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Prostate cancer (PC) develops in a microenvironment where the stromal cells modulate adjacent tumor growth and progression. Here, we demonstrated elevated levels of monoamine oxidase B (MAOB), a mitochondrial enzyme that degrades biogenic and dietary monoamines, in human PC stroma, which was associated with poor clinical outcomes of PC patients. Knockdown or overexpression of MAOB in human prostate stromal fibroblasts indicated that MAOB promotes cocultured PC cell proliferation, migration, and invasion and co-inoculated prostate tumor growth in mice. Mechanistically, MAOB induces a reactive stroma with activated marker expression, increased extracellular matrix remodeling, and acquisition of a protumorigenic phenotype through enhanced production of reactive oxygen species. Moreover, MAOB transcriptionally activates CXCL12 through Twist1 synergizing with TGFβ1-dependent Smads in prostate stroma, which stimulates tumor-expressed CXCR4-Src/JNK signaling in a paracrine manner. Pharmacological inhibition of stromal MAOB restricted PC xenograft growth in mice. Collectively, these findings characterize the contribution of MAOB to PC and suggest MAOB as a potential stroma-based therapeutic target.

The inner mitochondrial membrane (IMM) generates power to drive cell function, and its dynamics control mitochondrial health and cellular homeostasis. Here, we describe the cell-permeant, lipid-like small molecule MAO-N3 and use it to assemble high-density environmentally sensitive (HIDE) probes that selectively label and image the IMM in live cells and multiple cell states. MAO-N3 pairs with strain-promoted azide-alkyne click chemistry-reactive fluorophores to support HIDE imaging using confocal, structured illumination, single-molecule localization and stimulated emission depletion microscopy, all with significantly improved resistance to photobleaching. These probes generate images with excellent spatial and temporal resolution, require no genetic manipulations, are non-toxic in model cell lines and primary cardiomyocytes (even under conditions that amplify the effects of mitochondrial toxins) and can visualize mitochondrial dynamics for 12.5 h. This probe will enable comprehensive studies of IMM dynamics with high temporal and spatial resolution.

Background: Monoamine oxidase-B (MAO-B) is crucial in breaking down biogenic and dietary amines, with its dysregulation linked to Parkinson’s disease. Objective: This study aims to explore the MAO-B inhibitory potential of 34 hydrazine-linked thiazole derivatives through computational techniques. Methods: Molecular docking against MAO-B (2BYB) assessed binding affinity, complemented by MMGBSA for binding energy evaluation. Pharmacophore modeling and QSAR analysis identified structural features essential for inhibition, while molecular dynamics (MD) simulations validated the stability of ligand-MAO-B complexes. Results: Compound T18 exhibited outstanding binding affinity, while T9 showed the lowest. In vitro studies revealed that T2 had the weakest inhibitory potential, while T19 demonstrated the highest. Pharmacophore modeling identified the six-feature hypothesis ADHRRR_1 as the key structural feature for optimal inhibition. QSAR analysis provided insight into the importance of pharmacophoric features, including the electron-deficient 3-pyridine at N1 of hydrazine, which acts as an electron-withdrawing group that enhances interactions with the enzyme active site, making pyridine a valuable pharmacophore. Additionally, the electronegative fluorinated phenyl ring at C4 of thiazole enhances blood-brain barrier (BBB) permeability and selectivity for MAO-B. Notably, the methyl group on T19 acted as a hydrophobic feature, increasing electron density and boosting inhibitory activity. MD simulations confirmed the stability of the T18/2BYB and T19/2BYB complexes. Furthermore, T19 displayed superior CNS activity and BBB permeability, confirming the methyl group as crucial for enhanced action. Conclusion: These findings underscore the potential of hydrazine-linked thiazole derivatives as potent MAO-B inhibitors. Future in vivo studies are essential to explore their therapeutic benefits further. [ABSTRACT FROM AUTHOR]

Background Materials and methods Results Conclusion The present study aims to assess the therapeutic potential of vitamin C (Vit C) on anxiety‐ and depressive‐like behavior induced by abstinence from chronic nicotine‐ethanol co‐exposure in adolescent male rats.Adolescent male rats were divided into seven experimental groups with ten rats as follows: 1) vehicle, 2) Nicotine (Nic)‐Ethanol (Eth): received Nic (2 mg/kg) and Eth (20%) in drinking water from 21 to 42 days of age, 3–5) Nic‐Eth‐Vit C 100/200/400: received Nic and Eth from 21 to 42 days of age and received Vit C 100/200/400 mg/kg from 43 to 63 days of age, 6) Nic‐Eth‐Bupropion (Bup)‐ Naloxone (Nal): received Nic and Eth from 21 to 42 days of age and received Bup and Nal from 43 to 63 days of age, and 7) Vit C 400 mg/kg: received Vit C 400 mg/kg from 43 to 63 days of age. Behavioral assessments were done by elevated plus maze (EPM), forced swimming test (FST), marble burring test (MBT), and open field tests (OFT). Furthermore, specific biochemical variables associated with oxidative, inflammatory, and serotonergic profiles were quantified.According to the obtained results, Nic and Eth induced anxiety and depression in treated rats. We showed that two higher doses of Vit C increases the active struggling time in FST and decreases both the time spent in the peripheral zone of OFT and the time spent in the closed arms of EPM. In addition, animals treated by Vit C buried less number of marbles in MBT compared to their control counterparts. Nic and Eth induced oxidative stress and inflammation in cortical tissues of treated rats. Biochemical parameters were improved in the Nic‐Eth group receiving Vit C 200/400 mg/kg and Bup‐Nal through establishing a balance between oxidant/anti‐oxidant and inflammatory/anti‐inflammatory mediators. In addition, serotonin level was increased, while Monoamine oxidase (MAO) activity was notably decreased.The present findings support the beneficial effect of Vit C on anxiety‐ and depressive‐like behavior induced by Nic‐Eth withdrawal through various mechanisms such as the promotion of antioxidant defense, suppression of inflammatory mediators, and enhancement of serotoninergic function. [ABSTRACT FROM AUTHOR]

Monoamine oxidase (MAO) plays a key role in the pathogenesis of central nervous system disorders, and MAO inhibitors have been used in the treatment of depression and Parkinson's disease. In the search for new classes of MAO inhibitors, the present study investigated a series of 1,2,4-oxadiazin-5(6H)-one derivatives. This study provides the first optimization of the reaction conditions for the condensation of amidoximes with alkyl 2-halocarboxylates to yield the desired 1,2,4-oxadiazin-5(6H)-ones. The results of the in vitro MAO inhibition studies showed that the 1,2,4-oxadiazin-5(6H)-ones were indeed inhibitors of human MAO with the most potent inhibition observed for 5f (IC50 = 0.900 µM) and 7c (IC50 = 0.371 µM). It was concluded that, with appropriate substitution, 1,2,4-oxadiazin-5(6H)-one derivatives would act as good potency MAO-B inhibitors and lead compounds for the development of antiparkinsonian drugs. In Parkinson's disease, MAO-B inhibitors enhance central dopamine levels and reduce MAO-mediated production of hydrogen peroxide and resultant oxidative injury. This study represents one of few works to investigate synthetic approaches and biological activities of the 1,2,4-oxadiazin-5(6H)-one class of heterocycles. [ABSTRACT FROM AUTHOR]

Parkinson disease (PD) is the fastest growing neurological disorder globally and poses substantial management challenges owing to progressive disability, emergence of levodopa-resistant symptoms, and treatment-related complications. In this Review, we examine the current state of research into PD therapies and outline future priorities for advancing our understanding and treatment of the disease. We identify two main research priorities for the coming years: first, slowing the progression of the disease through the integration of sensitive biomarkers and targeted biological therapies, and second, enhancing existing symptomatic treatments, encompassing surgical and infusion therapies, with the goal of postponing complications and improving long-term patient management. The path towards disease modification is impeded by the multifaceted pathophysiology and diverse mechanisms underlying PD. Ongoing studies are directed at α-synuclein aggregation, complemented by efforts to address specific pathways associated with the less common genetic forms of the disease. The success of these efforts relies on establishing robust end points, incorporating technology, and identifying reliable biomarkers for early diagnosis and continuous monitoring of disease progression. In the context of symptomatic treatment, the focus should shift towards refining existing approaches and fostering the development of novel therapeutic strategies that target levodopa-resistant symptoms and clinical manifestations that substantially impair quality of life. Parkinson disease (PD) poses substantial management challenges owing to progressive disability and emergence of levodopa-resistant symptoms and treatment-related complications. This Review examines the current state of research into symptomatic and disease-modifying PD therapies and outlines future priorities for advancing our understanding and treatment of the disease. Key points: Parkinson disease (PD) is the fastest growing neurological disorder globally but, currently, no therapeutic intervention can modify disease progression and treatment is still based on levodopa (either alone or in combination with dopamine agonists or monoamine oxidase B or catechol-O-methyltransferase inhibitors) and device-aided therapies. Disease-modifying therapies targeting α-synuclein that are under investigation include active and passive immunization and small molecules that can inhibit protein aggregation. Studies of compounds that can enhance glucocerebrosidase activity, reduce leucine-rich repeat kinase 2 activity or prevent inflammation are ongoing or starting. Medications that can alleviate symptomatic manifestations, including new levodopa formulations, dopamine agonists with different dopamine receptor stimulation profiles or modes of administration, and gene and cell transplantation therapies, are under investigation. Early detection of PD is crucial, and educational programmes aimed at the general population could aid this effort by increasing awareness of the early symptoms. Biomarker discovery and validation initially require considerable financial and human resources, but the development of safe, easy-to-perform biomarker assays — for example, using blood samples or skin biopsies — would allow screening of large cohorts in a cost-effective manner. [ABSTRACT FROM AUTHOR]

