RESUMO
Cell-to-cell transmission of α-synuclein (α-syn) pathology is considered to underlie the spread of neurodegeneration in Parkinson's disease (PD). Previous studies have demonstrated that α-syn is secreted under physiological conditions in neuronal cell lines and primary neurons. However, the molecular mechanisms that regulate extracellular α-syn secretion remain unclear. In this study, we found that inhibition of monoamine oxidase-B (MAO-B) enzymatic activity facilitated α-syn secretion in human neuroblastoma SH-SY5Y cells. Both inhibition of MAO-B by selegiline or rasagiline and siRNA-mediated knock-down of MAO-B facilitated α-syn secretion. However, TVP-1022, the S-isomer of rasagiline that is 1000 times less active, failed to facilitate α-syn secretion. Additionally, the MAO-B inhibition-induced increase in α-syn secretion was unaffected by brefeldin A, which inhibits endoplasmic reticulum (ER)/Golgi transport, but was blocked by probenecid and glyburide, which inhibit ATP-binding cassette (ABC) transporter function. MAO-B inhibition preferentially facilitated the secretion of detergent-insoluble α-syn protein and decreased its intracellular accumulation under chloroquine-induced lysosomal dysfunction. Moreover, in a rat model (male Sprague Dawley rats) generated by injecting recombinant adeno-associated virus (rAAV)-A53T α-syn, subcutaneous administration of selegiline delayed the striatal formation of Ser129-phosphorylated α-syn aggregates, and mitigated loss of nigrostriatal dopaminergic neurons. Selegiline also delayed α-syn aggregation and dopaminergic neuronal loss in a cell-to-cell transmission rat model (male Sprague Dawley rats) generated by injecting rAAV-wild-type α-syn and externally inoculating α-syn fibrils into the striatum. These findings suggest that MAO-B inhibition modulates the intracellular clearance of detergent-insoluble α-syn via the ABC transporter-mediated non-classical secretion pathway, and temporarily suppresses the formation and transmission of α-syn aggregates.SIGNIFICANCE STATEMENT The identification of a neuroprotective agent that slows or stops the progression of motor impairments is required to treat Parkinson's disease (PD). The process of α-synuclein (α-syn) aggregation is thought to underlie neurodegeneration in PD. Here, we demonstrated that pharmacological inhibition or knock-down of monoamine oxidase-B (MAO-B) in SH-SY5Y cells facilitated α-syn secretion via a non-classical pathway involving an ATP-binding cassette (ABC) transporter. MAO-B inhibition preferentially facilitated secretion of detergent-insoluble α-syn protein and reduced its intracellular accumulation under chloroquine-induced lysosomal dysfunction. Additionally, MAO-B inhibition by selegiline protected A53T α-syn-induced nigrostriatal dopaminergic neuronal loss and suppressed the formation and cell-to-cell transmission of α-syn aggregates in rat models. We therefore propose a new function of MAO-B inhibition that modulates α-syn secretion and aggregation.
Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Indanos/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/fisiologia , Transtornos Parkinsonianos/tratamento farmacológico , Agregação Patológica de Proteínas/tratamento farmacológico , Selegilina/uso terapêutico , alfa-Sinucleína/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Morte Celular , Linhagem Celular Tumoral , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Meios de Cultivo Condicionados , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Técnicas de Silenciamento de Genes , Vetores Genéticos/administração & dosagem , Humanos , Injeções , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Monoaminoxidase/genética , Mutação de Sentido Incorreto , Neuroblastoma , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Transporte Proteico/efeitos dos fármacos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/toxicidade , Substância Negra/metabolismo , Substância Negra/patologia , alfa-Sinucleína/genéticaRESUMO
Accumulation of senescent cells in tissues during normal or accelerated aging has been shown to be detrimental and to favor the outcomes of age-related diseases such as heart failure (HF). We have previously shown that oxidative stress dependent on monoamine oxidase A (MAOA) activity in cardiomyocytes promotes mitochondrial damage, the formation of telomere-associated foci, senescence markers, and triggers systolic cardiac dysfunction in a model of transgenic mice overexpressing MAOA in cardiomyocytes (Tg MAOA). However, the impact of cardiomyocyte oxidative stress on the cardiac microenvironment in vivo is still unclear. Our results showed that systolic cardiac dysfunction in Tg MAOA mice was strongly correlated with oxidative stress induced premature senescence of cardiac stromal cells favoring the recruitment of CCR2+ monocytes and the installation of cardiac inflammation. Understanding the interplay between oxidative stress induced premature senescence and accelerated cardiac dysfunction will help to define new molecular pathways at the crossroad between cardiac dysfunction and accelerated aging, which could contribute to the increased susceptibility of the elderly to HF.
