Search Results (107)

This paper presents the modified arithmetic optimization algorithm (MAOA), a swift and effective optimization algorithm specifically designed for electromagnetic applications. Its primary advantage is its ability to avoid local minima by striking a balance between global exploration and local exploitation searches. This equilibrium is maintained through three key improvements: an enhanced initialization process, a distinctive guidance mechanism for steering searches, and an additional learning phase to refine newly found solutions. This process innovation significantly boosts MAOA’s performance in addressing both constrained and unconstrained optimization challenges. In this study, MAOA is applied to optimize the spacing and current amplitude of linear antenna array (LAA) elements, with the goal of minimizing peak side lobe level (PSLL), close-in side lobe level (CSLL), and overall side lobe level (SLL), both with and without constraints on first null beamwidth (FNBW), as well as null positioning with SLL minimization. Ten designs, comprising 10 and 20 antenna elements of LAA and one 14-element circular antenna array (CAA), showcase MAOA’s proficiency in antenna array pattern synthesis. Optimizing element positions results in a PSLL of −21.28 dB, a CSLL of −34.50 dB, and a null depth of −89.00 dB, while optimizing current amplitude achieves a PSLL of −24.32 dB, a CSLL of −29.73 dB, and a null depth of −77.60 dB across various antenna designs. Simulation results reveal that MAOA significantly surpasses traditional uniform linear arrays (ULA) and established optimization techniques. Its superiority is further confirmed through a Wilcoxon rank-sum and Friedman test. Full article

The development of more effective treatments for neurodegenerative disorders presents a significant challenge in modern medicine. Currently, scientists are focusing on discovering bioactive compounds from plant sources to prevent and treat neurodegenerative diseases. Fifteen flavonoids and saponins from C. foliosum Asch. and C. bonus-henricus L. were tested for their inhibitory activity on hMAO-A and hMAO-B. Five compounds (1 μM) exhibit a weak inhibitory effect on hMAO-A and show good inhibitory activity against the hMAO-B enzyme (30–35%), compared to the positive control selegiline (55%). These active compounds were examined on rat brain synaptosomes and mitochondria obtained by multiple differential centrifugations using a Percoll gradient. Their effects were also monitored on rat brain microsomes obtained by double differential centrifugation. The main parameters characterizing the functional–metabolic status of subcellular fractions are synaptosomal viability, GSH level, and MDA production. All tested compounds (50 μM) demonstrated significant neuroprotective and antioxidant activities across models of induced oxidative stress, including 6-OHDA, t-BuOOH, and Fe^2+/AA-induced lipid peroxidation. The plausible mechanisms of neuroprotection rely on MAO-B inhibition, the scavenging of ROS, stabilizing the cell membrane by reducing MDA production, and neutralizing free radicals by maintaining GSH levels. In addition, we developed and validated a UHPLC-HRMS method for identifying and simultaneously quantificatying flavonoids and saponins in the aerial parts of C. foliosum. Compounds 30-normedicagenic acid- HexA-Hex-TA 22f and medicagenic acid-HexA-Hex-TA 25f were considered new natural compounds. Full article

Background: Depression is one of the most serious and common health problems among the youth population and is responsible for the initiation of many diseases. As per the World Health Organization, 3.8% of the population suffers from mental depression, globally. The monoamine oxidase-A (MAO-A) enzyme is responsible for the degradation of neurotransmitters leading to lower levels of neurotransmitters. Methods: Chalcones (C1-C15) were synthesized by reacting substituted acetophenone with various benzaldehydes in a basic ethanolic solvent at 80 °C under microwave irradiation conditions. To compare the reaction time and product yield, a conventional method of synthesis of chalcones was also performed. The synthesized chalcones (C1-C15) were spectroscopically characterized and screened initially for inhibitory activities against MAO-A and MAO-B. The best active compounds were undertaken for IC₅₀ determination against MAO-A enzyme followed by the reversibility of inhibition analysis and the antioxidant assay. Moreover, in silico molecular docking and ADME pharmacokinetic investigations were accomplished. Results: Most of the compounds inhibited MAO-A, specifically, compounds C14 and C6 exhibited the highest inhibition at IC₅₀ values of 7.91 ± 0.08 μM and 8.45 ± 0.19 μM, respectively. Both these compounds exhibited a reversible MAO-A inhibition displaying up to 60% recovery of enzymatic activity when diluted with substrate (Tyramine). The results of the in silico study indicated docking scores of −9.56 Kcal/mol (C14) and −9.45 Kcal/mol (C6) and exhibited a π-π stacking interaction with the crucial amino acid Trp-397. The compounds were determined to cross the blood–brain barrier (BBB) and displayed favorable gastrointestinal (GI) absorption. Further, the antioxidant assay results demonstrated that the synthesized compounds possess modest free radical scavenging potential. Conclusions: This study displayed the MAO-A inhibitory potential of morpholine-substituted chalcones as a promising pharmacophore for the development of novel antidepressant lead compounds. Full article