Background: Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson's Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD. Patients and Methods: PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10-15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) via patient chart review/interview. Results: Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2-3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%). Conclusion: This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life. [ABSTRACT FROM AUTHOR]

Parkinson disease is a neurogenerative disease common in adults and results in different kinds of memory dysfuntions. This study evaluated the monoamine oxidase B (MAO-B) inhibitory potential of kaurane diterpenoids previously isolated from Xylopia aethiopica through comprehensive computational approaches. Molecular docking study and molecular dynamics simulation were used to access the binding mode and interaction of xylopic acid and MAO-B enzyme. The ADMET properties of the phytochemical were evaluated to provide information on its druggability. The molecular docking and molecular dynamics simulation revealed xylopic acid as potential MAO-B inhibitor due to the good binding energy elicited and stability throughout the 100 ns simulation period. The ADMET properties of the ligand showed it as a promising drug candidate. The study recommend further comprehensive in vitro investigation towards the development of xylopic acid as potent MAO-B inhibitor. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a specific form of neurodegeneration that is marked by impairments in memory and cognition. Exposure to some metal toxins, such as aluminum (AL), was directly linked to the onset of AD as it was hosted in the body via several exposure routes and can change the permeability and cross the blood–brain barrier. Due to amygdaline's existence, apricot kernel therapy for AD is believed to have been established to be successful in numerous investigations. Amygdaline has been shown to have antioxidant effects that mitigate oxidative damage, and free radicals scavenger activity, as well as amygdaline niosomes as a nanoparticle has been found to improve the drug's efficiency and selectivity. The objectives of this investigation are to study the neuroprotective role of amygdaline, and amygdaline-loaded niosomes formulation in the diminishment of the incidence of AD in neurotoxin (aluminum chloride; AlCl3) AD animal model. Results: Data revealed that AlCl3 caused cognitive decline that was confirmed by cognitive behavioral tests (novel object and Y-maze); biochemical disturbances that include marked oxidative stress (elevated malondialdehyde and reduced total antioxidant capacity), reduced acetylcholinesterase, and brain monoamines levels (nor adrenalin; 4-dihydroxyphenylacetic acid; 5-hydroxytryptamine /serotonin; dopamine), and gene regulation upset (down-regulated transcript levels of acetylcholinesterase; monoamine oxidase; BCL-2 and up-regulated transcript levels of BAX), as well as neurodegenerative changes were observed in the hippocampus of AlCl3-treated rats. Treatment with amygdaline and amygdaline-loaded niosomes formulation improved working memory and recognition, alleviated oxidative stress, and restored the levels of brain monoamines and neurotransmitters. Moreover, gene expression data showed a significant down-regulation of BAX, while BCL-2, acetylcholinesterase, and monoamine oxidase were significantly up-regulated. Additionally, the histopathological examination showed reduced neurodegeneration. Conclusion: Conclusively, it was evident that amygdaline and amygdaline-loaded niosomes formulation possess a neuroprotective and cognitive enhancement role in AD via their potent antioxidant potential, neurotransmitters, and gene expression regulations, as well as neural damage reduction capability. [ABSTRACT FROM AUTHOR]

[Display omitted] • Intermittent sucrose/fasting protocol led to overeating behavior. • Animals with loss-control eating also showed depressive-like behavior. • Fasting itself did not induce depressive-like or sucrose overeating behavior. • Activity of monoamine oxidases was disrupted in overeating mice. • Sucrose-exposed mice tend to exhibit increased risk behavior after 20 h-fasting. Binge eating disorder is the most prevalent eating disorder, affecting both sexes but more commonly found in women. Given the frequent co-occurrence of psychiatric disorders, this study aimed to establish a standardized experimental intermittent protocol to investigate overeating associated with depression. A 10-day protocol induced uncontrolled eating behavior in C57BL/6J female mice. The first experiment included the following groups: naive group (chow ad libitum), control group (chow and sucrose solution ad libitum), and fasting groups (16 and 20 h) exposed to an intermittent sucrose solution (10 %) and chow regimen. Subsequently, the feeding test, open field test, elevated plus maze test, tail suspension test, and light/dark conflict test were conducted. Furthermore, monoamine oxidase (MAO) A and B activities in brain structures and plasma corticosterone levels were assessed. Food overconsumption and depressive-like behavior were observed in both sucrose fasting groups, while risk-taking behaviors were specifically observed in the 20-hour fasting sucrose group. While both fasting sucrose groups caused reduced hippocampal MAO-A activity, only the F20 sucrose group inhibited MAO-B in the cortex and hypothalamus. Moreover, both fasting sucrose groups exhibited elevated corticosterone levels. In a separate design (Experiment 2), groups with 16 and 20 h of fasting alone (without sucrose) did not show the same behavioral results as the intermittent fasting sucrose groups, thus avoiding fasting bias. Based on these results, the 20-hour sucrose fasting group was chosen as the ideal protocol for mimicking overeating behavior associated with depression to investigate future therapeutic approaches for this comorbidity. [ABSTRACT FROM AUTHOR]

Background: The gut microbiome modulates the effects of diet on host health, but it remains unclear which specific foods and microbial features interact to influence risk of depression. To understand this interplay, we leveraged decades of dietary and depression data from a longitudinal cohort of women (n = 32,427), along with fecal metagenomics and plasma metabolomics from a substudy (n = 207) nested in this cohort, as well as an independent validation cohort of men (n = 307). Results: We report that citrus intake and its components are prospectively associated with a lower risk of depression and altered abundance of 15 gut microbial species, including enriched Faecalibacterium prausnitzii. In turn, we found a lower abundance of F. prausnitzii and its metabolic pathway, S-adenosyl-L-methionine (SAM) cycle I in participants with depression. To explore causality, we found that lower SAM production by F. prausnitzii may decrease intestinal monoamine oxidase A gene expression implicated in serotonin and dopamine synthesis. Conclusions: These data underscore the role of diet in the prevention of depression and offer a plausible explanation for how the intestinal microbiome modulates the influence of citrus on mental health. ELPzvN5keGYhLtpEkepcja Video Abstract [ABSTRACT FROM AUTHOR]

Ocimum basilicum is an important medicinal plant and culinary herb generally known as sweet basil (SB). These plants are effective radical scavengers, that have been employed in treatment of nervous system disorders, and thus, could be beneficial for the management of neurodegenerative diseases (NDs). Current clinical treatments for NDs present several side effects, therefore, there is need to develop new treatments that can mitigate these deadly diseases. Hence, this study investigated the neuroprotective activities of SB leaf and seed in aluminum chloride (AlCl3)-induced toxicity in Drosophila melanogaster. HPLC characterization of the leaves and seeds were carried out. AlCl3-diet was used to induce neurodegeneration and treated flies received SB leaf and seed extracts-supplemented diet. Survival and locomotor performance activities/levels of oxidative biomarkers [reactive oxygen species (ROS), thiobarbituric acid reactive species (TBARS), total thiol, catalase, superoxide dismutase (SOD) and glutathione-S-transferase (GST)], enzymes linked with neurodegeneration (acetylcholinesterase (AChE) and monoamine oxidase (MAO)) were investigated. SB leaf had significantly (p < 0.05) higher polyphenol contents; gallic acid and P-coumaric acid were the most abundant polyphenol in the leaf and seed respectively. Percentage survival and locomotor rates, level/activities of total thiol, catalase, SOD and GST were significantly (p < 0.05) reduced while ROS, TBARS, AChE and MAO activities were significantly (p < 0.05) increased in AlCl3-diet-fed flies. Treatment with SB leaf and seed diet lessened these observed impairments. However, SB leaf had better neuroprotective activities that could be related to the observed higher phenolic constituents. Hence, SB leaf diet may offer improved therapeutic effect in NDs. [ABSTRACT FROM AUTHOR]

