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AIMS: A mechanistic link between depression and risk of arrhythmias could be attributed to altered catecholamine metabolism in the heart. Monoamine oxidase-A (MAO-A), a key enzyme involved in catecholamine metabolism and longstanding antidepressant target, is highly expressed in the myocardium. The present study aimed to elucidate the functional significance and underlying mechanisms of cardiac MAO-A in arrhythmogenesis. METHODS AND RESULTS: Analysis of the TriNetX database revealed that depressed patients treated with MAO inhibitors had a lower risk of arrhythmias compared with those treated with selective serotonin reuptake inhibitors. This effect was phenocopied in mice with cardiomyocyte-specific MAO-A deficiency (cMAO-Adef), which showed a significant reduction in both incidence and duration of catecholamine stress-induced ventricular tachycardia compared with wild-type mice. Additionally, cMAO-Adef cardiomyocytes exhibited altered Ca2+ handling under catecholamine stimulation, with increased diastolic Ca2+ reuptake, reduced diastolic Ca2+ leak, and diminished systolic Ca2+ release. Mechanistically, cMAO-Adef hearts had reduced catecholamine levels under sympathetic stress, along with reduced levels of reactive oxygen species and protein carbonylation, leading to decreased oxidation of Type II PKA and CaMKII. These changes potentiated phospholamban (PLB) phosphorylation, thereby enhancing diastolic Ca2+ reuptake, while reducing ryanodine receptor 2 (RyR2) phosphorylation to decrease diastolic Ca2+ leak. Consequently, cMAO-Adef hearts exhibited lower diastolic Ca2+ levels and fewer arrhythmogenic Ca2+ waves during sympathetic overstimulation. CONCLUSION: Cardiac MAO-A inhibition exerts an anti-arrhythmic effect by enhancing diastolic Ca2+ handling under catecholamine stress.
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Calcio , Catecolaminas , Monoaminooxidasa , Taquicardia Ventricular , Animales , Femenino , Humanos , Masculino , Ratones , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Catecolaminas/metabolismo , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Diástole/efectos de los fármacos , Modelos Animales de Enfermedad , Frecuencia Cardíaca/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fosforilación , Especies Reactivas de Oxígeno/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Taquicardia Ventricular/enzimología , Taquicardia Ventricular/fisiopatologíaRESUMEN
Monoamine oxidase A (MAO A) and heat shock protein 90 (HSP90) inhibitors have been shown to decrease the progression of glioblastoma (GBM) and other cancers. In this study, a series of MAO A/HSP90 dual inhibitors were designed and synthesized in the hope to develop more effective treatment of GBM. Compounds 4-b and 4-c are conjugates of isopropylresorcinol (pharmacophore of HSP90 inhibitor) with the phenyl group of clorgyline (MAO A inhibitor) by a tertiary amide bond substituted with methyl (4-b) or ethyl (4-c) group, respectively. They inhibited MAO A activity, HSP90 binding, and the growth of both TMZ-sensitive and -resistant GBM cells. Western blots showed that they increased HSP70 expression indicating reduced function of HSP90, reduced HER2 and phospho-Akt expression similar to MAO A or HSP90 inhibitor itself. Both compounds decreased IFN-γ induced PD-L1 expression in GL26 cells, suggesting they can act as immune checkpoint inhibitor. Further, they reduced tumor growth in GL26 mouse model. NCI-60 analysis showed they also inhibited the growth of colon cancer, leukemia, non-small cell lung and other cancers. Taken together, this study demonstrates MAO A/HSP90 dual inhibitors 4-b and 4-c reduced the growth of GBM and other cancers, and they have potential to inhibit tumor immune escape.