Valerian possesses a multitude of pharmacological effects, including sedative and hypnotic properties, antihypertensive effects, antibacterial activity, and liver protection. Insomnia, one of the most prevalent disorders in contemporary society, significantly impacts people’s daily lives. This study aims to explore the anti-insomnia effects of valerian volatile oil (VVO) and investigate its potential mechanism of action through chemical analysis, network pharmacology, molecular docking, molecular dynamics simulations, and experimental validation. Through gas chromatography–mass spectrometry (GC-MS) analysis and drug-likeness screening, we identified 38 active compounds. Network pharmacology studies revealed that these 38 compounds might affect 103 targets associated with insomnia, such as monoamine oxidase B (MAOB), dopamine receptor D2 (DRD2), monoamine oxidase A (MAOA), interleukin 1β (IL1B), solute carrier family 6 member 4 (SLC6A4), prostaglandin-endoperoxide synthase 2 (PTGS2), and 5-hydroxytryptamine receptor 2A (HTR2A), which contribute to regulating the neuroactive ligand–receptor interaction, 5-hydroxytryptaminergic synapse, and calcium signaling pathways. The results of the molecular dynamics simulations indicated that bis[(6,6-dimethyl-3-bicyclo[3.1.1]hept-2-enyl)methyl] (E)-but-2-enedioate exhibited a stabilizing interaction with MAOB. The animal studies demonstrated that gavage administration of a high dose (100 mg/kg) of VVO significantly diminished autonomous activity, decreased sleep latency, and extended sleep duration in mice. Furthermore, the results of the Western blot experiment indicated that VVO interacts with MAOB, resulting in decreased expression levels of MAOB in the cerebral cortex. This study demonstrates the protective mechanism of VVO against insomnia through chemical analysis, network pharmacology, and experimental validation and extends the possible applications of VVO, which is a potential therapeutic ingredient for use in insomnia treatment. Full article

Given its antioxidant effects and central nervous system benefits, we hypothesized that RJ6601 should improve neurodegeneration in the hippocampus, a region critical for cognition and the maintenance of quality of life (QoL). To assure its safety, a single fixed dose of 2000 mg/kg BW was administered to female Wistar rats (250–450 g, 18 months old) to test the acute toxicity of RJ6601. No mortality and toxicity signs were observed. To prove that RJ6601 can protect against age-related neurodegeneration, RJ6601 at doses of 200 and 400 mg/kg BW was administered to the female Wistar rats once daily for 4 weeks. At the end of the study period, assessments were conducted to evaluate the neuron density; MDA levels; and activities of SOD, CAT, GSH-Px, AChE, total MAO, MAO-A, and MAO-B in the hippocampus. Our results reveal increased neuron density, SOD, CAT, and GSH-Px but decreased MDA, AChE, total MAO, MAO-A, and MAO-B in the hippocampi of female Wistar rats subjected to RJ6601 treatment at both doses used in this study. Therefore, RJ6601 is considered to have low toxicity and may improve neurodegeneration as well as cholinergic and monoaminergic dysfunctions. Subchronic toxicity studies and clinical trials are essential to confirm the safety of RJ6601 consumption and its health benefits. Full article

Monoamine oxidase B (MAO-B) inhibitors are widely used as part of combination drug therapy for Parkinson’s disease. As demonstrated in both in vitro and in vivo experiments, the monoterpenoid Prottremine and some of its derivatives exhibit high antiparkinsonian activity. In this study, the inhibitory activity of Prottremine and its derivatives (including 14 new 9-N- and S-derivatives) against MAO-A and MAO-B enzymes has been investigated for the first time. Compounds containing fragments of substituted anilines have demonstrated the highest activity against MAO-A; for example, compound 28 had an IC₅₀ of 178 ± 44 μM. A significant proportion of the compounds tested, including Prottremine, exhibited moderate inhibitory activity towards MAO-B, with the most active being the o-aminoacetophenone derivative, which had an IC₅₀ of 95 ± 5 μM. A molecular docking method for studying murine MAO-A and -B enzymes was developed using AlphaFold2 (v2.3.2), with further improvements. For the MAO-B enzyme, a strong correlation was observed between the molecular docking data and the measured activity of the compounds, with the maximum binding affinity registered for the most active compound. It is conceivable that the antiparkinsonian activity of Prottremine and some of its derivatives may be partially mediated, among other mechanisms, by MAO-B enzyme inhibition. Full article

