Natural Products as Regulators against Matrix Metalloproteinases for the Treatment of Cancer.

Cancers are currently the major cause of mortality in the world. According to previous studies, matrix metalloproteinases (MMPs) have an impact on tumor cell proliferation, which could lead to the onset and progression of cancers. Therefore, regulating the expression and activity of MMPs, especially MMP-2 and MMP-9, could be a promising strategy to reduce the risk of cancers. Various studies have tried to investigate and understand the pathophysiology of cancers to suggest potent treatments. In this review, we summarize how natural products from marine organisms and plants, as regulators of MMP-2 and MMP-9 expression and enzymatic activity, can operate as potent anticancer agents.

Chemical Insights into Topical Agents in Intraocular Pressure Management: From Glaucoma Etiopathology to Therapeutic Approaches.

Glaucoma encompasses a group of optic neuropathies characterized by complex and often elusive etiopathology, involvihttng neurodegeneration of the optic nerve in conjunction with abnormal intraocular pressure (IOP). Currently, there is no cure for glaucoma, and treatment strategies primarily aim to halt disease progression by managing IOP. This review delves into the etiopathology, diagnostic methods, and treatment approaches for glaucoma, with a special focus on IOP management. We discuss a range of active pharmaceutical ingredients used in glaucoma therapy, emphasizing their chemical structure, pharmacological action, therapeutic effectiveness, and safety/tolerability profiles. Notably, most of these therapeutic agents are administered as topical formulations, a critical aspect considering patient compliance and drug delivery efficiency. The classes of glaucoma therapeutics covered in this review include prostaglandin analogs, beta blockers, alpha agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and miotic (cholinergic) agents. This comprehensive overview highlights the importance of topical administration in glaucoma treatment, offering insights into the current state and future directions of pharmacological management in glaucoma.

Vitamin A, D, E, and K as Matrix Metalloproteinase-2/9 Regulators That Affect Expression and Enzymatic Activity.

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.

Metal Complexes as Promising Matrix Metalloproteinases Regulators.

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.

Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer's Disease.

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.

Aconitine Neurotoxicity According to Administration Methods.

We evaluated the toxic effects of aconitine on the human nervous system and its associated factors, and the general clinical characteristics of patients who visited the emergency room due to aconitine intoxication between 2008 and 2017. We also analyzed the differences related to aconitine processing and administration methods (oral pill, boiled in water, and alcohol-soaked), and the clinical characteristics of consciousness deterioration and neurological symptoms. Of the 41 patients who visited the hospital due to aconitine intoxication, 23 (56.1%) were female, and most were older. Aconitine was mainly used for pain control (28 patients, 68.3%) and taken as oral pills (19 patients, 46%). The patients showed a single symptom or a combination of symptoms; neurological symptoms were the most common (21 patients). All patients who took aconitine after processing with alcohol showed neurological symptoms and a higher prevalence of consciousness deterioration. Neurological symptoms occurred most frequently in patients with aconitine intoxication. Although aconitine intoxication presents with various symptoms, its prognosis may vary with the processing method and prevalence of consciousness deterioration during the early stages. Therefore, the administration method and accompanying symptoms should be comprehensively investigated in patients who have taken aconitine to facilitate prompt and effective treatment and better prognoses.

Target Enzymes Considered for the Treatment of Alzheimer's Disease and Parkinson's Disease.

Various amyloidogenic proteins have been suggested to be involved in the onset and progression of neurodegenerative diseases (ND) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Particularly, the aggregation of misfolded amyloid-ß and hyperphosphorylated tau and α-synuclein are linked to the pathogenesis of AD and PD, respectively. In order to care the diseases, multiple small molecules have been developed to regulate the aggregation pathways of these amyloid proteins. In addition to controlling the aggregation of amyloidogenic proteins, maintaining the levels of the proteins in the brain by amyloid degrading enzymes (ADE; neprilysin (NEP), insulin-degrading enzyme (IDE), asparagine endopeptidase (AEP), and ADAM10) is also essential to cure AD and PD. Therefore, numerous biological molecules and chemical agents have been investigated as either inducer or inhibitor against the levels and activities of ADE. Although the side effect of enhancing the activity of ADE could occur, the removal of amyloidogenic proteins could result in a relatively good strategy to treat AD and PD. Furthermore, since the causes of ND are diverse, various multifunctional (multitarget) chemical agents have been designed to control the actions of multiple risk factors of ND, including amyloidogenic proteins, metal ions, and reactive oxygen species. Many of them, however, were invented without considerations of regulating ADE levels and actions. Incorporation of previously created molecules with the chemical agents handling ADE could be a promising way to treat AD and PD. This review introduces the ADE and molecules capable of modulating the activity and expression of ADE.