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Antineoplásicos , Glioblastoma , Ratones , Animales , Monoaminooxidasa/metabolismo , Glioblastoma/tratamiento farmacológico , Inhibidores de la Monoaminooxidasa/farmacología , Clorgilina/farmacología , Antineoplásicos/farmacología , Proteínas HSP70 de Choque Térmico , Proteínas HSP90 de Choque TérmicoRESUMEN
Exploring the relationship between various neurotransmitters and breast cancer cell growth has revealed their likely centrality to improving breast cancer treatment. Neurotransmitters play a key role in breast cancer biology through their effects on the cell cycle, epithelial mesenchymal transition, angiogenesis, inflammation, the tumor microenvironment and other pathways. Neurotransmitters and their receptors are vital to the initiation, progression and drug resistance of cancer and progress in our biological understanding may point the way to lower-cost and lower-risk antitumor therapeutic strategies. This review discusses multiple neurotransmitters in the context of breast cancer. It also discusses risk factors, repurposing of pharmaceuticals impacting neurotransmitter pathways, and the opportunity for better integrated models that encompass exercise, the intestinal microbiome, and other non-pharmacologic considerations. Neurotransmitters' role in breast cancer should no longer be ignored; it may appear to complicate the molecular picture but the ubiquity of neurotransmitters and their wide-ranging impacts provide an organizing framework upon which further understanding and progress against breast cancer can be based.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/metabolismo , Neurotransmisores/metabolismo , Transición Epitelial-Mesenquimal , Microambiente TumoralRESUMEN
Emerging studies, including ours, have revealed the novel essential roles of monoamine oxidase A (MAO A) in mediating the growth and progression of several types of cancers. Recently, we presented the first evidence of MAO A's ability to promote cancer cell perineural invasion, the neoplastic invasion of nerves widely recognized as a significant route for cancer metastasis. Here, we describe a perineural invasion in vitro assay using a 3D coculture with a cancer cell line and an immortalized dorsal root ganglion neuronal cell line for rapid examination of MAO A's roles in cancer-nerve cell crosstalk and evaluating the efficacy of MAO A inhibitors for disrupting perineural invasion. We also summarized the fundamental methods for determining MAO A's effects on cancer cell proliferation in vitro and tumorigenesis in vivo.
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Ganglios Espinales , Monoaminooxidasa , Proliferación Celular , Técnicas de Cocultivo , Humanos , Monoaminooxidasa/metabolismo , Invasividad Neoplásica/patologíaRESUMEN
Monoamine oxidase A (MAO A) is the critical enzyme to degrade serotonin in the brain and the knockout mouse exhibits hyperserotonemia and abnormalities that are observed in autism spectrum disorder (ASD). Thus, the MAO A knockout mouse is a valuable model for studying neurological and behavioral impairments in ASD. Based on the immune dysfunction hypothesis, dysregulated humoral immunity may cause neurological impairments. To address this hypothesis, we use high-density proteome microarray to profile the serum antibodies in both wild-type and MAO A knockout mice. The distingue autoantibody signatures were observed in the MAO A knockout and wild-type controls and showed 165 up-regulated and 232 down-regulated autoantibodies. The up-regulated autoantibodies were prone to target brain tissues while down-regulated ones were enriched in sex organs. The identified autoantibodies help bridge the gap between ASD mouse models and humoral immunity, not only yielding insights into the pathological mechanisms but also providing potential biomarkers for translational research in ASD.
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Trastorno del Espectro Autista , Monoaminooxidasa , Animales , Ratones , Ratones Noqueados , Monoaminooxidasa/genética , Trastorno del Espectro Autista/genética , AutoanticuerposRESUMEN
We have previously shown that monoamine oxidase A (MAO A) mediates prostate cancer growth and metastasis. Further, MAO A/Pten double knockout (DKO) mice were generated and demonstrated that the deletion of MAO A delayed prostate tumor development in the Pten knockout mouse model of prostate adenocarcinoma. Here, we investigated its effect on immune cells in the tumor microenvironment in MAO A/Pten DKO mouse model. Our results shows that Paraffin embedded prostate tissues from MAO A/Pten DKO mice had elevated markers of immune stimulation (CD8+ cytotoxic T cells, granzyme B, and IFNγ) and decreased expression of markers of immune suppression (FoxP3, CD11b, HIF-1-alpha, and arginase 1) compared to parental Pten knockouts (MAO A wildtype). CD11b+ myeloid derived suppressor cells (MDSC) were the primary immunosuppressive cell types in these tumors. The data suggest that deletion of MAO A reduces immune suppression in prostate tumors to enhance antitumor immunity in prostate cancer. Thus, MAO A inhibitor may alleviate immune suppression, increase the antitumor immune response and be used for cancer immunotherapy.
