Targeting monoamine oxidase A: a strategy for inhibiting tumor growth with both immune checkpoint inhibitors and immune modulators.

Monoamine oxidase A (MAOA) is a membrane-bound mitochondrial enzyme present in almost all vertebrate tissues that catalyzes the degradation of biogenic and dietary-derived monoamines. MAOA is known for regulating neurotransmitter metabolism and has been implicated in antitumor immune responses. In this review, we retrospect that MAOA inhibits the activities of various types of tumor-associated immune cells (such as CD8+ T cells and tumor-associated macrophages) by regulating their intracellular monoamines and metabolites. Developing novel MAOA inhibitor drugs and exploring multidrug combination strategies may enhance the efficacy of immune governance. Thus, MAOA may act as a novel immune checkpoint or immunomodulator by influencing the efficacy and effectiveness of immunotherapy. In conclusion, MAOA is a promising immune target that merits further in-depth exploration in preclinical and clinical settings.

Effect of MAOA rs1465108 polymorphism on susceptibility to substance/alcohol use disorder: a novel PCR-RFLP assay for the detection of MAOA rs1465108.

BACKGROUND: The health and social consequences of substance/alcohol use disorders are harmful. Most of the individuals cannot stop using them due to more likely their genetic background. The current study aimed both to develop a novel PCR-RFLP method for genotyping of MAOA rs1465108 and to analyze the effect of MAOA rs1465108 on the risk of alcohol (AUD), opioid (OUD) or methamphetamine (MUD) use disorders and on the depressive and anxiety symptoms in a Turkish population. METHODS AND RESULTS: A total of 353 individual with AUD (n = 154), OUD (n = 160) or MUD (n = 39) and 109 healthy subjects were included. The intensity of anxiety and depressive symptoms and craving and opioid withdrawal were measured by appropriate scales. Logistic regression analysis revealed no association between MAOA rs1465108 polymorphism and substance/alcohol use disorder (p > 0.05). Healthy subjects (3.0) had significantly lower levels of depressive symptoms than individuals with OUD (27.0), AUD (21.0) and MUD (25.5) groups. The severity of depressive symptoms was significantly higher in OUD as compared to AUD. There was a statistically significant difference between individuals with AUD, OUD and MUD in view of the average ages of first use (17, 19 and 20 years, respectively) (p < 0.05). CONCLUSIONS: The results presented here do not support the hypothesis that MAOA rs1465108 is associated with substance/alcohol use disorders. The intensity of depressive symptoms could be changed according to the abused substance type. A novel PCR-RFLP was developed for genotyping of MAOA rs1465108 polymorphism, which could be a better option for laboratories without high technology equipment.

Key Enzymes of the Serotonergic System - Tryptophan Hydroxylase 2 and Monoamine Oxidase A - In the Brain of Rats Selectively Bred for a Reaction toward Humans: Effects of Benzopentathiepin TC-2153.

At the Institute of Cytology and Genetics (Novosibirsk, Russia) for over 85 generations, gray rats have been selected for high aggression toward humans (aggressive rats) or its complete absence (tame rats). Aggressive rats are an interesting model for studying fear-induced aggression. Benzopentathiepin TC-2153 exerts an antiaggressive effect on aggressive rats and affects the serotonergic system: an important regulator of aggression. The aim of this study was to investigate effects of TC-2153 on key serotonergic-system enzymes - tryptophan hydroxylase 2 (TPH2) and monoamine oxidase A (MAOA) - in the brain of aggressive and tame rats. Either TC-2153 (10 or 20 mg/kg) or vehicle was administered once intraperitoneally to aggressive and tame male rats. TPH2 and MAOA enzymatic activities and mRNA and protein levels were assessed. The selection for high aggression resulted in upregulation of Tph2 mRNA in the midbrain, of the TPH2 protein in the hippocampus, and of proteins TPH2 and MAOA in the hypothalamus, as compared to tame rats. MAO enzymatic activity was higher in the midbrain and hippocampus of aggressive rats while TPH2 activity did not differ between the strains. The single TC-2153 administration decreased TPH2 and MAO activity in the hypothalamus and midbrain, respectively. The drug affected MAOA protein levels in the hypothalamus: upregulated them in aggressive rats and downregulated them in tame ones. Thus, this study shows profound differences in the expression and activity of key serotonergic system enzymes in the brain of rats selectively bred for either highly aggressive behavior toward humans or its absence, and the effects of benzopentathiepin TC-2153 on these enzymes may point to mechanisms of its antiaggressive action.

Monoamine oxidase mediated oxidative stress: a potential molecular and biochemical crux in the pathogenesis of obesity.

