Designing multi-target-directed flavonoids: a strategic approach to Alzheimer's disease.

The underlying causes of Alzheimer's disease (AD) remain a mystery, with multiple pathological components, including oxidative stress, acetylcholinesterase, amyloid-β, and metal ions, all playing a role. Here we report a strategic approach to designing flavonoids that can effectively tackle multiple pathological elements involved in AD. Our systematic investigations revealed key structural features for flavonoids to simultaneously target and regulate pathogenic targets.

Novel conformation of hyaluronic acid with improved cosmetic efficacy.

Background: Hyaluronic acid presents a valuable cosmetic ingredient that occurs naturally. Its direct links to skin aging has led to its broad application. The aim of this study was to improve the cosmetic efficacy of high molecular weight hyaluronic acid (HMWHA) without chemical modifications and evaluate such improvements through clinical and in vitro studies.

Drug repurposing: small molecules against Cu(II)-amyloid-β and free radicals.

Alzheimer's disease (AD) presents a complex pathology entangling numerous pathological factors, including amyloid-β (Aβ), metal ions, and reactive oxygen species (ROS). Increasing evidence reveals pathological connections among these distinct components in AD. For instance, the association between the amyloid cascade and metal ion hypotheses has introduced a novel pathogenic target: metal-bound Aβ.

Impact of sphingosine and acetylsphingosines on the aggregation and toxicity of metal-free and metal-treated amyloid-β.

Pathophysiological shifts in the cerebral levels of sphingolipids in Alzheimer's disease (AD) patients suggest a link between sphingolipid metabolism and the disease pathology. Sphingosine (), a structural backbone of sphingolipids, is an amphiphilic molecule that is able to undergo aggregation into micelles and micellar aggregates. Considering its structural properties and cellular localization, we hypothesized that potentially interacts with amyloid-β (Aβ) and metal ions that are found as pathological components in AD-affected brains, with manifesting its reactivity towards metal-free Aβ and metal-bound Aβ (metal-Aβ).

Multiple reactivities of flavonoids towards pathological elements in Alzheimer's disease: structure-activity relationship.

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 elements of AD: metal-free and metal-bound Aβ, free radicals, and acetylcholinesterase. A series of 12 flavonoids was selected based on the molecular structures that are responsible for multiple reactivities including hydroxyl substitution and transfer of the B ring from C2 to C3.

A Glycosylated Prodrug to Attenuate Neuroinflammation and Improve Cognitive Deficits in Alzheimer's Disease Transgenic Mice.

We report a prodrug, , to overcome the shortcomings of an anti-neuroinflammatory molecule, -diacetyl--phenylenediamine (), in biological applicability for potential therapeutic applications. We suspect that can release through endogenous enzymatic bioconversion. Consequently, exhibits in vivo efficacies in alleviating neuroinflammation, reducing amyloid-β aggregate accumulation, and improving cognitive function in Alzheimer's disease transgenic mice.

Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia.

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 approaches for chemically modifying the coordination sphere of copper-amyloid-β complexes.

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.

,'-Diacetyl--phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer's disease transgenic mice.

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 (,'-diacetyl--phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the 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.

Chemical strategies to modify amyloidogenic peptides using iridium(iii) complexes: coordination and photo-induced oxidation.

Amyloidogenic peptides are considered central pathological contributors towards neurodegeneration as observed in neurodegenerative disorders [, amyloid-β (Aβ) peptides in Alzheimer's disease (AD)]; however, their roles in the pathologies of such diseases have not been fully elucidated since they are challenging targets to be studied due to their heterogeneous nature and intrinsically disordered structure. Chemical approaches to modify amyloidogenic peptides would be valuable in advancing our molecular-level understanding of their involvement in neurodegeneration. Herein, we report effective chemical strategies for modification of Aβ peptides (, coordination and coordination-/photo-mediated oxidation) implemented by a single Ir(iii) complex in a photo-dependent manner.

Orobol: An Isoflavone Exhibiting Regulatory Multifunctionality against Four Pathological Features of Alzheimer's Disease.

We report orobol as a multifunctional isoflavone with the ability to (i) modulate the aggregation pathways of both metal-free and metal-bound amyloid-β, (ii) interact with metal ions, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase. Such a framework with multifunctionality could be useful for developing chemical reagents to advance our understanding of multifaceted pathologies of neurodegenerative disorders, including Alzheimer's disease.

Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis in the Last Decade.

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.

Strategic Design of 2,2'-Bipyridine Derivatives to Modulate Metal-Amyloid-β Aggregation.

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-β (metal-Aβ) aggregation in AD pathology, among the pathogenic features found in the AD-affected brain, small molecules as chemical tools capable of controlling metal-Aβ 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-Aβ aggregation over metal-free Aβ analogue.

Cell death mechanistic study of photodynamic therapy against breast cancer cells utilizing liposomal delivery of 5,10,15,20-tetrakis(benzo[b]thiophene) porphyrin.

5,10,15,20-Tetrakis(benzo[b]thiophene) porphyrin (BTP) is a newly synthesized hydrophobic photosensitizer with fluorescence quantum yield in toluene: Φ=0.062. Previously, its limitations in solubility had hindered scientific experimentation regarding its photodynamic effects on cancer cells.

Electrocatalytic H2 Evolution by Supramolecular Ru(II)-Rh(III)-Ru(II) Complexes: Importance of Ligands as Electron Reservoirs and Speciation upon Reduction.

The supramolecular water reduction photocatalysts [{(Ph2phen)2Ru(dpp)}2RhX2](PF6)5 (Ph2phen = 4,7-diphenyl-1,10-phenanthroline, dpp =2,3-bis(2-pyridyl)pyrazine X = Cl, Br) are efficient electrocatalysts for the reduction of CF3SO3H, CF3CO2H, and CH3CO2H to H2 in DMF or DMF/H2O mixtures. The onset of catalytic current occurs at -0.82 V versus Ag/AgCl for CF3SO3H, -0.