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.

Even with the prevalence of wounds, the medical technology for efficiently managing skin damage is still primitive. The disruption of any of the numerous healing processes can lead to problems in the time-sensitive healing actions of the dermal and epidermal layers. Bacterial infection is one of the major obstacles to proper wound healing as it poses a danger of causing long-term negative effects. Keeping the wound free of bacteria is imperative to the proper and hasty repair of dermal wounds. Silver has been widely used to treat wounds for its bactericidal properties. Although the mechanism of silver's antibacterial action is not fully understood, it exhibits a significant antimicrobial efficacy against a wide spectrum of bacterial species. A number of different approaches to the mechanism are reported and presented in this review. Silver nanoparticles (AgNPs) have been reported to exhibit enhanced antibacterial activity due to their increased surface-area-to-volume ratio. AgNPs are capable of various modifications, significantly broadening the therapeutic properties of the material as a result. This review explores the different aspects of silver and silver nanoparticles, and their antibacterial properties, which can be applied in the field of wound treatments.

Amyloid-β (Aβ) accumulation, metal ion dyshomeostasis, oxidative stress, and cholinergic deficit are four major characteristics of Alzheimer’s disease (AD). Herein, we report the reactivities of 12 flavonoids against four pathogenic...

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-β (Aβ), and metal-bound Aβ 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 Aβ, leading to chemical modifications of the Aβ peptides to form covalent adducts that alter the aggregation of Aβ. 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.

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N′-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-β (Aβ) species and significantly improving cognitive function in the brains of 2 types of Alzheimer’s disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aβ clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

Neurotoxic implications of the interactions between Cu(I/II) and amyloid-β (Aβ) 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 Aβ utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)–Aβ was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)–Aβ was able to disrupt binding of Cu(II) to Aβ and result in chemically modified Aβ with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)–Aβ could stem from the molecule’s ability to 1) interact with Cu(II)–Aβ and 2) foster copper–O2 chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)–Aβ at a metal-binding amino acid residue and consequently alter Aβ’s coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity.

A lzheimer's disease (AD), the most common form of dementia, is characterized by neurodegeneration, memory loss, and cognitive impairment. 1a Notably reduced levels of neurotransmitters (e.g., acetylcholine, amino acids, monoamines) leading to neurotransmission deficits are indicated to prompt the symptoms and progression of AD. 1a Cholinergic deficit as a consequence of the insufficient acetylcholine levels in the AD-affected brain is strongly implicated in undermining the central nervous system and compromising the patient's ability to learn and recall information. 1a In addition, the dyshomeostasis and miscompartmentalization of metal ions, which are involved in neurotransmission with modulatory implications (e.g., antagonistic effects on neurotransmitter receptors and influence on activating ion channels), represent a key pathological feature of AD. 1a Association of neurotransmitters or metal ions with amyloid-β (Aβ), an aggregation-prone peptide formed through the amyloidogenic processing of amyloid precursor protein (APP) at the synaptic membrane, indicates the intertwined pathology of AD. Despite the significance of such research, however, information on the effects of interactions among metal ions, Aβ, and neurotransmitters on AD-associated neurodegeneration is limited due to (i) the heterogeneous and metastable nature of Aβ and (ii) the dynamic environment at the synapse.In the brains of AD patients, highly concentrated metals (e.g., 0.4 mM Cu, 0.9 mM Fe, 1 mM Zn) are localized in senile plaques composed of Aβ aggregates. 1a Furthermore, copper is reported to reach high micromolar concentrations at the synapse upon neuronal excitation, 1b which suggests the potential interaction between copper and Aβ at the synaptic cleft. Ying et al. simulated Cu(I/II) binding to Aβ in an in vitro model of the synaptic environment with a firing frequency in the range of 1−100 Hz. 2 Using reaction-diffusion simulations, a model system used to indicate potential binding reactions under specific conditions, when synaptic concentrations of Cu(I/II) or Zn(II) and Aβ were mimicked (e.g., 30 μM of Cu, 300 μM of Zn, 3 nM of Aβ), the newly generated Cu(I)−Aβ and Cu(II)−Aβ accounted for ca. 27% and 9% of the total Aβ concentration, respectively. 2 On the other hand, Zn(II) exhibited a low propensity for Aβ with Zn(II)−Aβ reaching only a picomolar concentration at the end of reaction-diffusion simulations. 2 Cu(I/II) coordination to Aβ occurs through the N-terminal and histidine amino acid residues (e.g., D1, A2, H6, H13, H14) with notable binding affinities [i.e., K d (for Cu(I)−Aβ), 10 −15 −10 −8 M; K d (for Cu(II)−Aβ), 10 −11 −10 −7 M]. 1a Direct interactions of Aβ with Cu(I/II) change the conformation and aggregation pathways of the peptide (e.g., formation and stabilization of toxic oligomeric species, facilitation of Aβ

Silver nanoparticles (AgNPs) are capable of inhibiting the growth of a broad spectrum of bacterial species. The minute size of the nanoparticulates enhances their biocidal activity and is thus widely utilized as antibacterial agents. The most recently researched and recognized antibacterial and wound-healing properties of published AgNPs were investigated in this article. The following parameters of the AgNPs affecting their properties and potency were explored: particle size, shape, and type of ligand or stabilizing agent. Research regarding the antibacterial activity enhancement of high-valent silver nanoparticles compared to those of the lower valent forms were summarized and analyzed. Nanocrystalline silver is capable of binding to components that may enhance their preparation and antibacterial properties. By forming complexes with ligands that exhibit desired properties, silver nanoparticles can be synthesized to exhibit those desired properties without compromising their performance. This review will provide a detailed discussion regarding the parameter-dependent bactericidal properties of silver nanoparticles and nanocomposite silver complexes as potent multifunctional wound-healing agents. Graphical AbstractKeywords Silver nanoparticles Á High-valence silver Á Antibacterial Á Wound healing Á Cell proliferation Abbreviations AgNPsSilver nanoparticles ADP Adenosine diphosphate ATP Adenosine triphosphate SEM Scanning electron microscopy AFM Atomic force microscopy DLS Dynamic light scattering TEM Transmission electron microscopy XPS X-ray photoelectron spectroscopy XRD Powder X-ray diffraction