Obesity has become a global health concern with an increasing prevalence as years pass by but the researchers have not come to a consensus on the exact pathophysiological mechanism underlying this disease. In the past three decades, Monoamine Oxidases (MAO), has come into limelight for a possible involvement in orchestrating the genesis of obesity but the exact mechanism is not well elucidated. MAO is essentially an enzyme involved in the catabolism of neurotransmitters and other biogenic amines to form a corresponding aldehyde, hydrogen peroxide (H2O2) and ammonia. This review aims to highlight the repercussions of MAO's catabolic activity on the redox balance, carbohydrate metabolism and lipid metabolism of adipocytes which ultimately leads to obesity. The H2O2 produced by these enzymes seems to be the culprit causing oxidative stress in pre-adipocytes and goes on to mimic insulin's activity independent of its presence via the Protein Kinase B Pathway facilitating glucose influx. The H2O2 activates Sterol regulatory-element binding protein-1c and peroxisome proliferator activated receptor gamma crucial for encoding enzymes like fatty acid synthase, acetyl CoA carboxylase 1, Adenosine triphosphate-citrate lyase, phosphoenol pyruvate carboxykinase etc., which helps promoting lipogenesis at the same time inhibits lipolysis. More reactive oxygen species production occurs via NADPH Oxidases enzymes and is also able activate Nuclear Factor kappa B leading to inflammation in the adipocyte microenvironment. This chronic inflammation is the seed for insulin resistance.

Dihydroxanthene-based monoamine oxidase A-activated photosensitizers for photodynamic/photothermal therapy of tumors.

Small molecule photosensitizers for combined in vivo tailored cancer diagnostics and photodynamic/photothermal therapy are desperately needed. Monoamine oxidase A (MAO-A)-activated therapeutic and diagnostic compounds provide great selectivity because MAO-A can be employed as a biomarker for associated Tumors. In order to screen photosensitizers with photodynamic therapeutic potential, we have created a range of near-infrared fluorescent molecules in this work by combining dihydroxanthene parent with various heterocyclic fluorescent dyes. The NIR fluorescent diagnostic probe, DHMQ, was created by combining the screened fluorescent dye matrices with the propylamino group, which is the recognition moiety of MAO-A, based on the oxidative deamination mechanism of the enzyme. This probe has a low toxicity level and can identify MAO-A precisely. It has the ability to use fluorescence imaging on mice and cells to track MAO-A activity in real-time. It has strong phototoxicity and can produce singlet oxygen when exposed to laser light. The temperature used in photothermal imaging can get up to 50 °C, which can harm tumor cells permanently and have a positive phototherapeutic impact on tumors grown from SH-SY5Y xenograft mice. The concept of using MAO-A effectively in diseases is expanded by the MAO-A-activated diagnostic-integrated photosensitizers, which offer a new platform for in vivo cancer diagnostics and targeted anticancer treatment.

Association between serum catecholamine levels and VNTR polymorphism in the promoter region of the monoamine oxidase A gene in forensic autopsy cases.

Monoamine oxidase A (MAOA) catalyzes oxidative deamination of catecholamines. A functional variable number tandem repeat (VNTR) polymorphism in the promoter region of the MAOA gene has been previously reported. In the present study, we measured serum adrenaline (Adr), noradrenaline (Nad), and dopamine (DA) levels in 90 male and 34 female Japanese autopsy cases in which amphetamines or psychotropic drugs were not detected.We examined the frequencies of MAOA-uVNTR alleles in these cases and investigated the effects of the MAOA-uVNTR polymorphism on serum Adr, Nad, and DA levels. Evaluation indicated no significant association between MAOA-uVNTR polymorphism and serum Adr, Nad, or DA levels in males, although a significant association between MAOA-uVNTR polymorphism and serum Adr and DA levels were observed in females. Females with the 3/3 genotype had higher serum Adr and DA levels than those with a 4-repeat allele (3/4 and 4/4 genotypes) (p = 0.048 and 0.020, respectively). There was no significant association between MAOA-uVNTR polymorphism and serum Nad levels in females. The present study indicates that MAOA-uVNTR polymorphism influences serum Adr and DA levels only in females.

A magnetic beads-based ligand fishing method for rapid discovery of monoterpene indoles as monoamine oxidase A inhibitors from Hunteria zeylanica.