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Próstata , Neoplasias de la Próstata , Humanos , Masculino , Ratones , Animales , Próstata/patología , Monoaminooxidasa/genética , Neoplasias de la Próstata/patología , Terapia de Inmunosupresión , Microambiente Tumoral , Línea Celular TumoralRESUMEN
The brain-gut axis, a bidirectional network between the central and enteric nervous system, plays a critical role in modulating the gastrointestinal tract function and homeostasis. Recently, increasing evidence suggests that neuronal signaling molecules can promote gastrointestinal cancers, however, the mechanisms remain unclear. Aberrant expression of neurotransmitter signaling genes in colorectal cancer supports the role of neurotransmitters to stimulate tumor growth and metastatic spread by promoting cell proliferation, migration, invasion, and angiogenesis. In addition, neurotransmitters can interact with immune and endothelial cells in the tumor microenvironment to promote inflammation and tumor progression. As such, pharmacological targeting of neurotransmitter signaling represent a promising novel anticancer approach. Here, we present an overview of the current evidence supporting the role of neurotransmitters in colorectal cancer biology and treatment.
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Neoplasias Colorrectales , Neoplasias Gastrointestinales , Humanos , Células Endoteliales/metabolismo , Neurotransmisores , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Biología , Microambiente TumoralRESUMEN
We have recently identified a pool of intracellular ß1 adrenergic receptors (ß1ARs) at the sarcoplasmic reticulum (SR) crucial for cardiac function. Here, we aim to characterize the integrative control of intracellular catecholamine for subcellular ß1AR signaling and cardiac function. Using anchored Förster resonance energy transfer (FRET) biosensors and transgenic mice, we determined the regulation of compartmentalized ß1AR-PKA signaling at the SR and plasma membrane (PM) microdomains by organic cation transporter 3 (OCT3) and monoamine oxidase A (MAO-A), two critical modulators of catecholamine uptake and homeostasis. Additionally, we examined local PKA substrate phosphorylation and excitation-contraction coupling in cardiomyocyte. Cardiac-specific deletion of MAO-A (MAO-A-CKO) elevates catecholamines and cAMP levels in the myocardium, baseline cardiac function, and adrenergic responses. Both MAO-A deletion and inhibitor (MAOi) selectively enhance the local ß1AR-PKA activity at the SR but not PM, and augment phosphorylation of phospholamban, Ca2+ cycling, and myocyte contractile response. Overexpression of MAO-A suppresses the SR-ß1AR-PKA activity and PKA phosphorylation. However, deletion or inhibition of OCT3 by corticosterone prevents the effects induced by MAOi and MAO-A deletion in cardiomyocytes. Deletion or inhibition of OCT3 also negates the effects of MAOi and MAO-A deficiency in cardiac function and adrenergic responses in vivo. Our data show that MAO-A and OCT3 act in concert to fine-tune the intracellular SR-ß1AR-PKA signaling and cardiac fight-or-flight response. We reveal a drug contraindication between anti-inflammatory corticosterone and anti-depressant MAOi in modulating adrenergic regulation in the heart, providing novel perspectives of these drugs with cardiac implications.
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Corticosterona , Proteínas Quinasas Dependientes de AMP Cíclico , Adrenérgicos/metabolismo , Adrenérgicos/farmacología , Animales , Calcio/metabolismo , Catecolaminas/metabolismo , Catecolaminas/farmacología , Cationes/metabolismo , Cationes/farmacología , Corticosterona/metabolismo , Corticosterona/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/farmacología , Ratones , Monoaminooxidasa/metabolismo , Monoaminooxidasa/farmacología , Contracción Miocárdica , Miocitos Cardíacos/metabolismo , Fosforilación , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Retículo SarcoplasmáticoRESUMEN
Glioma treatment remains a challenge with a low survival rate due to the lack of effective therapeutics. Monoamine oxidase A (MAO A) plays a role in glioma development, and MAO A inhibitors reduce glioma growth. Histone deacetylase (HDAC) inhibition has emerged as a promising therapy for various malignancies including gliomas. We have synthesized and evaluated N-methylpropargylamine-conjugated hydroxamic acids as dual inhibitors of MAO A and HDAC. Compounds display potent MAO A inhibition with IC50 from 0.03 to <0.0001 µM and inhibit HDAC isoforms and cell growth in the micromolar to nanomolar IC50 range. These selective MAO A inhibitors increase histone H3 and α-tubulin acetylation and induce cell death via nonapoptotic mechanisms. Treatment with 15 reduced tumor size, reduced MAO A activity in brain and tumor tissues, and prolonged the survival. This first report on dual inhibitors of MAO A and HDAC establishes the basis of translational research for an improved treatment of glioma.