Introduction: Our investigation aims to appraise the neuroprotective impact of Bone Marrow-Mesenchymal Stem Cells (BM-MSCs) derived exosomes against Ag NPs-inducing neurotoxicity in rats. Materials and Methods: Twenty-four albino rats were divided into 3 groups. Group I (control negative), Group II (intraperitoneally injected with Ag NPs for 28 days, whereas Group III (intraperitoneally injected with Ag NP and BM-MSCs derived exosomes. Results: There was a marked elevation of Malondialdehyde (MDA) along with a reduction of brain antioxidants, Gamma-aminobutyric acid (GABA) and Monoamine Oxidase (MAO) in the Ag NPs receiving group. Ag NPs upregulated c-Jun N-terminal Kinases (JNK) genes and c-Myc and downregulated the tissue inhibitors of metalloproteinases (TIMP-1) and Histone deacetylase 1 (HDAC1) genes. Otherwise, the co-treatment of BM-MSCs derived exosomes with Ag NPs could markedly increase the rat's body weight, activity and learning while, decreasing anxiety, restoring all the toxicological parameters and improving the microscopic appearance of different brain areas. Conclusion: BM-MSCs-derived exosomes downregulated both apoptotic and inflammatory mediators and upregulated the antiapoptotic genes. BM-MSCs-derived exosomes exhibit a great therapeutic effect against the neurotoxic effects of Ag NPs. [ABSTRACT FROM AUTHOR]

Rationale: The compound 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) has recently been shown to inhibit in vitro acetylcholinesterase activity, reduce cognitive damage, and improve neuropsychic behavior in mice, making it a promising molecule to treat depression. Objectives: This study investigated the antidepressant-like action of MTDZ in mice and its potential mechanisms of action. Results: Molecular docking assays were performed and suggested a potential inhibition of monoamine oxidase A (MAO-A) by MTDZ. The toxicity study revealed that MTDZ displayed no signs of toxicity, changes in oxidative parameters, or alterations to biochemistry markers, even at a high dose of 300 mg/kg. In behavioral tests, MTDZ administration reduced immobility behavior during the forced swim test (FST) without adjusting the climbing parameter, suggesting it has an antidepressant effect. The antidepressant-like action of MTDZ was negated with the administration of 5-HT1A, 5-HT1A/1B, and 5-HT3 receptor antagonists, implying the involvement of serotonergic pathways. Moreover, the antidepressant-like action of MTDZ was linked to the NO system, as L-arginine pretreatment inhibited its activity. The ex vivo assays indicated that MTDZ normalized ATPase activity, potentially linking this behavior to its antidepressant-like action. MTDZ treatment restricted MAO-A activity in the cerebral cortices and hippocampi of mice, proposing a selective inhibition of MAO-A associated with the antidepressant-like effect of the compound. Conclusions: These findings suggest that MTDZ may serve as a promising antidepressant agent due to its selective inhibition of MAO-A and the involvement of serotonergic and NO pathways [ABSTRACT FROM AUTHOR]

Non-muscle-invasive bladder cancer (NMIBC) presents management challenges due to its high recurrence rate and a complex tumor microenvironment (TME). This study investigated the effects of OncoTherad® (MRB-CFI1) nanoimmunotherapy on the TME of BCG-unresponsive NMIBC, focusing on alterations in monoamine oxidases (MAO-A and MAO-B) and immune markers: CD163, FOXP3, CD8, and CX3CR1. A comparative analysis of immunoreactivities was made before and after OncoTherad® treatment and an immune score (IS) was established to evaluate the correlation between immunological changes and clinical outcomes. Forty bladder biopsies of twenty patients were divided into 2 groups (n = 20/group): 1 (pre-treatment biopsies); and 2 (post-treatment biopsies). Our results showed stable MAO-A levels but a significant (p < 0.05) decrease in MAO-B immunoreactivity after treatment, suggesting OncoTherad®'s efficacy in targeting the tumor-promoting and immunosuppressive functions of MAO-B. Significant (p < 0.05) reductions in CD163 and FOXP3 immunoreactivities were seen in post-treatment biopsies, indicating a decreased presence of M2 macrophages and Tregs. Corroborating with these results, we observed reductions in tumor histological grading, focality and size, factors that collectively enhanced recurrence-free survival (RFS) and pathological complete response (PCR). Moreover, elevated IFN-γ immunoreactivities in treated biopsies correlated with increased counts of CD8+ T cells and higher CX3CR1 expression, underscoring OncoTherad®'s enhancement of cytotoxic T cell functionality and overall antitumor immunity. The IS revealed improvements in immune responses post-treatment, with higher scores associated with better RFS and PCR outcomes. These findings validate OncoTherad®'s capability to modify the bladder cancer microenvironment favorably, promoting effective immune surveillance and response. [ABSTRACT FROM AUTHOR]

Depression and Parkinson's disease (PD) are devastating psychiatric and neurological disorders that require the development of novel therapeutic interventions. Drug repurposing targeting predefined pharmacological targets is a widely use approach in modern drug discovery. Monoamine oxidase B (MAOB) is a critical protein implicated in Depression and PD. In this study, we undertook a systematic exploration of repurposed drugs as potential inhibitors of MAO-B. Exploring a library of 3,648 commercially available drug molecules, we conducted virtual screening using a molecular docking approach to target the MAO-B binding pocket. Two promising drug molecules, Brexpiprazole and Trifluperidol, were identified based on their exceptional binding potential and drug profiling. Subsequently, all-atom molecular dynamics (MD) simulations were performed on the MAO-B-ligand complexes for a trajectory of 300 nanoseconds (ns). Simulation results demonstrated that the binding of Brexpiprazole and Trifluperidol induced only minor structural alterations in MAO-B and showed significant stabilization throughout the simulation trajectory. Overall, the finding suggests that Brexpiprazole and Trifluperidol exhibit strong potential as repurposed inhibitors of MAO-B that might be explored further in experimental investigations for the development of targeted therapies for depression and PD. [ABSTRACT FROM AUTHOR]

By reaction between acetylbenzenesulfonamides with several substituted isatins, we have synthesized a series of 22 primary sulfonamides, 16 of which were tested for inhibition activity against MAO-A and MAO-B. At the same time, in order to diversify the resulting structures, we have carried out decarboxylation as well as further functionalization at the carboxylic acid. The results of the study show that methyl 6-chloro-2-(3-sulfamoylphenyl)quinoline-4-carboxylate selectively inhibited MAO-B with a value of IC50 = 13.7 μM. [ABSTRACT FROM AUTHOR]

St. John's wort (Hypericum perforatum, Hypericaceae) is the most well-known species in the genus Hypericum, which comprises several hundred species. This study investigates the biological and phytochemical potential of the under-researched Hypericum species, H. hirsutum, H. barbatum, and H. rochelii. A high level of similarity between the chemical profiles of H. hirsutum and H. barbatum and the official source of the herbal drug (H. perforatum) was shown, but a higher content of quercetin and rutin was also found in all three evaluated species (116–230 µg/g dry herb). The highest amount of phenolics (195 mg GAE/g) was recorded in H. hirsutum extract, while the highest amount of flavonoids (47 mg QE/g) was recorded in H. barbatum extract. The evaluated species were excellent scavengers of DPPH, OH, and NO radicals, as well as strong ferric ion reducers in the FRAP test. Prominent monoamine oxidase A and α-glucosidase inhibition was observed, compared to modest inhibition of monoamine oxidase B, α-amylase, and acetylcholinesterase. High activity against Gram-positive MRSA S. aureus was demonstrated for the tested species, with MIC/MBC values recorded at 12.5 µg/mL. Antifungal activity against Candida strains was not observed. The obtained results emphasize the need for further investigation of species of the genus Hypericum to discover potentially new sources of biologically active compounds. [ABSTRACT FROM AUTHOR]