Three new acylated benzophenone O-glycosides named aucherosides A–C (4–6), together with five known compounds such as mangiferin (1), maclurin-6-O-β-D-glucopyranoside (2), 1-O-galloyl-β-D-glucose (3), vanillic acid (7), and 5-hydroxy-2-isopropylchromone-7-O-β-glucoside (8), were isolated from the aerial parts of Hypericum aucheri Jaub. and Spach and identified with spectroscopic methods (1D and 2D NMR, and HRESIMS). Compounds 2, 4–6, 8, and previously isolated from the title plant aucherines A–C (9–11), were tested for hMAO-A and B inhibitory effects and neuroprotection. All tested compounds (1 µM) did not exhibit any inhibitory effect on hMAO-A and showed significant inhibitory activity against the hMAO-B enzyme. Notably, compound 8 demonstrated the strongest hMAO-B inhibition, approaching that of the positive control selegiline. At high concentrations (100 µM), all tested compounds showed no neurotoxic or pro-oxidant effects on rat brain synaptosomes, mitochondria, and microsomes. All tested compounds exhibited good neuroprotective and antioxidant activities in various neurotoxicity models (6-hydroxydopamine-induced neurotoxicity on synaptosomes, tert-butyl hydroperoxide-induced oxidative stress on mitochondria, and non-enzymatic lipid peroxidation on microsomes). The neuroprotective mechanisms of these compounds may include MAO-B inhibition, reactive oxygen species (ROS) scavenging, membrane stabilization, and preservation of reduced glutathione (GSH), the primary nucleophilic ROS scavenger. Full article

Multi-target-directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies like Alzheimer’s disease (AD). The synergistic inhibition of MAO-B, MAO-A, and AChE is believed to enhance treatment efficacy. A novel coumarin-based molecule substituted with O-phenylpiperazine via three- and four-carbon linkers at the 5- and 7-positions, has been identified as an effective MTDL against AD. Employing a medicinal chemistry approach, combined with molecular docking, molecular dynamic simulation, and ΔG_bind estimation, two series of derivatives emerged as potent MTDLs: 8-acetyl-7-hydroxy-4-methylcoumarin (IC₅₀: 1.52–4.95 μM for hAChE, 6.97–7.65 μM for hMAO-A) and 4,7-dimethyl-5-hydroxycoumarin (IC₅₀: 1.88–4.76 μM for hMAO-B). They displayed binding free energy (ΔG_bind) of −76.32 kcal/mol (11) and −70.12 kcal/mol (12) against AChE and −66.27 kcal/mol (11) and −62.89 kcal/mol (12) against MAO-A. It is noteworthy that compounds 11 and 12 demonstrated efficient binding to both AChE and MAO-A, while compounds 3 and 10 significantly reduced MAO-B and AChE aggregation in vitro. These findings provide structural templates for the development of dual MAO and AChE inhibitors for the treatment of neurodegenerative diseases. Full article

Background/Objectives: Corema album berries are edible fruits from the Iberian Atlantic coast, characterized by a rich polyphenolic composition, which endows their juice with potential protective effects against neurodegeneration. This study aimed to evaluate the potential of the relatively lesser-known C. album berries as a novel neuroprotective agent against neurodegenerative diseases. Methods: The phenolic compounds of the juice were characterized using UHPLC-HRMS (Orbitrap). The SH-SY5Y neuroblastoma line was used to determine the preventive effect of the juice against H₂O₂-induced oxidative stress. Furthermore, neuronal cells were differentiated into dopaminergic and cholinergic lines and exposed to 6-hydroxydopamine and okadaic acid, respectively, to simulate in vitro models of Parkinson’s disease and Alzheimer’s disease. The ability of the juice to enhance neuronal viability under toxic conditions was examined. Additionally, its inhibitory effects on neuroprotective-related enzymes, including MAO-A and MAO-B, were assessed in vitro. Results: Phytochemical characterization reveals that 5-O-caffeoylquinic acid constitutes 80% of the total phenolic compounds. Higher concentrations of the juice effectively protected both differentiated and undifferentiated SH-SY5Y cells from H₂O₂-induced oxidative damage, reducing oxidative stress by approximately 20% and suggesting a dose-dependent mechanism. Moreover, the presence of the juice significantly enhanced the viability of dopaminergic and cholinergic cells exposed to neurotoxic agents. In vitro, the juice inhibited the activity of MAO-A (IC₅₀ = 87.21 µg/mL) and MAO-B (IC₅₀ = 56.50 µg/mL). Conclusions: While these findings highlight C. album berries as a promising neuroprotective agent, further research is required to elucidate its neuroprotective mechanisms in cell and animal models and, ultimately, in human trials. Full article