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Inhibidores Enzimáticos/química , Histona Desacetilasas/química , Ácidos Hidroxámicos/química , Monoaminooxidasa/química , Acetilación/efectos de los fármacos , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/mortalidad , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/metabolismo , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Estimación de Kaplan-Meier , Masculino , Ratones , Ratones Endogámicos C57BL , Monoaminooxidasa/metabolismo , Pargilina/análogos & derivados , Pargilina/química , Propilaminas/química , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
Monoamine oxidase B (MAO B) oxidizes trace amine phenylethylamine (PEA), and neurotransmitters serotonin and dopamine in the brain. We reported previously that PEA levels increased significantly in all brain regions, but serotonin and dopamine levels were unchanged in MAO B knockout (KO) mice. PEA and dopamine are both synthesized from phenylalanine by aromatic L-amino acid decarboxylase in dopaminergic neurons in the striatum. A high concentration of PEA in the striatum may cause dopaminergic neuronal death in the absence of MAO B. We isolated the RNA from brain tissue of MAO B KO mice (2-month old) and age-matched wild type (WT) male mice and analyzed the altered genes by Affymetrix microarray. Differentially expressed genes (DEGs) in MAO B KO compared to WT mice were analyzed by Partek Genomics Suite, followed by Ingenuity Pathway Analysis (IPA) to assess their functional relationships. DEGs in MAO B KO mice are involved in brain inflammation and the genesis of GABAnergic neurons. The significant DEGs include four brain injury or inflammation genes (upregulated: Ido1, TSPO, AVP, Tdo2), five gamma-aminobutyric acid (GABA) receptors (down-regulated: GABRA2, GABRA3, GABRB1, GABRB3, GABRG3), five transcription factors related to adult neurogenesis (upregulated: Wnt7b, Hes5; down-regulated: Pax6, Tcf4, Dtna). Altered brain injury and inflammation genes in MAO B knockout mice are involved in various neurological disorders: attention deficit hyperactive disorder, panic disorder, obsessive compulsive disorder, autism, amyotrophic lateral sclerosis, Parkinson's diseases, Alzheimer's disease, bipolar affective disorder. Many were commonly involved in these disorders, indicating that there are overlapping molecular pathways.
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Lesiones Encefálicas/metabolismo , Encéfalo/metabolismo , Neuronas GABAérgicas/metabolismo , Inflamación/metabolismo , Monoaminooxidasa/metabolismo , Animales , Lesiones Encefálicas/genética , Muerte Celular/fisiología , Neuronas Dopaminérgicas/metabolismo , Inflamación/genética , Ratones , Ratones Noqueados , Monoaminooxidasa/genética , Serotonina/metabolismoRESUMEN
Our previous work has shown that monoamine oxidase A (MAO A) is overexpressed in glioma and prostate cancer. Near-infrared dye conjugate MAO A Inhibitor (NMI) inhibited the growth of these cancers. This study investigated the effects of NMI on other cancers by NCI60 screening. Our results showed that 48 out of 59 screened cell lines from nine types of cancer had 100% growth inhibition at 10 µM NMI treatment. The in vitro efficacy of NMI determined by growth inhibition (GI50 and TGI) and lethal doses (LC50) has been further studied in various cell lines of CNS cancer, prostate cancer, and non-small cell lung cancer (NSCLC), these three cancers showed increased MAO A expression in tumors compared to normal tissues. Based on the waterfall plots and the 3D scatter plot of GI50, TGI, and LC50 data, NMI showed higher potency to several CNS cancer and NSCLC cell lines than prostate cancer cell lines. In vitro efficacy of NMI outperformed FDA-approved drugs for CNS cancer, prostate cancer, and NSCLC, respectively. The Pairwise Pearson Correlation Coefficient (PCC) showed that NMI has a unique mechanism compared to the existing anticancer drugs. This study shows that NMI is a novel theragnostic drug with high potency and unique mechanisms for brain, prostate, NSCLC, and other cancers.