Background: Lavandula dentata is recognized for its therapeutic properties and has been traditionally used in various medicinal applications. Monoamine oxidases (MAOs) are critical for neurotransmitters breaking down; therefore, their inhibitors treat neurodegenerative disorders such as Alzheimer, Parkinson and amyotrophic lateral sclerosis diseases. Methods: The current study was done to analyze the bioactive compounds present in the methanolic extract of Lavandula dentata of Taif region, Saudi Arabia using Gas Chromatography-Mass Spectrometry (GC-MS) analysis. In addition, computational analysis using SwissADME and ProTox-II was used to predict the physicochemical and biological activities and predicted toxicity of four selected components from lavender extract. Moreover, linalool and 7-Methoxy-2-oxo-2H-chromene-3-carboxylic acid were selected for the molecular docking of Monoamine Oxidase A. Result: GC-MS analysis revealed a diverse array of bioactive compounds, including but not limited to linalool, retinal, chromene-2-one and 7-Methoxy-2-oxo-2H-chromene-3-carboxylic acid, which are known for their pharmacological activities such as antimicrobial, anti-inflammatory and anxiolytic effects. In silico analysis has assumed that linalool is safe with a predicted toxicity LD50 2200 mg/kg (Class: 5). The docking affinity score of linalool to Monoamine Oxidase A is -24.4 and appears more stable in the docking site box due to the presence of nine hydrophobic interactions. Collectively this study contributes to the understanding of the chemical profile of Lavandula dentata and highlights its suitability for pharmaceutical and therapeutic applications along with exploring the specific bioactivities and potential synergistic effects of these compounds. In particular, linalool emerges as a promising bioactive compound in neurodegenerative disorders therapy through Monoamine oxidase A inhibition. [ABSTRACT FROM AUTHOR]

Bisphenol A, a traditional endocrine disruptor, has been implicated in male infertility. This study investigated the effect of Cucumeropsis mannii seed oil (CMSO) on bisphenol A (BPA)‐induced biochemical toxicity in the testicular mitochondria of male albino rats. The rats were assigned randomly to six experimental groups (n = 6), A, B, C, D, E, and F. Group A received 1 mL of olive oil. Groups B and C received 100 mL/kg body weight (BW) of BPA and 7.5 mL/kg BW CMSO, respectively. Rats in groups D, E, and F received preadministered doses of 100 mL/kg BW of BPA, 5 mL/kg BW of BPA, and 2.5 mL/kg BW of CMSO, respectively, followed by 6 weeks of exposure to those doses. Some mitochondrial enzymes, mitochondrial membrane potential (MMP), mitochondria testicular protein, and body weight of rats were determined using standard methods. BPA significantly reduced succinate dehydrogenase, malate dehydrogenase, isocitrate dehydrogenase, NADH dehydrogenase, and monoamine oxidase activity. Also, BPA prominently decreased the MMP, mitochondrial testicular protein, and body weight of rats. Interestingly, coadministration of BPA and CMSO restored the dysregulated activities of the enzymes and levels of other biomarkers. We postulated that CMSO may be a promising drug for treating systemic toxicity caused by environmental toxicants such as BPA. [ABSTRACT FROM AUTHOR]

Background: Glaucoma is a progressive optic neuropathy characterized by the neurodegeneration and death of retinal ganglion cells (RGCs), leading to blindness. Current glaucoma interventions reduce intraocular pressure but do not address retinal neurodegeneration. In this effort, to identify new pharmacological targets for glaucoma management, we employed a network pharmacology approach. Methods: We first retrieved transcriptomic data from GEO, an NCBI database, and carried out GEO2R (an interactive web tool aimed at comparing two or more groups of samples in a GEO dataset). The GEO2R statistical analysis aimed at identifying the top differentially expressed genes (DEGs) and used these as input of STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) app within Cytoscape software, which builds networks of proteins starting from input DEGs. Analyses of centrality metrics using Cytoscape were carried out to identify nodes (genes or proteins) involved in network stability. We also employed the web-server software MIRNET 2.0 to build miRNA–target interaction networks for a re-analysis of the GSE105269 dataset, which reports analyses of microRNA expressions. Results: The pharmacological targets, identified in silico through analyses of the centrality metrics carried out with Cytoscape, were rescored based on correlations with entries in the PubMed and clinicaltrials.gov databases. When there was no match (82 out of 135 identified central nodes, in 8 analyzed networks), targets were considered "potential innovative" targets for the treatment of glaucoma, after further validation studies. Conclusions: Several druggable targets, such as GPCRs (e.g., 5-hydroxytryptamine 5A (5-HT5A) and adenosine A2B receptors) and enzymes (e.g., lactate dehydrogenase A or monoamine oxidase B), were found to be rescored as "potential innovative" pharmacological targets for glaucoma treatment. [ABSTRACT FROM AUTHOR]

Background: Monoamine oxidases (MAO) are flavoenzymes that metabolize a range of brain neurotransmitters, whose dysregulation is closely associated with the development of various neurological disorders. This is why MAOs have been the central target in pharmacological interventions for neurodegeneration for more than 60 years. Still, existing drugs only address symptoms and not the cause of the disease, which underlines the need to develop more efficient inhibitors without adverse effects. Methods: Our drug design strategy relied on docking 25 organic scaffolds to MAO-B, which were extracted from the ChEMBL20 database with the highest cumulative counts of unique member compounds and bioactivity assays. The most promising candidates were substituted with the inactivating propargylamine group, while further affinity adjustment was made by its N-methylation. A total of 46 propargylamines were submitted to the docking and molecular dynamics simulations, while the best binders underwent mechanistic DFT analysis that confirmed the hydride abstraction mechanism of the covalent inhibition reaction. Results: We identified indole-2-propargylamine 4fH and indole-2-N-methylpropargylamine 4fMe as superior MAO-B binders over the clinical drugs rasagiline and selegiline. DFT calculations highlighted 4fMe as more potent over selegiline, evident in a reduced kinetic requirement (ΔΔG‡ = −2.5 kcal mol−1) and an improved reaction exergonicity (ΔΔGR = −4.3 kcal mol−1), together with its higher binding affinity, consistently determined by docking (ΔΔGBIND = −0.1 kcal mol−1) and MM-PBSA analysis (ΔΔGBIND = −1.5 kcal mol−1). Conclusions: Our findings strongly advocate 4fMe as an excellent drug candidate, whose synthesis and biological evaluation are highly recommended. Also, our results reveal the structural determinants that influenced the affinity and inhibition rates that should cooperate when designing further MAO inhibitors, which are of utmost significance and urgency with the increasing prevalence of brain diseases. [ABSTRACT FROM AUTHOR]

Objective: To explore the effect and anxiolytic mechanism of a natural remedy called Fructus gardeniae (FG). Methods: The elevated-plus maze (EPM) test was used to confirm the anxiolytic effect of FG. The potential and anxiolytic components, targets, and route processes of FG were investigated using the network pharmacology method in conjunction with metabolomics and molecular docking technologies. Results: FG could greatly enhance the proportion of time and times of opening arms, according to the EPM data. As to the metabolomics findings, a total of 61 distinct metabolites were found, mainly involved in glycine, serine, and threonine metabolism as well as alanine, aspartate, and glutamate metabolism. The primary active ingredients of FG, nicotiflorin, jasminodiol, and crocetin, demonstrated substantial binding affinities with monoamine oxidase A (MAOA), monoamine oxidase A (ACHE), malate dehydrogenase 2 (MDH2), glutamate decarboxylase 2 (GAD2), glutamate decarboxylase 1 (GAD1), and nitric oxide synthase (NOS1), according to the findings of network pharmacology and molecular docking. Conclusion: FG exerts an anxiolytic action via targeting MAOA, ACHE, MDH2, GAD2, GAD1, and NOS1, and regulating the metabolism of glycine, serine, and threonine as well as alanine, aspartic acid, and glutamic acid. [ABSTRACT FROM AUTHOR]

Perry disease (PeD) is a rare, neurodegenerative, genetic disorder inherited in an autosomal dominant manner. The disease manifests as parkinsonism, with psychiatric symptoms on top, such as depression or sleep disorders, accompanied by unexpected weight loss, central hypoventilation, and aggregation of DNA-binding protein (TDP-43) in the brain. Due to the genetic cause, no causal treatment for PeD is currently available. The only way to improve the quality of life of patients is through symptomatic therapy. This work aims to review the latest data on potential PeD treatment, specifically from the medicinal chemistry and computer-aided drug design (CADD) points of view. We select proteins that might represent therapeutic targets for symptomatic treatment of the disease: monoamine oxidase B (MAO-B), serotonin transporter (SERT), dopamine D2 (D2R), and serotonin 5-HT1A (5-HT1AR) receptors. We report on compounds that may be potential hits to develop symptomatic therapies for PeD and related neurodegenerative diseases and relieve its symptoms. We use Phase pharmacophore modeling software (version 2023.08) implemented in Schrödinger Maestro as a ligand selection tool. For each of the chosen targets, based on the resolved protein–ligand structures deposited in the Protein Data Bank (PDB) database, pharmacophore models are proposed. We review novel, active compounds that might serve as either hits for further optimization or candidates for further phases of studies, leading to potential use in the treatment of PeD. [ABSTRACT FROM AUTHOR]