Assuntos
Envelhecimento/patologia , Efeito Espectador , Senescência Celular , Monoaminoxidase/fisiologia , Miócitos Cardíacos/patologia , Estresse Oxidativo , Células Estromais/patologia , Envelhecimento/metabolismo , Animais , Células Cultivadas , Dano ao DNA , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Células Estromais/metabolismoRESUMO
Cardiovascular disease (CVD) is prevalent worldwide and remains a leading cause of death. Although substantial progress has been made in the diagnosis and treatment of CVD, the prognosis remains unsatisfactory. Renalase is a newly discovered cytokine that is synthesized by the kidney and then secreted into blood. Numerous studies have suggested the efficacy of renalase in treating CVD by metabolizing catecholamines in the circulatory system. As a new biomarker of heart disease, renalase is normally recognized as a signalling molecule that activates cytoprotective intracellular signals to lower blood pressure, protect ischaemic heart muscle and promote atherosclerotic plaque stability in CVD, which subsequently improves cardiac function. Due to its important regulatory role in the circulatory system, renalase has gradually become a potential target in the treatment of CVD. This review summarizes the structure, mechanism and function of renalase in CVD, thereby providing preclinical evidence for alternative approaches and new prospects in the development of renalase-related drugs against CVD.
Assuntos
Doenças Cardiovasculares/etiologia , Monoaminoxidase/fisiologia , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doença da Artéria Coronariana/etiologia , Insuficiência Cardíaca/etiologia , Humanos , Hipertensão/etiologia , Monoaminoxidase/química , Monoaminoxidase/uso terapêuticoRESUMO
Over the past two decades, research has revealed that genetic factors shape the propensity for aggressive, antisocial, and violent behavior. The best-documented gene implicated in aggression is MAOA (Monoamine oxidase A), which encodes the key enzyme for the degradation of serotonin and catecholamines. Congenital MAOA deficiency, as well as low-activity MAOA variants, has been associated with a higher risk for antisocial behavior (ASB) and violence, particularly in males with a history of child maltreatment. Indeed, the interplay between low MAOA genetic variants and early-life adversity is the best-documented gene × environment (G × E) interaction in the pathophysiology of aggression and ASB. Additional evidence indicates that low MAOA activity in the brain is strongly associated with a higher propensity for aggression; furthermore, MAOA inhibition may be one of the primary mechanisms whereby prenatal smoke exposure increases the risk of ASB. Complementary to these lines of evidence, mouse models of Maoa deficiency and G × E interactions exhibit striking similarities with clinical phenotypes, proving to be valuable tools to investigate the neurobiological mechanisms underlying antisocial and aggressive behavior. Here, we provide a comprehensive overview of the current state of the knowledge on the involvement of MAOA in aggression, as defined by preclinical and clinical evidence. In particular, we show how the convergence of human and animal research is proving helpful to our understanding of how MAOA influences antisocial and violent behavior and how it may assist in the development of preventative and therapeutic strategies for aggressive manifestations.
Assuntos
Agressão/fisiologia , Transtorno da Personalidade Antissocial , Comportamento Animal/fisiologia , Interação Gene-Ambiente , Monoaminoxidase/fisiologia , Comportamento Social , Violência , Animais , Transtorno da Personalidade Antissocial/etiologia , Transtorno da Personalidade Antissocial/genética , Transtorno da Personalidade Antissocial/metabolismo , Transtorno da Personalidade Antissocial/fisiopatologia , Humanos , Monoaminoxidase/deficiênciaRESUMO
Isatin is an endogenous indole that inhibits monoamine oxidase (MAO). When exogenously administered, it increases the striatal dopamine and acetylcholine levels and presents neuroprotective effects in the brain. Previous studies show that intrastriatal administration of isatin increased the in vivo dopamine release from striatum in a concentration-dependent form. In the present work, we investigated the effects of combined administration of isatin together with other substances actually used in antiparkinsonian pharmacotherapy on in vivo dopamine overflow. For this, we co-administered isatin with the MAO inhibitors selegiline and clorgyline, l-DOPA, the catechol-o-methyl-transferase (COMT) inhibitors tropolone and dinitrocatechol, with the dopaminergic agonist ropinirole, and with the psychostimulant caffeine, in order to evaluate possible synergies between these substances to increase the dopamine extracellular levels in freely moving rats. Intrastriatal administration of isatin (10 mM, 60 min) significantly increased dopamine release to 1164 ± 152%, compared to the baseline. Co-administration of isatin together with selegiline (1 mM) or clorgyline (1 mM) alone or in combinations showed a similar profile to increase in vivo dopamine release. Intrastriatal infusion of isatin together with antiparkinsonian drugs l-DOPA (25 µM), tropolone (1 mM), dinitrocatechol (100 µM), amantadine (5 mM) and caffeine (5 mM) significantly elevated extracellular dopamine levels more than any single drug, showing a good neurochemical synergy by improving the effect of isatin on the extracellular dopamine levels in the striatum. Infusion of isatin + ropinirole (5 mM) did not change the isatin-induced increase in dopamine overflow. These results could be useful to carry out further investigations with a possible clinical application.