RESUMEN
PURPOSE: The biodistribution imaging kinetics of near-infrared monoamine oxidase inhibitor (NMI) are reported here. METHODS: NMI was administered intravenously or orally to mice and detected by NIR fluorescence optical imaging within minutes and the longitudinal signal distribution was measured for up to 1 week after a single dose. RESULTS: NMI rapidly reached 3.7-fold higher ventral and 3.2-fold higher brain region fluorescent signal intensity compared to oral route at 24 h. Similar patterns of NMI biodistribution were found in mice with or without intracranial implanted GL26 brain tumors. NMI was highly associated with tumors in contrast to adjacent non-tumor brain, confirming diagnostic utility. NMI 5 mg/kg imaging signal in brain at 48 h was optimal (tumor/non-tumor ratio > 3.5) with minimum off-target distribution. Intravenous NMI imaging signal peaked between 24 h and 48 h for lung, liver, kidney, blood, brain, and most other tissues. Clearance (signal weaker, but still present) from most tissues occurred by day 7. Intravenous low dose (0.5 mg/kg) minimally labeled tumor and other tissues, 5 mg/kg showed optimal imaging signal in glioma at a dose we previously reported as efficacious, and 50 mg/kg was tolerable but saturated the tissue signals beyond tumor specificity. Gel electrophoresis showed two major bands present in brain tumor and tissue protein lysates. CONCLUSIONS: Intravenous 5 mg/kg was optimal dose to target brain tumor and identified off-target organs of concern: lungs, liver, and kidneys. These results demonstrate the biodistribution and optimal dose range of NMI for treatment and diagnostic monitoring of glioma.
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Neoplasias Encefálicas/diagnóstico por imagen , Colorantes Fluorescentes/química , Glioma/diagnóstico por imagen , Inhibidores de la Monoaminooxidasa/farmacocinética , Imagen Óptica/métodos , Animales , Encéfalo , Relación Dosis-Respuesta a Droga , Rayos Infrarrojos , Riñón , Hígado , Pulmón , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibidores de la Monoaminooxidasa/administración & dosificación , Neoplasias Experimentales , Distribución TisularRESUMEN
PURPOSE: Monoamine oxidase A (MAOA) influences prostate cancer growth and metastasis in pre-clinical models. We examined effects of phenelzine (a monoamine oxidase inhibitor) in patients with biochemical recurrent castrate-sensitive prostate cancer. MATERIALS AND METHODS: An open-label single arm clinical trial enrolled subjects with biochemical recurrent prostate cancer defined by PSA ≥ 0.4 ng/ml (post prostatectomy) or PSA ≥ 2 ng/ml above nadir (post-radiation therapy); no evidence of metastasis on imaging; and normal androgen levels. Subjects received phenelzine 30 mg orally twice daily. Mood symptoms were assessed with the hospital anxiety depression score (HADS) questionnaire. The primary endpoint was the proportion of patients who achieved a PSA decline of ≥50% from baseline. RESULTS: Characteristics of the 20 eligible patients enrolled included: mean ± SD age 66.9 ± 4.8 years and PSA 4.7 ± 5.8 ng/dl. Maximal PSA declines ≥30% and ≥50% were observed in 25% (n = 5/20) and 10% (n = 2/20) of subjects, respectively. At 12 weeks, 17 subjects remained on treatment with PSA declines ≥30% and ≥50% of 24% (n = 4/17) and 6% (n = 1/17), respectively. Common toxicities observed included dizziness (grade 1 = 45%, grade 2 = 35%), hypertension (grade ≥ 2 = 30%), and edema (grade 1 = 25%, grade 2 = 10%). There was one episode of grade 4 hypertension (cycle 4) and two episodes of grade 3 syncope (cycle 12 and cycle 14) requiring treatment discontinuation. HADS questionnaires demonstrated a significant decrease in anxiety with no change in depressive symptoms on treatment. CONCLUSIONS: Phenelzine demonstrated efficacy in patients with biochemical recurrent castrate-sensitive prostate cancer. Most treatment-related toxicities were mild, but rare significant and reversible cardiovascular toxicities were observed. Therapies directed at MAOA may represent a new avenue for treatment in patients with recurrent prostate cancer.
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Adenocarcinoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Fenelzina/administración & dosificación , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/sangre , Adenocarcinoma/patología , Anciano , Biomarcadores de Tumor/sangre , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Monoaminooxidasa/administración & dosificación , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Resultado del TratamientoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Monoamine oxidase (MAO) metabolizes cytosolic dopamine (DA), thereby limiting auto-oxidation, but is also thought to generate cytosolic hydrogen peroxide (H2O2). We show that MAO metabolism of DA does not increase cytosolic H2O2 but leads to mitochondrial electron transport chain (ETC) activity. This is dependent upon MAO anchoring to the outer mitochondrial membrane and shuttling electrons through the intermembrane space to support the bioenergetic demands of phasic DA release.
