptococcus pneumoniae. METHODS: A nationwide multicenter case-control study was conducted in Korea. Cases of meningitis caused by L. monocytogenes between 1998 and 2013 were included. Patients with pneumococcal meningitis were included as controls. Multivariate logistic regression analysis was used to predict the risk factors of Listeria meningitis. RESULTS: A total of 36 cases and 113 controls were enrolled. The most significant predictive risk factor of Listeria meningitis was a prior history of receiving immunosuppressive therapy (odds ratio 8.12, 95 % CI 2.47-26.69). Chronic liver disease was the second most important predictive risk factor (OR 5.03, 95 % CI 1.56-16.22). Delaying appropriate antibiotic therapy by more than 6 h (hazard ratio 2.78) and fatal underlying disease (hazard ratio 2.88) were associated with increased mortality. CONCLUSIONS: Patients with a prior history of receiving immunosuppressive therapy within 1 month and chronic liver disease have 8.1-fold and 5-fold increased risk of meningitis by L. monocytogenes compared to S. pneumoniae, respectively.
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Listeria monocytogenes , Meningite por Listeria/epidemiologia , Meningite Pneumocócica/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Fatores de Risco , Resultado do TratamentoRESUMO
The complexity of Alzheimer's disease (AD) stems from the inter-relation of multiple pathological factors upon initiation and progression of the disease. To identify the involvement of metal-bound amyloid-ß (metal-Aß) aggregation in AD pathology, among the pathogenic features found in the AD-affected brain, small molecules as chemical tools capable of controlling metal-Aß aggregation were developed. Herein, we report a new class of 2,2'-bipyridine (bpy) derivatives (1-4) rationally designed to be chemical modulators toward metal-Aß aggregation over metal-free Aß analogue. The bpy derivatives were constructed through a rational design strategy employing straightforward structural variations onto the backbone of a metal chelator, bpy: (i) incorporation of an Aß interacting moiety; (ii) introduction of a methyl group at different positions. The newly prepared bpy derivatives were observed to bind to metal ions [i.e., Cu(II) and Zn(II)] and interact with metal-Aß over metal-free Aß to varying degrees. Distinguishable from bpy, the bpy derivatives (1-3) were indicated to noticeably modulate the aggregation pathways of Cu(II)-Aß and Zn(II)-Aß over metal-free Aß. Overall, our studies of the bpy derivatives demonstrate that the alteration of metal binding properties as well as the installation of an Aß interacting capability onto a metal chelating framework, devised via the rational structure-based design, were able to achieve evident modulating reactivity against metal-Aß aggregation. Obviating the need for complicated structures, our design approach, presented in this work, could be appropriately utilized for inventing small molecules as chemical tools for studying desired metal-related targets in biological systems.
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2,2'-Dipiridil/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Cobre/farmacologia , Desenho de Fármacos , Zinco/farmacologia , 2,2'-Dipiridil/síntese química , 2,2'-Dipiridil/química , Peptídeos beta-Amiloides/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade , Zinco/químicaRESUMO
To prevent car accidents, it is important to evaluate the thermal stability of tire rubbers, such as natural rubber (NR), butadiene rubber (BR), and styrene-butadiene rubber (SBR). Controlling the glass transition temperature (Tg) is the main factor for obtaining desirable thermal stability. Here, we developed an optimized equation for the prediction of the Tg of the various rubber systems using molecular dynamics (MD) simulations. We modeled a random copolymer system, blended monomers, and calculated the Tg of butadiene isomers in each composition. From these results, we designed the Tg contour of ternary cis-trans-vinyl butadiene and derived an equation of Tg for the ternary system. Moreover, we developed an equation to evaluate the pseudo-ternary Tg of quaternary SBR and plotted it. Our results present a novel way of predicting the Tg of ternary BR and quaternary SBR, which is critical for rational tire design with optimized thermal and mechanical stability.
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By treating oleylamine (OA)-capped Ag-Cu nanoparticles with tetramethylammonium hydroxide (TMAH), we obtained metal nanoparticles that are suspended in polar solvents and sinterable at low temperatures. The simple process with ultra sonication enables synthesis of monodispersed and high purity nanoparticles in an organic base, where the resulting nanoparticles are dispersible in polar solvents such as ethanol and isopropyl alcohol. To investigate the surface characteristics, we conducted Fourier-transform infrared and zeta-potential analyses. After thermal sintering at 200 °C, which is approximately 150 °C lower than the thermal decomposition temperature of OA, an electrically conductive thin film was obtained. Electrical resistivity measurements of the TMAH-treated ink demonstrate that surface modified nanoparticles have a low resistivity of 13.7 × 10(-6) Ω cm. These results confirm the prospects of using low-temperature sinterable nanoparticles as the electrode layer for flexible printed electronics without damaging other stacked polymer layers.
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The mechanism of the catalytic oxidation of CO activated by MoS2-supported Au19 nanoparticles (NPs) was studied using density functional theory calculations. Of particular interest were the effects of the physical/chemical modification of a MoS2 support on the CO oxidation pathway and the activation of specific reactive centers, i.e., the Au atoms of Au19 or the Au-MoS2 perimeter sites. We systematically modified MoS2 by introducing an S vacancy or 5% tensile strain and studied the shift of each reaction step and the overall change in the reaction pathway and activity. Despite the lack of direct involvement of the Au-MoS2 perimeter in the reaction, the combination of an S vacancy and the tensile strain in the MoS2 support was found to improve the stability and catalytic activity of Au NPs for CO oxidation. The results show that support modification can provide information for new pathways for the rational design of Au-based catalysts.
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Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. Herein, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-ß (Aß) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand-peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer's disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aß forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, our in vitro and in vivo studies of DMPD toward Aß with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.