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor because it does not bind to a known specific receptor on the plasma membrane and functions primarily as an unfolded protein response (UPR) regulator in the endoplasmic reticulum. Data on the effects of CDNF on nonmotor behavior and monoamine metabolism are limited. Here, we performed the intracerebroventricular injection of a recombinant CDNF protein at doses of 3, 10, and 30 μg in C57BL/6 mice. No adverse effects of the CDNF injection on feed and water consumption or locomotor activity were observed for 3 days afterwards. Decreases in body weight and sleep duration were transient. CDNF-treated animals demonstrated improved performance on the operant learning task and a substantial decrease in anxiety and behavioral despair. CDNF in all the doses enhanced serotonin (5-HT) turnover in the murine frontal cortex, hippocampus, and midbrain. This alteration was accompanied by changes in the mRNA levels of the 5-HT1A and 5-HT7 receptors and in monoamine oxidase A mRNA and protein levels. We found that CDNF dramatically increased c-Fos mRNA levels in all investigated brain areas but elevated the phosphorylated-c-Fos level only in the midbrain. Similarly, enhanced CREB phosphorylation was found in the midbrain in experimental animals. Additionally, the upregulation of a spliced transcript of XBP1 (UPR regulator) was detected in the midbrain and frontal cortex. Thus, we can hypothesize that exogenous CDNF modulates the UPR pathway and overall neuronal activation and enhances 5-HT turnover, thereby affecting learning and emotion-related behavior. [ABSTRACT FROM AUTHOR]

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 H2O2. 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. [ABSTRACT FROM AUTHOR]

Background and Purpose: Demand for new antidepressants has resulted in a re‐evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin‐containing "magic" mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects. Experimental Approach: We compared baeocystin, norbaeocystin and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, similarly penetrate the blood–brain barrier, serve as ligands for similar receptors and modulate behaviour in rodents similarly. We also assessed the stability and optimal storage and handling conditions for each compound. Key Results: In vitro enzyme kinetics assays found that all compounds had nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin crossed a blood–brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. The dephosphorylated form of norbaeocystin was found to activate the 5‐HT2A receptor with similar efficacy to psilocin and norpsilocin in in vitro cell imaging assays. Behaviourally, only psilocybin induced head twitch responses in rats, a marker of 5‐HT2A‐mediated psychedelic effects and hallucinogenic potential. However, like psilocybin, norbaeocystin improved outcomes in the forced swim test. All compounds caused minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. Conclusions and Implications: Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations. [ABSTRACT FROM AUTHOR]

The Monoamine Oxidase-A (MAOA) EcoRV polymorphism (rs1137070) is a unique synonymous mutation (c.1409 T > C) within the MAOA gene, which plays a crucial role in Maoa gene expression and function. This study aimed to explore the relationship between the mouse Maoa rs1137070 genotype and differences in MAOA gene expression. Mice carrying the CC genotype of rs1137070 exhibited a significantly lower Maoa expression level, with an odds ratio of 2.44 compared to the T carriers. Moreover, the wild-type TT genotype of MAOA demonstrated elevated mRNA expression and a longer half-life. We also delved into the significant expression and structural disparities among genotypes. Furthermore, it was evident that different aspartic acid synonymous codons within Maoa influenced both MAOA expression and enzyme activity, highlighting the association between rs1137070 and MAOA. To substantiate these findings, a dual-luciferase reporter assay confirmed that GAC was more efficient than GAT binding. Conversely, the synonymous mutation altered Maoa gene expression in individual mice. An RNA pull-down assay suggested that this alteration could impact the interaction with RNA-binding proteins. In summary, our results illustrate that synonymous mutations can indeed regulate the downregulation of gene expression, leading to changes in MAOA function and their potential association with neurological-related diseases. [ABSTRACT FROM AUTHOR]

A set of sesamol-derived acetamides was designed, synthesized, and evaluated against monoamine oxidases (MAO-A and MAO-B) and cholinesterases (AChE and BChE) for targeting neurodegenerative diseases. Most of the tested compounds showed inhibition activity at micromolar to nanomolar ranges. The 3,4-dichoro derivative (compound 19) was the most potent MAO-A inhibitor (IC50 = 0.053 ± 0.001 µM) while the 4-methyl analog (compound 16) emerged as a lead MAO-B inhibitor (IC50 = 0.019 ± 0.001 µM) compared to the reference inhibitors clorgyline (MAO-A IC50 = 0.096 ± 0.003 µM) and selegyline (MAO B IC50 = 0.021 ± 0.002 µM). Further, the 2,4-dichloro analog (compound 20) emerged as a potent dual MAO (MAO-A IC50 = 0.160 ± 0.009 µM, MAO-B IC50 = 0.071 ± 0.002 µM) and ChE (AChE IC50 = 2.611 ± 0.086 µM and BChE IC50 = 4.22 ± 0.162 µM) inhibitor. Moreover, molecular simulation studies revealed that H-bonding and hydrophobic interactions stabilize the virtual lead inhibitor-protein complex. Selected MAO-ChE inhibitors showed significant antioxidant and iron-chelation properties, suggesting their potential in treating neurological disorders characterized by impaired iron homeostasis. In summary, the structural modification attempted in the present study yielded a few nanomolar MAO (MAO-B) inhibitors and, thus, provided new insights into the linker requirements for dual MAO/ChE inhibitory properties. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders are caused by the progressive death of neuronal cells in specific regions of the brain and spinal cord. The most common neurodegenerative disorders are Alzheimer's disease and Parkinson's disease. The inhibition of enzymes that metabolise neurotransmitter amines is an important approach in the treatment of these disorders and monoamine oxidase (MAO) B inhibitors have thus been used for the treatment of Parkinson's disease. Inhibitors of the MAO-A isoform, in turn, are used clinically for the treatment of affective (e.g., major depression) and anxiety disorders. Recent studies have shown that benzothiazole derivatives act as potent MAO inhibitors. Based on these findings, the present study group synthesised thirteen 2-methylbenzo[d]thiazole derivatives and evaluated their in vitro MAO inhibition properties. The results showed that the benzothiazole derivatives were potent and selective inhibitors of human MAO-B, with all compounds exhibiting IC50 values < 0.017 µM. The most potent MAO-B inhibitor (4d) had an IC50 value of 0.0046 µM, while the most potent MAO-A inhibitor (5e) had an IC50 value of 0.132 µM. It may be concluded that active benzothiazole derivatives may serve as potential leads for the development of MAO inhibitors for the treatment of neuropsychiatric and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

The potent hallucinogen N,N-dimethyltryptamine (DMT) has garnered significant interest in recent years due to its profound effects on consciousness and its therapeutic psychopotential. DMT is an integral (but not exclusive) psychoactive alkaloid in the Amazonian plant-based brew ayahuasca, in which admixture of several β-carboline monoamine oxidase A (MAO-A) inhibitors potentiate the activity of oral DMT, while possibly contributing in other respects to the complex psychopharmacology of ayahuasca. Irrespective of the route of administration, DMT alters perception, mood, and cognition, presumably through agonism at serotonin (5-HT) 1A/2A/2C receptors in brain, with additional actions at other receptor types possibly contributing to its overall psychoactive effects. Due to rapid first pass metabolism, DMT is nearly inactive orally, but co-administration with β-carbolines or synthetic MAO-A inhibitors (MAOIs) greatly increase its bioavailability and duration of action. The synergistic effects of DMT and MAOIs in ayahuasca or synthetic formulations may promote neuroplasticity, which presumably underlies their promising therapeutic efficacy in clinical trials for neuropsychiatric disorders, including depression, addiction, and post-traumatic stress disorder. Advances in neuroimaging techniques are elucidating the neural correlates of DMT-induced altered states of consciousness, revealing alterations in brain activity, functional connectivity, and network dynamics. In this comprehensive narrative review, we present a synthesis of current knowledge on the pharmacology and neuroscience of DMT, β-carbolines, and ayahuasca, which should inform future research aiming to harness their full therapeutic potential. [ABSTRACT FROM AUTHOR]