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Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Transporte de Electrón/fisiología , Metabolismo Energético/fisiología , Monoaminooxidasa/metabolismo , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Oxidación-ReducciónRESUMEN
Chronic remodeling postmyocardial infarction consists in various maladaptive changes including interstitial fibrosis, cardiomyocyte death and mitochondrial dysfunction that lead to heart failure (HF). Reactive aldehydes such as 4-hydroxynonenal (4-HNE) are critical mediators of mitochondrial dysfunction but the sources of mitochondrial 4-HNE in cardiac diseases together with its mechanisms of action remain poorly understood. Here, we evaluated whether the mitochondrial enzyme monoamine oxidase-A (MAO-A), which generates H2O2 as a by-product of catecholamine metabolism, is a source of deleterious 4-HNE in HF. We found that MAO-A activation increased mitochondrial ROS and promoted local 4-HNE production inside the mitochondria through cardiolipin peroxidation in primary cardiomyocytes. Deleterious effects of MAO-A/4-HNE on cardiac dysfunction were prevented by activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2), the main enzyme for 4-HNE metabolism. Mechanistically, MAO-A-derived 4-HNE bound to newly identified targets VDAC and MCU to promote ER-mitochondria contact sites and MCU higher-order complex formation. The resulting mitochondrial Ca2+ accumulation participated in mitochondrial respiratory dysfunction and loss of membrane potential, as shown with the protective effects of the MCU inhibitor, RU360. Most interestingly, these findings were recapitulated in a chronic model of ischemic remodeling where pharmacological or genetic inhibition of MAO-A protected the mice from 4-HNE accumulation, MCU oligomer formation and Ca2+ overload, thus mitigating ventricular dysfunction. To our knowledge, these are the first evidences linking MAO-A activation to mitoCa2+ mishandling through local 4-HNE production, contributing to energetic failure and postischemic remodeling.
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Aldehídos/metabolismo , Insuficiencia Cardíaca/metabolismo , Mitocondrias Cardíacas/metabolismo , Monoaminooxidasa/metabolismo , Infarto del Miocardio/metabolismo , Miocitos Cardíacos , Animales , Calcio/metabolismo , Células Cultivadas , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Remodelación VentricularRESUMEN
The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy. Maoa hypomorphic transgenic mice were exposed to an early-life stress regimen consisting of maternal separation and daily intraperitoneal saline injections and were then compared with their wild-type and non-stressed controls for ASB-related neurobehavioral phenotypes. Maoa hypomorphic mice subjected to stress from postnatal day (PND) 1 through 7 - but not during the second postnatal week - developed overt aggression, social deficits and abnormal stress responses from the fourth week onwards. On PND 8, these mice exhibited low resting heart rate - a well-established premorbid sign of ASB - and a significant and selective up-regulation of serotonin 5-HT2A receptors in the prefrontal cortex. Notably, both aggression and neonatal bradycardia were rescued by the 5-HT2 receptor antagonist ketanserin (1-3â¯mgâ¯kg-1, IP), as well as the selective 5-HT2A receptor blocker MDL-100,907 (volinanserin, 0.1-0.3â¯mgâ¯kg-1, IP) throughout the first postnatal week. These findings provide the first evidence of a molecular basis of G×E interactions in ASB and point to early-life 5-HT2A receptor activation as a key mechanism for the ontogeny of this condition. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.
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Trastorno de Personalidad Antisocial/metabolismo , Interacción Gen-Ambiente , Privación Materna , Receptor de Serotonina 5-HT2A/metabolismo , Estrés Psicológico/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Trastorno de Personalidad Antisocial/psicología , Relación Dosis-Respuesta a Droga , Femenino , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Ratones Transgénicos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Estrés Psicológico/psicologíaRESUMEN
BACKGROUND: Monoamine oxidase A (MAOA) is best known for its role in neuro-transmitter regulation. Monoamine oxidase inhibitors are used to treat atypical depression. MAOA is highly expressed in high grade prostate cancer and modulates tumorigenesis and progression in prostate cancer. Here, we investigated the potential role of MAOA inhibitors (MAOAIs) in relation to the androgen receptor (AR) pathway and resistance to antiandrogen treatment in prostate cancer. METHODS: We examined MAOA expression and the effect of MAOI treatment in relation to AR-targeted treatments using the LNCaP, C4-2B, and 22Rv1 human prostate cancer cell lines. MAOA, AR-full length (AR-FL), AR splice variant 7 (AR-V7), and PSA expression was evaluated in the presence of MAOAIs (clorgyline, phenelzine), androgenic ligand (R1881), and antiandrogen (enzalutamide) treatments. An enzalutamide resistance cell line was generated to test the effect of MAOAI treatment in this model. RESULTS: We observed that MAOAIs, particularly clorgyline and phenelzine, were effective at decreasing MAOA activity in human prostate cancer cells. MAOAIs significantly decreased growth of LNCaP, C4-2B, and 22Rv1 cells and produced additive growth inhibitory effects when combined with enzalutamide. Clorgyline decreased expression of AR-FL and AR-V7 in 22Rv1 cells and was effective at decreasing growth of an enzalutamide-resistant C4-2B cell line with increased AR-V7 expression. CONCLUSIONS: MAOAIs decrease growth and proliferation of androgen-sensitive and castration-resistant prostate cancer cells. Clorgyline, in particular, decreases expression of AR-FL and AR-V7 expression and decreases growth of an enzalutamide-resistant cell line. These findings provide preclinical validation of MAOA inhibitors either alone or in combination with antiandrogens for therapeutic intent in patients with advanced forms of prostate cancer.