Monoamine oxidases (MAOs), mitochondrial enzymes that constantly produce hydrogen peroxide (H₂O₂) as a byproduct of their activity, have been recently acknowledged as contributors to oxidative stress in cardiometabolic pathologies. The present study aimed to assess whether MAOs are mediators of valvular oxidative stress and interact in vitro with angiotensin 2 (ANG2) to mimic the activation of the renin–angiotensin system. To this aim, valvular tissue samples were harvested from 30 patients diagnosed with severe primary mitral regurgitation and indication for surgical repair. Their reactive oxygen species (ROS) levels were assessed by means of a ferrous oxidation xylenol orange (FOX) assay, while MAO expression was assessed by immune fluorescence (protein) and qRT-PCR (mRNA). The experiments were performed using native valvular tissue acutely incubated or not with angiotensin 2 (ANG2), MAO inhibitors (MAOI) and the angiotensin receptor blocker, irbesartan (Irb). Correlations between oxidative stress and echocardiographic parameters were also analyzed. Ex vivo incubation with ANG2 increased MAO-A and -B expression and ROS generation. The level of valvular oxidative stress was negatively correlated with the left ventricular ejection fraction. MAOI and Irb reduced valvular H₂O_2. production. In conclusion, both MAO isoforms are expressed in pathological human mitral valves and contribute to local oxidative stress and ventricular functional impairment and can be modulated by the local renin–angiotensin system_. Full article

Neurodegenerative diseases such as Parkinson’s and Alzheimer’s continue to be some of the most significant challenges in modern medicine. Recent research related to the molecular mechanisms of parkinsonism has opened up new approaches to antiparkinsonian therapy. In response to this, we present the evaluation of the potential neuroprotective and MAOA/MAOB inhibitory effects of newly synthesized hydrazones, containing a pyrrole moiety in the carboxyl fragment of the structure. The substances were studied on different brain subcellular fractions, including rat brain synaptosomes, mitochondria, and microsomes. The single application of 50 µM of each compound to the subcellular fractions showed that all substances exhibit a weak neurotoxic effect, with 7b, 7d, and 8d being the least neurotoxic representatives. The corresponding neuroprotective and antioxidant effects were also evaluated in different injury models on subcellular fractions, single out 7b, 7d, and 8d as the most prominent derivatives. A 1 µM concentration of each molecule from the series was also studied for potential hMAOA/hMAOB inhibitory effects. The results revealed a lack of hMAOA activity for all evaluated structures and the appearance of hMAOB effects, with compounds 7b, 7d, and 8d showing effects similar to those of selegiline. The best hMAOB selectivity index (>204) was determined for 7d and 8d, distinguishing these two representatives as the most promising molecules for further studies as potential selective MAOB inhibitors. The performed molecular docking simulations defined the appearance of selective MAOB inhibitory effects based on the interaction of the tested molecules with Tyr398, which is one of the components of the aromatic cage of MAOB and participated in π–π stabilization with the aromatic pyrrole ring. The preliminary PAMPA testing indicated that in relation to the blood–brain barrier (BBB) permeability, the tested pyrrole-based hydrazones may be considered as high permeable, except for 8a and 8e, which were established to be permeable in the medium range with −logP of 5.268 and 5.714, respectively, compared to the applied references. Full article