Plants of the genus Tribulus have been used in folk medicine for wound healing, alleviating liver, stomach, and rheumatism pains, and as cognitive enhancers, sedatives, antiseptics, tonics, and stimulants. The present work aimed to evaluate whether Tribulus terrestris (Tt) administered for 15 days attenuated cognitive deficits and exhibited anxiolytic and antidepressant profiles in scopolamine-induced amnesia in zebrafish. Animals were randomly divided into six groups (eight animals per group): (1)–(3) Tt treatment groups (1, 3 and 6 mg/L), (4) control, (5) scopolamine (SCOP, 0.7 mg/kg), and (6) galantamine (Gal, 1 mg/L). Exposure to SCOP (100 µM) resulted in anxiety in zebrafish, as assessed by the novel tank diving test (NTT) and novel approach test (NAT). When zebrafish were given SCOP and simultaneously given Tt (1, 3, and 6 mg/L once daily for 10 days), the deficits were averted. Molecular interactions of chemical compounds from the Tt fractions with the monoamine oxidase A (MAO-A) were investigated via molecular docking experiments. Using behavioral experiments, we showed that administration of Tt induces significant anxiolytic-antidepressant-like effects in SCOP-treated zebrafish. Our result indicated that flavonoids of Tt, namely kaempferol, quercetin, luteolin, apigetrin, and epigallocatechin, could act as promising phytopharmaceuticals for improving anxiety-related disorders. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) stands as the second most common neurological disorder after Alzheimer's disease, primarily affecting the elderly population and significantly compromising their quality of life. The precise etiology of PD remains elusive, but recent research has shed light on potential factors, including the formation of α‐synuclein aggregates, oxidative stress, neurotransmitter imbalances, and dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc) region of the brain, culminating in motor symptoms such as bradykinesia, akinesia, tremors, and rigidity. Monoamine oxidase (MAO) is an essential enzyme, comprising two isoforms, MAO‐A and MAO‐B, responsible for the oxidation of monoamines such as dopamine. Increased MAO‐B activity is responsible for decreased dopamine levels in the SNpc region of mid brain which is remarkably associated with the pathogenesis of PD‐like manifestations. Inhibitors of MAO‐B enhance striatal neuronal responses to dopamine, making them valuable in treating PD, which involves dopamine deficiency. Clinically approved MAO‐B inhibitors such as selegiline, L‐deprenyl, pargyline, and rasagiline are employed in the management of neurodegenerative conditions associated with PD. Current therapeutic interventions including MAO‐B inhibitors for PD predominantly aim to alleviate these motor symptoms but often come with a host of side effects that can be particularly challenging for the patients. While effective, they have limitations, prompting a search for alternative treatments, there is a growing interest in exploring natural products notably flavonoids as potential sources of novel MAO‐B inhibitors. In line with that, the present review focuses on natural flavonoids of plant origin that hold promise as potential candidates for the development of novel MAO‐B inhibitors. The discussion encompasses both in vitro and in vivo studies, shedding light on their potential therapeutic applications. Furthermore, this review underscores the significance of exploring natural products as valuable reservoirs of MAO‐B inhibitors, offering new avenues for drug development and addressing the pressing need for improved treatments in PD‐like pathological conditions. The authors of this review majorly explore the neuroprotective potential of natural flavonoids exhibiting notable MAO‐B inhibitory activity and additionally multi‐targeted approaches in the treatment of PD with clinical evidence and challenges faced in current therapeutic approaches. [ABSTRACT FROM AUTHOR]

Zebrafish (Danio rerio) are unusual in having two paralogues of the serotonin re-uptake transporter (Sert), slc6a4a (serta) and slc6a4b (sertb), the transporter that serves in serotonin re-uptake from a synapse into the pre-synaptic cell or in serotonin uptake from the extracellular milieu into cells in the peripheral tissues. To address a knowledge gap concerning the specific roles of these paralogues, we used CRISPR/Cas9 technology to generate zebrafish knockout lines predicted to lack functional expression of Serta or Sertb. The consequences of loss-of-function of Serta or Sertb were assessed at the gene expression level, focusing on the serotonergic signalling pathway, and at the behaviour level, focusing on aggression. Whereas serta mRNA was expressed in all tissues examined, with high expression in the heart, gill and brain, only the brain displayed substantial sertb mRNA expression. In both serta−/− and sertb−/− fish, changes in transcript abundances of multiple components of the serotonin signalling pathway were detected, including proteins involved in serotonin synthesis (tph1a, tph1b, tph2, ddc), packaging (vmat2) and degradation (mao), and serotonin receptors (htr1aa, htr1ab). Using a mirror aggression test, serta−/− male but not female fish exhibited greater aggression than wildtype fish. However, both male and female sertb−/− fish displayed less aggression than their wildtype counterparts. These differences in behaviour between serta−/− and sertb−/− individuals hold promise for increasing our understanding of the neurophysiological basis of aggression in zebrafish. [ABSTRACT FROM AUTHOR]

Levamisole is an anti-helminthic drug developed and introduced in veterinary medicine, and it has been used more frequently after the inclusion of its usage in human medicine regarding disorders with immunomodulatory properties. In recent years, it has started to attract attention since it has beneficial effects on the treatment of COVID-19 due to its immunomodulatory properties. To investigate the effects of levamisole on sexual behavior and the reproductive system in male rats, two groups were formed the vehicle (n = 10) and levamisole (n = 10) groups. The vehicle group was given purified water whereas the levamisole group was administered with levamisole (2 mg/kg) by oral gavage daily for 4 weeks. Levamisole treatment significantly increased the mount latency (ML, P < 0.001) as well as the intromission latency (IL, P < 0.01). It also significantly prolonged postejaculatory interval (PEI, P < 0.01), decreased copulatory rate (CR, P < 0.05), and sexual activity index (SAI, P < 0.05). It significantly decreased serum monoamine oxidase A (MAO-A) levels (P < 0.05). Additionally, levamisole induced disorganizations of germinal epithelial cells of seminiferous tubules, congestion, edema in the interstitial area, and metaphase arrest in some spermatocytes (P < 0.001), and it significantly increased the immunohistochemical expressions of apoptotic Bax and cytochrome c, which is crucial proapoptotic protein, in the testis (P < 0.001). Also, levamisole significantly upregulated the mRNA levels of the apoptosis-related key regulatory genes, including Bax (Bcl-2-associated X protein, P = 0.05) and Bax/Bcl-2 ratio (P < 0.01) in testis. The current research is the first to show that levamisole may decrease sexual performance, potency, sexual motivation, and libido and induce apoptosis in the testis. [ABSTRACT FROM AUTHOR]

Nowadays, an efficient and robust virtual screening procedure is crucial in the drug discovery process, especially when performed on large and chemically diverse databases. Virtual screening methods, like molecular docking and classic QSAR models, are limited in their ability to handle vast numbers of compounds and to learn from scarce data, respectively. In this study, we introduce a universal methodology that uses a machine learning-based approach to predict docking scores without the need for time-consuming molecular docking procedures. The developed protocol yielded 1000 times faster binding energy predictions than classical docking-based screening. The proposed predictive model learns from docking results, allowing users to choose their preferred docking software without relying on insufficient and incoherent experimental activity data. The methodology described employs multiple types of molecular fingerprints and descriptors to construct an ensemble model that further reduces prediction errors and is capable of delivering highly precise docking score values for monoamine oxidase ligands, enabling faster identification of promising compounds. An extensive pharmacophore-constrained screening of the ZINC database resulted in a selection of 24 compounds that were synthesized and evaluated for their biological activity. A preliminary screen discovered weak inhibitors of MAO-A with a percentage efficiency index close to a known drug at the lowest tested concentration. The approach presented here can be successfully applied to other biological targets as target-specific knowledge is not incorporated at the screening phase. [ABSTRACT FROM AUTHOR]

The seeds of ginkgo biloba L (GB) have been widely used worldwide. This study investigated the bioefficacies of whole GB seed powder (WGP) retaining the full nutrients of ginkgo against aging, atherosclerosis, and fatigue. The experimental results indicated that WGP lowered brain monoamine oxidase and serum malondialdehyde levels, enhanced thymus/spleen indexes, and improved learning ability, and delayed aging in senescent mice. WGP regulated lipid levels and prevented atherosclerosis by reducing triglycerides, lowering low-density lipoprotein cholesterol, increasing high-density lipoprotein cholesterol, and decreasing the atherosclerosis index. WGP improved exercise performance by reducing blood lactate accumulation and extending exhaustive swimming and climbing times, improved energy storage by increasing muscle/liver glycogen levels, and relieved physical fatigue. Network pharmacology analysis revealed 270 potential targets of WGP that play roles in cellular pathways related to inflammation inhibition, metabolism regulation, and anti-cellular senescence, etc. Protein-protein interaction analysis identified 10 hub genes, including FOS, ESR1, MAPK8, and SP1 targets. Molecular docking and molecular dynamics simulations showed that the bioactive compounds of WGP bound well to the targets. This study suggests that WGP exerts prominent health-promoting effects through multiple components, targets, and pathways. [ABSTRACT FROM AUTHOR]