Asunto(s)
Clorgilina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Fenelzina/farmacología , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Benzamidas , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Masculino , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Clasificación del Tumor , Nitrilos , Feniltiohidantoína/farmacología , Próstata/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamine neurotransmitters and dietary amines. Two pharmacological types with different substrate and inhibitor specificities were reported. Molecular cloning revealed that the two types of MAO were different genes expressed as different proteins with different functions. MAO A and B have identical intron-exon organization derived by duplication of a common ancestral gene thus they are termed isoenzymes. MAO A knockout mice exhibited aggression, the first clear evidence linking genes to behavior. MAO A KO mice exhibited autistic-like behaviors which could be prevented by reducing serotonin levels at an early developmental age (P1-P7) providing potential therapy. MAO B KO mice were non-aggressive and resistant to Parkinsongenic neurotoxin. More recently it was found that MAO A is overexpressed in prostate cancer and correlates with degree of malignancy. The oncogenic mechanism involves a ROS-activated AKT/FOXO1/TWIST1 signaling pathway. Deletion of MAO A reduced prostate cancer stem cells and suppressed invasive adenocarcinoma. MAO A was also overexpressed in classical Hodgkin lymphoma and glioma brain tumors. MAO B was overexpressed in glioma and non-small cell lung cancer. MAO A inhibitors reduce the growth of prostate cancer, drug sensitive and resistant gliomas and classical Hodgkin lymphoma, and enhance standard chemotherapy. Currently, we are developing NIR dye-conjugated clorgyline (MAO A inhibitor) as a novel dual therapeutic/diagnostic agent for cancer. A phase II clinical trial of MAO inhibitor for biochemical recurrent prostate cancer is ongoing. The role of MAO A and B in several cancer types opens new avenues for cancer therapies.
Asunto(s)
Monoaminooxidasa/fisiología , Animales , Antineoplásicos/farmacología , Conducta/fisiología , Humanos , Isoenzimas , Inhibidores de la Monoaminooxidasa/farmacologíaRESUMEN
Prostate cancer is a prevalent public health problem, especially because noncutaneous advanced malignant forms significantly affect the lifespan and quality of life of men worldwide. New therapeutic targets and approaches are urgently needed. The current study reports elevated expression of R1 (CDCA7L/RAM2/JPO2), a c-Myc-interacting protein and transcription factor, in human prostate cancer tissue specimens. In a clinical cohort, high R1 expression is associated with disease recurrence and decreased patient survival. Overexpression and knockdown of R1 in human prostate cancer cells indicate that R1 induces cell proliferation and colony formation. Moreover, silencing R1 dramatically reduces the growth of prostate tumor xenografts in mice. Mechanistically, R1 increases c-Myc protein stability by inhibiting ubiquitination and proteolysis through transcriptional suppression of HUWE1, a c-Myc-targeting E3 ligase, via direct interaction with a binding element in the promoter. Moreover, transcriptional repression is supported by a negative coexpression correlation between R1 and HUWE1 in a prostate cancer clinical dataset. Collectively, these findings, for the first time, characterize the contribution of R1 to prostate cancer pathogenesis. IMPLICATIONS: These findings provide evidence that R1 is a novel regulator of prostate tumor growth by stabilizing c-Myc protein, meriting further investigation of its therapeutic and prognostic potential.