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-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.

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

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.

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

Amyloid-ß (Aß) 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 Aß, 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. Our experimental and computational studies reveal that the catechol moiety, the hydroxyl groups at C3 and C7, and the position of the B ring are important for instilling multiple functions in flavonoids. We establish a structure-activity relationship of flavonoids that should be useful for designing chemical reagents with multiple reactivities against the pathological factors of AD.

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

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 (SP), 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 SP potentially interacts with amyloid-ß (Aß) and metal ions that are found as pathological components in AD-affected brains, with manifesting its reactivity towards metal-free Aß and metal-bound Aß (metal-Aß). Herein, we report, for the first time, that SP is capable of interacting with both Aß and metal ions and consequently affects the aggregation of metal-free Aß and metal-Aß. Moreover, incubation of SP with Aß in the absence and presence of metal ions results in the aggravation of toxicity induced by metal-free Aß and metal-Aß in living cells. As the simplest acyl derivatives of SP, N-acetylsphingosine and 3-O-acetylsphingosine also influence metal-free Aß and metal-Aß aggregation to different degrees, compared to SP. Such slight structural modifications of SP neutralize its ability to exacerbate the cytotoxicity triggered by metal-free Aß and metal-Aß. Notably, the reactivity of SP and the acetylsphingosines towards metal-free Aß and metal-Aß is determined to be dependent on their formation of micelles and micellar aggregates. Our overall studies demonstrate that SP and its derivatives could directly interact with pathological factors in AD and modify their pathogenic properties at concentrations below and above critical aggregation concentrations.

Correction: Monitoring metal-amyloid-ß complexation by a FRET-based probe: design, detection, and inhibitor screening.

[This corrects the article DOI: 10.1039/C8SC04943B.].

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 [e.g., amyloid-ß (Aß) 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 Aß peptides (i.e., coordination and coordination-/photo-mediated oxidation) implemented by a single Ir(iii) complex in a photo-dependent manner. Such peptide variations can be achieved by our rationally designed Ir(iii) complexes (Ir-Me, Ir-H, Ir-F, and Ir-F2) leading to significantly modulating the aggregation pathways of two main Aß isoforms, Aß40 and Aß42, as well as the production of toxic Aß species. Overall, we demonstrate chemical tactics for modification of amyloidogenic peptides in an effective and manageable manner utilizing the coordination capacities and photophysical properties of transition metal complexes.

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-ß, (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.

Monitoring metal-amyloid-ß complexation by a FRET-based probe: design, detection, and inhibitor screening.

Aggregation of amyloidogenic peptides could cause the onset and progression of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. These amyloidogenic peptides can coordinate to metal ions, including Zn(ii), which can subsequently affect the peptides' aggregation and toxicity, leading to neurodegeneration. Unfortunately, the detection of metal-amyloidogenic peptide complexation has been very challenging. Herein, we report the development and utilization of a probe (A-1) capable of monitoring metal-amyloid-ß (Aß) complexation based on Förster resonance energy transfer (FRET). Our probe, A-1, is composed of Aß1-21 grafted with a pair of FRET donor and acceptor capable of providing a FRET signal upon Zn(ii) binding even at nanomolar concentrations. The FRET intensity of A-1 increases upon Zn(ii) binding and decreases when Zn(ii)-bound A-1 aggregates. Moreover, as the FRET intensity of Zn(ii)-added A-1 is drastically changed when their interaction is disrupted, A-1 can be used for screening a chemical library to determine effective inhibitors against metal-Aß interaction. Eight natural products (out of 145 compounds; >80% inhibition) were identified as such inhibitors in vitro, and six of them could reduce Zn(ii)-Aß-induced toxicity in living cells, suggesting structural moieties useful for inhibitor design. Overall, we demonstrate the design of a FRET-based probe for investigating metal-amyloidogenic peptide complexation as well as the feasibility of screening inhibitors against metal-bound amyloidogenic peptides, providing effective and efficient methods for understanding their pathology and finding therapeutic candidates against neurodegenerative disorders.

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. 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.

Calprotectin influences the aggregation of metal-free and metal-bound amyloid-ß by direct interaction.