Assuntos
Antiparkinsonianos/farmacologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Isatina/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Catecol O-Metiltransferase/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Sinergismo Farmacológico , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Feminino , Ácido Homovanílico/metabolismo , Masculino , Microinjeções , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND AND AIMS: Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (CNS) as well as enterochromaffin cells of the gastrointestinal tract. Tryptophan hydroxylase (TPH1) and monoamine oxidase (MAO-A) are the key enzymes for the synthesis and catabolism of 5HT, respectively. Previous studies demonstrated that 5-hydroxytryptamine receptor (5HTR)1A/1B receptor agonists inhibit biliary hyperplasia in bile-duct ligated (BDL) rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis (LF) in mice. Our aim was to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. APPROACH AND RESULTS: While in vivo studies were performed in BDL rats and the multidrug resistance gene 2 knockout (Mdr2-/- ) mouse model of PSC, in vitro studies were performed in cell lines of cholangiocytes and hepatic stellate cells (HSCs). 5HTR2A/2B/2C and MAO-A/TPH1 are expressed in cholangiocytes and HSCs from BDL rats and Mdr2-/- - mice. Ductular reaction, LF, as well as the mRNA expression of proinflammatory genes increased in normal, BDL rats, and Mdr2-/- - mice following treatment 5HTR2A/2B/2C agonists, but decreased when BDL rats and Mdr2-/- mice were treated with 5HTR2A/2B/2C antagonists compared to BDL rats and Mdr2-/- mice, respectively. 5HT levels increase in Mdr2-/- mice and in PSC human patients compared to their controls and decrease in serum of Mdr2-/- mice treated with 5HTR2A/2B/2C antagonists compared to untreated Mdr2-/- mice. In vitro, cell lines of murine cholangiocytes and human HSCs express 5HTR2A/2B/2C and MAO-A/TPH1; treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls. CONCLUSIONS: Modulation of the TPH1/MAO-A/5HT/5HTR2A/2B/2C axis may represent a therapeutic approach for management of cholangiopathies, including PSC.
Assuntos
Ductos Biliares/patologia , Colestase/patologia , Cirrose Hepática/etiologia , Monoaminoxidase/fisiologia , Receptores de Serotonina/fisiologia , Serotonina/fisiologia , Triptofano Hidroxilase/fisiologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/fisiologia , Animais , Proliferação de Células , Colangite Esclerosante/etiologia , Humanos , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/fisiologia , Receptor 5-HT2B de Serotonina/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Serotonina/sangue , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATPRESUMO
Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age-related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21CIP and p16INK4a, and results in a non-canonical senescence-associated secretory phenotype, which is pro-fibrotic and pro-hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age-related myocardial dysfunction and in the wider setting to ageing in post-mitotic tissues.
Assuntos
Cardiomegalia/patologia , Senescência Celular , Dano ao DNA , Fibrose/patologia , Mitose , Miócitos Cardíacos/patologia , Encurtamento do Telômero , Envelhecimento , Animais , Cardiomegalia/etiologia , Feminino , Fibrose/etiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Monoaminoxidase/fisiologia , Miócitos Cardíacos/metabolismo , Fenótipo , RNA/fisiologia , Ratos Sprague-Dawley , Telomerase/fisiologiaRESUMO
Testosterone and the monoamine oxidase-A (MAOA) polymorphism are potential neuromodulators for aggression. By acting on similar brain circuits, they might interactively influence human behavior. The current study investigates the causal role of testosterone on aggression-related brain activity and the potential interaction with the MAOA polymorphism. In a double-blind process, 93 healthy males received a testosterone or placebo gel. In an fMRI session, participants performed a Taylor aggression paradigm in which they received provoking feedback and could afterwards decide how aggressively they would react. Testosterone and cortisol levels as well as subjective anger were assessed prior and after the task. Circulating testosterone levels were higher in carriers of the long compared to the short MAOA allele. An interaction of the MAOA polymorphism and testosterone administration was identified in the cuneus, where short allele carriers in the placebo group showed diminished activity in the decision period. Task-related anger was significantly higher in this group. Overall, a mesocorticolimbic network was implicated in processing of high versus low provoking feedback, and core hubs of the default mode network were implicated in the subsequent decision after high versus low provocation. Testosterone administration increased activation in this network. The data provides evidence for an interaction of the MAOA polymorphism and exogenous testosterone on anger and suggests that interactive effects on the brain signal could underlie differential emotional reactivity. The increased default mode activation in the testosterone group suggests an enhanced engagement of social cognition related regions possibly supporting responsivity towards social provocation. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.