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 β -hydroxysteroid dehydrogenase type 1 (11 β -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 β -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. [ABSTRACT FROM AUTHOR]

The study aimed to evaluate the potential of piperidine-based 2H chromen-2-one derivatives against targeted enzymes, i.e., cholinesterase's and monoamine oxidase enzymes. The compounds were divided into three groups, i.e., 4a–m ((3,4-dimethyl-7-((1-methylpiperidin-4-yl)oxy)-2H-chromen-2-one derivatives), 5a–e (3,4-dimethyl-7-((1-methypipridin-3-yl)methoxy)-2H-chromen-2-one derivatives), and 7a–b (7-(3-(3,4-dihydroisoquinolin-2(1H)-yl)propoxy)-3,4-dimethyl-2H-chromen-2-one derivatives) with slight difference in the basic structure. The comprehensive computational investigations were conducted including density functional theories studies (DFTs), 2D-QSAR studies, molecular docking, and molecular dynamics simulations. The QSAR equation revealed that the activity of selected chromen-2-one-based piperidine derivatives is being affected by the six descriptors, i.e., Nitrogens Count, SdssCcount, SssOE-Index, T-2–2-7, ChiV6chain, and SssCH2E-Index. These descriptor values were further used for the preparation of chromen-2-one based piperidine derivatives. Based on this, 83 new derivatives were created from 7 selected parent compounds. The QSAR model predicted their IC50 values, with compound 4 k and 4kk as the most potent multi-targeted derivative. Molecular docking results exhibited these compounds as the best inhibitors; however, 4kk exhibited greater activity than the parent compounds. The results were further validated by molecular dynamic simulation studies along with the suitable physicochemical properties. These results prove to be an essential guide for the further design and development of new piperidine based chromen-2-one derivatives having better activity against neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

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Genetic and environmental factors have been linked with neurodegeneration, especially in the elderly. Yet, efforts to impede neurodegenerative processes have at best addressed symptoms instead of underlying pathologies. The gap in the understanding of neuro-behavioral plasticity is consistent from insects to mammals, and cockroaches have been proven to be effective models for studying the toxicity mechanisms of various chemicals. We therefore used head injection of 74 and 740 nmol STZ in Nauphoeta cinerea to elucidate the mechanisms of chemical-induced neurotoxicity, as STZ is known to cross the blood-brain barrier. Neurolocomotor assessment was carried out in a new environment, while head homogenate was used to estimate metabolic, neurotransmitter and redox activities, followed by RT-qPCR validation of relevant cellular signaling. STZ treatment reduced the distance and maximum speed travelled by cockroaches, and increased glucose levels while reducing triglyceride levels in neural tissues. The activity of neurotransmitter regulators – AChE and MAO was exacerbated, with concurrent upregulation of glucose sensing and signaling, and increased mRNA levels of redox regulators and inflammation-related genes. Consequently, STZ neurotoxicity is conserved in insects, with possible implications for using N. cinerea to target the multi-faceted mechanisms of neurodegeneration and test potential anti-neurodegenerative agents. [ABSTRACT FROM AUTHOR]

Five dimethylamino-based chalcone derivatives (AC) were synthesized and evaluated for their inhibition degree against monoamine oxidase (MAO) enzymes. All AC compounds showed better inhibitory activity against MAO-B than that against MAO-A. AC4 showed the highest inhibitory ability with an IC50 value of 0.020 µM, similar to that of a reference drug safinamide (IC50 = 0.019 µM) against MAO-B, followed by AC1 (IC50 = 0.068 µM) and AC3 (IC50 = 0.083 µM). Substituent -F in ring A (AC4) increased the MAO-B inhibition, followed by -H (AC1), -Br (AC3), and -Cl (AC2). The selectivity index (SI) value of AC4 was high (SI = 82.00) as well as other compounds (44.41 to 98.15). AC4 was found to be a reversible inhibitor as confirmed through analysis using the dialysis method. Interestingly, AC4 was observed to be a noncompetitive MAO-B inhibitor with a rare case and with Ki values of 0.011 ± 0.0036 µM. These experiments confirmed that AC4 is a reversible and potent selective inhibitor of MAO-B. Molecular docking experiments revealed that AC4 showed the highest inhibitory activity with a docking score (-9.510 kcal/mol). A study using molecular dynamics modeling revealed that the protein–ligand complex was more stable. It was observed that AC4 was non-cytotoxic in the study using L929 cell line. In conclusion, compound AC4 shows promise as a MAO-B inhibitor. [ABSTRACT FROM AUTHOR]

Black mulberry (Morus nigra L.) is a common edible fruit from the Moraceae family with a wide variety of nutritional and medicinal applications, mainly due to its antioxidant and anti-inflammatory properties. The purpose of this work was to investigate the cytoprotective and neuroprotective capacity of a hydrophilic black mulberry solvent-free extract rich in polyphenols, including the antioxidant, antiradical, and enzymatic mechanisms that would explain these effects. Its neuroprotective potential was evaluated in vitro using the Neuro-2a cell line and in vivo through the Caenorhabditis elegans organism model. Neuro-2a cells were treated at different concentrations of the extract (25–500 µg/mL) and hydrogen peroxide (300 µM) as an oxidant agent, simultaneously. From these treatments, redox status (intracellular ROS production) and cellular activity (MTT) were also quantified in Neuro-2a. Regarding the C. elegans assay, the protection of the extract against β-amyloid toxicity was measured against the CL4176 strain, which is a model of Alzheimer disease. As a complementary neuroprotective assay, its potential to inhibit the monoamine oxidase A (MAO-A) enzyme was measured. In addition, an Artemia salina bioassay was performed for preliminary toxicity screening. And its antioxidant properties were evaluated by means of the FRAP assay. The results confirm its neuroprotective potential and its ability to scavenge free radicals and decrease ROS production, also acting as a moderate MAO-A inhibitor. Moreover, the polyphenolic extract alleviates the toxicity induced by β-amyloid accumulation in C. elegans. Concluding, Morus nigra can be considered a functional food with bioactive compounds that may prevent the onset of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The pharmacological effects of pomegranates have been described considering metabolic aspects such as hypoglycemic and hypolipidemic activities. The pomegranate extract has activity on the central nervous system (CNS) as a natural antidepressant and anxiolytic. The chemical composition of pomegranates is complex since the bioactive compounds are multiple secondary metabolites that have been identified in the extracts derived from the peel, seed, flowers, leaves, or in their combination; so, it has not been easy to identify an individual compound as responsible for its observed pharmacological properties. From this point of view, the present review analyzes the effects of crude extracts or fractions of pomegranates and their possible mechanisms of action concerning antidepressant- and anxiolytic-like effects in animal models. Serotonin receptors, estrogen receptors, the peroxisome proliferator-activated receptor gamma (PPARγ), or monoamine oxidase enzymes, as well as potent antioxidant and neuroplasticity properties, have been described as possible mediators involved in the antidepressant- and anxiolytic-like behaviors after pomegranate treatment. The pharmacological effects observed on the CNS in experimental models associated with a specific stress level suggest that pomegranates could simultaneously modulate the stress response by activating several targets. For the present review, scientific evidence was gathered to integrate it and suggest a possible pathway for mediators to be involved in the mechanisms of action of the pomegranate's antidepressant- and anxiolytic-like effects. Furthermore, the potential benefits are discussed on comorbid conditions with anxiety and depression, such as perimenopause transition and pain. [ABSTRACT FROM AUTHOR]