In this study, a novel magnetic bead-based ligand fishing method was developed for rapid discovery of monoterpene indoles as monoamine oxidase A inhibitors from natural products. In order to improve the screening efficiency, two different magnetic beads, i.e. amine and carboxyl terminated magnetic beads, were comprehensively compared in terms of their ability to immobilize monoamine oxidase A (MAOA), biocatalytic activity and specific adsorption rates for affinity ligands. Carboxyl terminated magnetic beads performed better for MAOA immobilization and demonstrated superior performance in ligand fishing. The MAOA immobilized magnetic beads were applied to screen novel monoamine oxidase inhibitors in an alkaloid-rich plant, Hunteria zeylanica. Twelve MAOA affinity ligands were screened out, and ten of them were identified as monoterpene indole alkaloids by HPLC-Obitrap-MS/MS. Among them, six ligands, namely geissoschizol, vobasinol, yohimbol, dihydrocorynanthenol, eburnamine and (+)-isoeburnamine which exhibited inhibitory activity against MAOA with low IC50 values. To further explore their inhibitory mechanism, enzyme kinetic analysis and molecular docking studies were conducted.

REM sleep behavior disorder in Brunner syndrome.

Brunner syndrome is a recessive X-linked disorder characterized by intellectual disability and impulsive aggressiveness associated with Monoamine Oxidase-A (MAOA) deficiency leading to increased monoaminergic activity. We report the presence of REM sleep behavior disorder (RBD) in a 46-year-old patient with Brunner syndrome due to a c.1438A>G/iVS14-2 A>G mutation of the MAOA gene. He suffered from mild intellectual disability and psychotic disturbances. He presented a 15-year history of nightmares (chase, attacks and fights), sleep-related vocalizations and motor behaviors characterized by talking, screaming, crying, gesturing, punching, and kicking. Video-polysomnography showed RBD characterized by excessive tonic and phasic muscle activity in the mentalis and limb muscles with dream enacting behaviors during REM sleep. Clonazepam achieved a significant reduction of RBD symptomatology. We conclude that RBD can be a manifestation of Brunner syndrome probably due to an increased monoaminergic neurotransmission occurring in this rare genetic disorder.

An in vitro analysis of an innovative standardized phospholipid carrier-based Melissa officinalis L. extract as a potential neuromodulator for emotional distress and related conditions.

Background: Melissa officinalis L. (MO), commonly known as lemon balm, a member of the mint family, is considered a calming herb. In various traditional medicines, it has been utilized to reduce stress and anxiety and promote sleep. A growing body of clinical evidence suggests that MO leaf extract supplementation possesses considerable neuropharmacological properties. However, its possible mechanism of action largely remains unknown. Objective: In the present in vitro studies, we comparatively investigated the central nervous system (CNS)-calming and antioxidative stress properties of an innovative standardized phospholipid carrier-based (Phytosome™) MO extract (Relissa™) vs. an unformulated dry MO extract. Methods: The neuropharmacological effect of the extract was studied in the anti-depressant enzymes γ-aminobutyrate transaminase (GABA-T) and monoamine oxidase A (MAO-A) assays and SH-SY5Y cells brain-derived neurotrophic factor (BDNF) expression assay. The neuroprotective effect of the extract against oxidative stress was assessed in SH-SY5Y cell-based (H2O2-exposed) Total Antioxidant Status (TAS) and Total Reactive Oxygen Species (ROS) assays. The cytotoxic effect of the extract was evaluated using MTT and LDH assays. The extract antioxidant effect was also evaluated in cell-free chemical tests, including TEAC-ABTS, DPPH, Ferric Reducing Antioxidant Power (FRAP), Oxygen Radical Antioxidant Capacity (ORAC), and Hydroxyl Radical Antioxidant Capacity (HORAC) assays. Results: Relissa™ exhibited high GABA-T inhibitory activity, IC50 (mg/mL) = 0.064 vs. unformulated dry MO extract, IC50 (mg/mL) = 0.27. Similar inhibitory effects were also observed for MAO-A. Relissa™ demonstrated an improved neuroprotective antioxidant effect on SH-SY5Y cells against H2O2-induced oxidative stress. Compared to unformulated dry MO extract, Relissa™ exerted high protective effect on H2O2-exposed SH-SY5Y cells, leading to higher cells BDNF expression levels. Moreover, cell-free chemical tests, including TEAC-ABTS, DPPH radical scavenging, FRAP, ORAC, and HORAC assays, validated the improved antioxidant effect of Relissa™ vs. unformulated dry MO extract. Conclusion: The results of the present study support the neuromodulating and neuroprotective properties of Relissa™, and its supplementation may help in the amelioration of emotional distress and related conditions.

Good parent-child relationship protects against alcohol use in maltreated adolescent females carrying the MAOA-uVNTR susceptibility allele.

Introduction: Risk-allele carriers of a Monoamine oxidase A (MAOA) gene, short-allele (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.