Stress-related anxiety disorders and anxiety-like behavior in post-traumatic stress disorder (PTSD) are associated with altered neurocircuitry pathways, neurotransmitter systems, and the activities of monoamine and glucocorticoid-metabolizing enzymes. Resveratrol, a natural polyphenol, is recognized for its antioxidant, anti-inflammatory, and antipsychiatric properties. Previous studies suggest that resveratrol reduces anxiety-like behavior in animal PTSD models by downregulating key enzymes such as 11$\beta$-hydroxysteroid dehydrogenase type 1 (11$\beta$-HSD-1) and monoamine oxidases (MAOs). However, the underlying mechanisms remain unclear. In this study, we explored the efficacy of resveratrol in treating stress-induced anxiety using a chronic predator stress model in rats. Resveratrol was administered intraperitoneally at 100 mg/kg following a 10-day stress exposure, and anxiety behavior was assessed with an elevated plus maze. Our results indicated that stress-related anxiety correlated with increased activities of brain MAO-A, MAO-B, and hepatic 11$\beta$-HSD-1, alongside elevated oxidative stress markers in the brain and liver. Resveratrol treatment improved anxiety behavior and decreased enzyme activities, oxidative stress, and hepatic damage. We demonstrate that resveratrol exerts antianxiogenic effects by modulating glucocorticoid and monoamine metabolism in the brain and liver. These findings suggest resveratrol’s potential as a therapeutic agent for anxiety disorders, warranting further clinical investigation. Full article

Considering the complex pathogenesis of Alzheimer’s disease (AD), the multi-target ligand strategy is expected to provide superior effects for the treatment of the neurological disease compared to the classic single target strategy. Thus, one novel pyrrole-based hydrazide (vh0) and four corresponding hydrazide–hydrazones (vh1-4) were synthesized by applying highly efficient MW-assisted synthetic protocols. The synthetic pathway provided excellent yields and reduced reaction times under microwave conditions compared to conventional heating. The biological assays indicated that most of the novel pyrroles are selective MAO-B inhibitors with IC₅₀ in the nanomolar range (665 nM) and moderate AChE inhibitors. The best dual-acting MAO-B/AChE inhibitor (IC₅₀ hMAOB–0.665 μM; IC₅₀ eeAChE—4.145 μM) was the unsubstituted pyrrole-based hydrazide (vh0). Importantly, none of the novel molecules displayed hMAOA-blocking capacities. The radical-scavenging properties of the compounds were examined using DPPH and ABTS in vitro tests. Notably, the hydrazide vh0 demonstrated the best antioxidant activities. In addition, in silico simulations using molecular docking and MM/GBSA, targeting the AChE (PDB ID: 4EY6) and MAO-B (PDB: 2V5Z), were utilized to obtain active conformations and to optimize the most prominent dual inhibitor (vh0). The ADME and in vitro PAMPA studies demonstrated that vh0 could cross the blood–brain barrier, and it poses good lead-like properties. Moreover, the optimized molecular structures and the frontier molecular orbitals were examined via DFT studies at 6-311G basis set in the ground state. Full article

Due to the health benefits of polyphenols and dietary fiber in combating mental disorders, we hypothesized that a polyphenol- and dietary fiber-enriched soup (RJ6601) would improve mental wellness in a rat model of middle-aged women. To test this hypothesis, female Wistar rats aged 18 months (350–450 g) were orally administered RJ6601 at doses of 200 and 400 mg/kg BW for 28 days. The anxiolytic, antidepression, and memory-enhancing effects were assessed every 7 days throughout the study period. The neuron density and levels of activities of AChE, total MAO, MAO-A, MAO-B, MDA, SOD, CAT, GSH-Px, IL-1β, IL-6, and BDNF in the prefrontal cortex at the end of study were also investigated. Furthermore, the amounts of Lactobacillus spp. and Bifidobacterium spp. in their feces were also determined. The results revealed that the developed soup shows anxiolytic, antidepression, and memory-enhancing effects. An increased neuron density; reductions in AChE, total MAO, MAO-A, MAO-B, and MDA; and an elevation of serum BDNF, together with increased amounts of both bacterial species in feces, were also observed. Our results suggest that RJ6601 is a potential mental wellness promotion supplement that enhances BDNF levels, brain plasticity, neurotransmitter balance, and oxidative stress and inflammation status, along with improving microbiota. Full article

Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson’s disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC₅₀ value of 0.203 μM, followed by S16 (IC₅₀ = 0.979 μM). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC₅₀ value of 3.691 μM, followed by S5 (IC₅₀ = 3.857 μM). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH₃ > -F > -CN > -CH₃ > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the K_i values of S5 and S16 for MAO-B were 0.155 ± 0.050 and 0.721 ± 0.074 μM, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood–brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-S5 complex by pi–pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders. Full article