Ginkgo biloba extracts (GBE) have been shown to effectively improve cognitive function in patients with Alzheimer's disease (AD). One potential therapeutic strategy for AD is to prevent loss of adult hippocampal neurons. While recent studies have reported that GBE protects against oxidative stress in neurons, the underlying mechanisms remain unclear. In this study, an AD-like rat model was established via bidirectional injection of amyloid beta 25–35 (Aβ25–35; 20 μg) in the hippocampal CA1 region. Learning and memory abilities of experimental rats were AD assessed in response to oral administration of 7.5 g/L or 15 g/L Ginkgo biloba extract 50 (GBE50) solution and the peroxidation phenomenon of hippocampal mitochondria determined via analysis of mitochondrial H2O2 and several related enzymes. Levels of the oxidative stress-related signaling factor cytochrome C (Cyto C), apoptosis-related proteins (Bax, Bcl-2 and caspase-3) and caspase-activated DNase (CAD) were further detected via western blot. 8-Hydroxydeoxyguanosine (8-OHdG), the major product of DNA oxidative stress, was evaluated to analyze DNA status. Our results showed elevated H2O2 levels and monoamine oxidase (MAO) activity, and conversely, a decrease in the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the hippocampus of AD rats. Administration of GBE50 regulated the activities of these three enzymes and induced a decrease in H2O2. GBE50 exerted regulatory effects on abnormally expressed apoptotic proteins in the AD rat hippocampus, enhancing the expression of Bcl-2, inhibiting release of Cyto C from mitochondria, and suppressing the level of caspase-3 (excluding cleaved caspase-3). Furthermore, GBE50 inhibited DNA damage by lowering the generation of 8-OHdG rather than influencing expression of CAD. The collective findings support a protective role of GBE50 in hippocampal neurons of AD-like animals against mitochondrial oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease. Unfortunately, efficient and affordable treatments are still lacking for this neurodegenerative disorder, it is therefore urgent to identify new pharmacological targets. Astrocytes are playing a crucial role in the tuning of synaptic transmission and several studies have pointed out severe astrocyte reactivity in AD. Reactive astrocytes show altered physiology and function, suggesting they could have a role in the early pathophysiology of AD. Objective: We aimed to characterize early synaptic impairments in the AppNL-F knock-in mouse model of AD, especially to understand the contribution of astrocytes to early brain dysfunctions. Methods: The AppNL-F mouse model carries two disease-causing mutations inserted in the amyloid precursor protein gene. This strain does not start to develop amyloid-β plaques until 9 months of age. Thanks to electrophysiology, we investigated synaptic function, at both neuronal and astrocytic levels, in 6-month-old animals and correlate the synaptic activity with emotional behavior. Results: Electrophysiological recordings in the hippocampus revealed an overall synaptic mistuning at a pre-plaque stage of the pathology, associated to an intact social memory but a stronger depressive-like behavior. Astrocytes displayed a reactive-like morphology and a higher tonic GABA current compared to control mice. Interestingly, we here show that the synaptic impairments in hippocampal slices are partially corrected by a pre-treatment with the monoamine oxidase B blocker deprenyl or the fast-acting antidepressant ketamine (5 mg/kg). Conclusions: We propose that reactive astrocytes can induce synaptic mistuning early in AD, before plaques deposition, and that these changes are associated with emotional symptoms. [ABSTRACT FROM AUTHOR]

Monoamine oxidase (MAO) inhibitors are effective therapeutic agents for the treatment of neurodegenerative diseases, and natural flavonoids found in the species Agastache belong to them. In the present study, six new acylated flavone-O-glycosides were isolated from A. foeniculum and identified using UV, NMR spectroscopy, and mass spectrometry as agastoside A (acacetin 7-O-(2′′-O-malonyl)-β-D-glucopyranoside), B (acacetin 7-O-(4′′-O-malonyl)-β-D-glucopyranoside), C (acacetin 7-O-(2′′,6′′-di-O-malonyl)-β-D-glucopyranoside), D (acacetin 7-O-(4′′,6′′-di-O-malonyl)-β-D-glucopyranoside), E (acacetin 7-O-(2′′-O-malonyl-6′′-O-acetyl)-β-D-glucopyranoside), and F (acacetin 7-O-(4′′-O-acetyl-6′′-O-malonyl)-β-D-glucopyranoside). Using flash chromatography and liquid chromatography–mass spectrometry, an additional 34 known phenolic compounds were detected. A study of biological activity showed that A. foeniculum flavonoids had an inhibitory effect on MAO-A and MAO-B, with the greatest effect noted for acacetin 7-O-glucoside acetate and malonate esters, which may be promising compounds for the development new drugs. [ABSTRACT FROM AUTHOR]

Hypothyroidism has adverse effects on heart metabolism and functions including reduced heart rate, cardiac output and cardiac contractility. The therapeutic effects of alpha lipoic acid (LA) and metformin (MET) against hypothyroidism-induced myocardial complications were assessed in the current study. Rats were divided into control, propylthiouracil (PTU)-induced hypothyroidism model, hypothyroidism model treated with LA and/or MET. Serum thyroid hormones (T3, T4 and TSH) were measured. Lipid peroxidation (MDA), nitric oxide (NO), reduced glutathione (GSH), nuclear factor erythroid 2–related factor 2 (NrF2), B-cell lymphoma 2 (BCL2), nuclear factor kappa B (NF-κB), serotonin (5-HT), norepinephrine (NE) and dopamine (DA), acetylcholinesterase (AChE), monoamine oxidase (MAO) and Na+,K+,ATPase were measured in the cardiac tissue. The histopathological changes were also assessed. PTU significantly decreased T3 and T4 and significantly increased TSH. A significant increase in MDA, GSH, NrF2, BCL2, NF-κB, 5-HT, NE, DA, AChE, MAO and Na+,K+,ATPase and a significant decrease in NO were observed in the cardiac tissue of hypothyroidism model. This was associated with histopathological changes. LA alone or with MET restored T3 and TSH and improved almost all the biochemical changes except the decreased NO and the increased DA. MET restored T3, T4 and TSH and the biochemical changes induced in the cardiac tissue. MET ameliorated the histopathological changes that were still observed with LA alone or with MET. The present findings indicate that MET had cardioprotective effect against hypothyroidism and its myocardial complications. This effect was less prominent with LA alone or in combination with MET. [ABSTRACT FROM AUTHOR]

Resveratrol (3,5,4′-trihydroxy-trans-stilbene), a phenol commonly found in grapes and wine, has been associated as protective in experimental models involving alterations in different neurotransmitter systems. However, studies are reporting that resveratrol could have adverse effects. This study evaluated if the association of a low dose of ketamine and resveratrol could induce behavioral manifestations associated with biochemical alterations. Moreover, the effects of treatment with resveratrol and/or ketamine on monoamine oxidase (MAO) activity, oxidative stress markers, and IL-6 levels in the brain were also investigated. Male Swiss mice received a low dose of ketamine (20 mg/kg) for 14 consecutive days, and resveratrol (10, 30, or 100 mg/kg) from day 8 up to day 14 of the experimental period, intraperitoneally. Locomotor, stereotyped behavior, Y-maze, novel recognition object test (NORT), and social interaction were quantified as well as ex vivo analysis of MAO activity, IL-6 levels, and oxidative stress markers (TBARS and total thiol levels) in brain tissues. Ketamine per se reduced the number of bouts of stereotyped behavior on day 8 of the experimental period. Resveratrol per se reduced the locomotor and exploratory activity in the open field, the time of exploration of new objects in the NORT, MAO-A activity in the striatum and increased the IL-6 levels in the cortex. These effects were attenuated when the mice were co-treated with ketamine and resveratrol. There was a decrease in MAO-A activity in the cortex of mice treated with ketamine + resveratrol 100 mg/kg. No significant alterations were found in oxidative stress markers. Resveratrol does not appear to cause summative effects with ketamine on behavioral alterations. However, the effect of resveratrol per se, mainly on locomotor and exploratory activity, should be better investigated. [ABSTRACT FROM AUTHOR]

Introduction: Risk-allele carriers of a Monoamine oxidase A (MAOA) gene, shortallele (MAOA-S) in males and long-allele (MAOA-L) in females, in the presence of a negative environment, are associated with alcohol misuse. Whether MAOA-S/L alleles also present susceptibility to a positive environment to mitigate the risk of alcohol misuse is unknown. Thus, we assessed the association of the three-way interaction of MAOA, maltreatment, and positive parent-child relationship with alcohol consumption among adolescents. Methods: This prospective study included 1416 adolescents (females: 59.88%) aged 16-19 years from Sweden, enrolled in the "Survey of Adolescent Life in Västmanland" in 2012. Adolescents self-reported alcohol consumption, maltreatment by a family (FM) or non-family member (NFM), parent-child relationship, and left saliva for MAOA genotyping. Results and discussion: We observed sex-dependent results. Females carrying MAOA-L with FM or NFM and a good parent-child relationship reported lower alcohol consumption than those with an average or poor parent-child relationship. In males, the interactions were not significant. Results suggest MAOA-L in females, conventionally regarded as a "risk", is a "plasticity" allele as it is differentially susceptible to negative and positive environments. Results highlight the importance of a good parent-child relationship in mitigating the risk of alcohol misuse in maltreated individuals carrying genetic risk. However, the interactions were not significant after adjusting to several environmental and behavioural covariates, especially parent's alcohol use, negative parent-child relationship, and nicotine use (smoking and/or snus), suggesting predictor and outcome intersection. Future studies and frameworks for preventive strategies should consider these covariates together with alcohol consumption. More studies with larger sample sizes are needed to replicate the findings. [ABSTRACT FROM AUTHOR]