Proteins from the S100 family perform numerous functions and may contribute to Alzheimer's disease (AD). Herein, we report the effects of S100A8/S100A9 heterooligomer calprotectin (CP) and the S100B homodimer on metal-free and metal-bound amyloid-ß (Aß; Aß40 and Aß42) aggregation in vitro. Studies performed with CP-Ser [S100A8(C42S)/S100A9(C3S) oligomer] indicate that the protein influences the aggregation profile for Aß40 in both the absence and presence of metal ions [i.e., Zn(ii) and Cu(ii)]. Moreover, the detection of Aß40-CP-Ser complexes by mass spectrometry suggests a direct interaction as a possible mechanism for the involvement of CP in Aß40 aggregation. Although the interaction of CP-Ser with Aß40 impacts Aß40 aggregation in vitro, the protein does not attenuate Aß-induced toxicity in SH-SY5Y cells. In contrast, S100B has a slight effect on the aggregation of Aß. Overall, this work supports a potential association of CP with Aß in the absence and presence of metal ions in AD.

Tailoring Hydrophobic Interactions between Probes and Amyloid-ß Peptides for Fluorescent Monitoring of Amyloid-ß Aggregation.

Despite their unique advantages, the full potential of molecular probes for fluorescent monitoring of amyloid-ß (Aß) aggregates has not been fully exploited. This limited utility stems from the lack of knowledge about the hydrophobic interactions between the molecules of Aß probes, as well as those between the probe and the Aß aggregate. Herein, we report the first mechanistic study, which firmly establishes a structure-signaling relationship of fluorescent Aß probes. We synthesized a series of five fluorescent Aß probes based on an archetypal donor-acceptor-donor scaffold (denoted as SN1-SN5). The arylamino donor moieties were systematically varied to identify molecular factors that could influence the interactions between molecules of each probe and that could influence their fluorescence outcomes in conditions mimicking the biological milieu. Our probes displayed different responses to aggregates of Aß, Aß40 and Aß42, two major isoforms found in Alzheimer's disease: SN2, having pyrrolidine donors, showed noticeable ratiometric fluorescence responses (Δν = 797 cm-1) to the Aß40 and Aß42 samples that contained oligomeric species, whereas SN4, having N-methylpiperazine donors, produced significant fluorescence turn-on signaling in response to Aß aggregates, including oligomers, protofibrils, and fibrils (with turn-on ratios of 14 and 10 for Aß42 and Aß40, respectively). Mechanistic investigations were carried out by performing field-emission scanning electron microscopy, X-ray crystallography, UV-vis absorption spectroscopy, and steady-state and transient photoluminescence spectroscopy experiments. The studies revealed that the SN probes underwent preassembly prior to interacting with the Aß species and that the preassembled structures depended profoundly on the subtle differences between the amino moieties of the different probes. Importantly, the studies demonstrated that the mode of fluorescence signaling (i.e., ratiometric response versus turn-on response) was primarily governed by stacking geometries within the probe preassemblies. Specifically, ratiometric fluorescence responses were observed for probes capable of forming J-assembly, whereas fluorescence turn-on responses were obtained for probes incapable of forming J-aggregates. This finding provides an important guideline to follow in future efforts at developing fluorescent probes for Aß aggregation. We also conclude, on the basis of our study, that the rational design of such fluorescent probes should consider interactions between the probe molecules, as well as those between Aß peptides and the probe molecule.

Tuning Structures and Properties for Developing Novel Chemical Tools toward Distinct Pathogenic Elements in Alzheimer's Disease.

Multiple pathogenic factors [e.g., amyloid-ß (Aß), metal ions, metal-bound Aß (metal-Aß), reactive oxygen species (ROS)] are found in the brain of patients with Alzheimer's disease (AD). In order to elucidate the roles of pathological elements in AD, chemical tools able to regulate their activities would be valuable. Due to the complicated link among multiple pathological factors, however, it has been challenging to invent such chemical tools. Herein, we report novel small molecules as chemical tools toward modulation of single or multiple target(s), designed via a rational structure-property-directed strategy. The chemical properties (e.g., oxidation potentials) of our molecules and their coverage of reactivities toward the pathological targets were successfully differentiated through a minor structural variation [i.e., replacement of one nitrogen (N) or sulfur (S) donor atom in the framework]. Among our compounds (1-3), 1 with the lowest oxidation potential is able to noticeably modify the aggregation of both metal-free Aß and metal-Aß, as well as scavenge free radicals. Compound 2 with the moderate oxidation potential significantly alters the aggregation of Cu(II)-Aß42. The hardly oxidizable compound, 3, relative to 1 and 2, indicates no noticeable interactions with all pathogenic factors, including metal-free Aß, metal-Aß, and free radicals. Overall, our studies demonstrate that the design of small molecules as chemical tools able to control distinct pathological components could be achieved via fine-tuning of structures and properties.