Assuntos
Agressão/fisiologia , Ira/fisiologia , Encéfalo/fisiologia , Monoaminoxidase/fisiologia , Testosterona/fisiologia , Adolescente , Adulto , Método Duplo-Cego , Humanos , Hidrocortisona/sangue , Masculino , Monoaminoxidase/genética , Polimorfismo Genético , Testosterona/administração & dosagem , Adulto JovemRESUMO
Monoamine oxidases (MAOs) are the enzymes that catalyze the oxidation of monoamines, such as dopamine, norepinephrine, and serotonin, which serve as key neurotransmitters in the central nervous system (CNS). MAOs play important roles in maintaining the homeostasis of monoamines, and the aberrant expression or activation of MAOs underlies the pathogenesis of monoamine neurotransmitter disorders, including neuropsychiatric and neurodegenerative diseases. Clearly, detecting and inhibiting the activities of MAOs is of great value for the diagnosis and therapeutics of these diseases. Accordingly, many specific detection probes and inhibitors have been developed and substantially contributed to basic and clinical studies of these diseases. In this review, progress in the detecting and inhibiting of MAOs and their applications in mechanism exploration and treatment of neurotransmitter-related disorders is summarized. Notably, how the detection probes and inhibitors of MAOs were developed has been specifically addressed. It is hoped that this review will benefit the design of more effective and sensitive probes and inhibitors for MAOs, and eventually the treatment of monoamine neurotransmitter disorders.
Assuntos
Doenças do Sistema Nervoso Central , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase , Animais , Monoaminas Biogênicas/metabolismo , Células Cultivadas , Doenças do Sistema Nervoso Central/tratamento farmacológico , Humanos , Monoaminoxidase/química , Monoaminoxidase/fisiologiaRESUMO
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.
Assuntos
Monoaminoxidase/fisiologia , Animais , Antineoplásicos/farmacologia , Comportamento/fisiologia , Humanos , Isoenzimas , Inibidores da Monoaminoxidase/farmacologiaRESUMO
BACKGROUND Studies on monoamine oxidase B (MAO-B) expression in renal cell carcinoma (RCC) are lacking. This study focused on the immunohistochemical evaluation of MAO-B in RCC. MATERIAL AND METHODS Sixty-three RCC samples were compared on basic clinical and histopathological parameters, including histopathological type and tumor grade. RCC samples were divided according to the histopathological type into 2 groups: conventional type (51 samples) and other types (12 samples). For MAO-B detection, a standard immunohistochemical procedure was employed. RESULTS In healthy kidney samples, MAO-B was detected predominantly in tubules. Fifty-two cancer tissue samples were MAO-B negative and 11 tissue samples were MAO-B low positive. Enzymes were detected only in the cytoplasm. We did not find any significant correlation between the percentage of positive MAO-B specimens and nuclear grade. Additionally, Fisher's test did not reveal any difference in numbers of positive and negative MAO-B samples between the 2 RCC types (P>0.05). CONCLUSIONS From our results, it was clear that MAO-B expression played no significant role in stimulation of renal cancer development. We found that MAO-B occurred only in 19% of kidney tumors and that the positivity of protein expression was low. Moreover, it seems that the disappearance of this enzyme in RCC is a consequence of replacement of healthy tissue by cancer cells. On the other hand, one can assume that the loss of MAO-B expression could be associated with severe pathological processes in the kidney.
Assuntos
Carcinoma de Células Renais/patologia , Monoaminoxidase/metabolismo , Monoaminoxidase/fisiologia , Adulto , Idoso , Carcinoma de Células Renais/metabolismo , Feminino , Humanos , Imuno-Histoquímica/métodos , Rim/patologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
It has been demonstrated, in a long line of research, that the low-activity genotype of the monoamine oxidase A (MAOA) gene is associated with aggression. Previous work has linked impaired response inhibition to aggression, but little is known about how this relates to the purported MAOA-aggression relationship in adolescents. Here, we examined how MAOA genotype influences neural correlates of inhibitory control in 74 healthy male adolescents using a GoStop and a Go/Nogo task while differentiating between action cancelation and action restraint. Carriers of the low-expressing MAOA alleles (MAOA-L) did not show altered brain activation in the prefrontal-subcortical inhibition network relative to carriers of the high-expressing alleles across inhibition conditions. However, they exhibited a more pronounced deactivation during response inhibition in the posterior cingulate cortex (PCC) and precuneus, areas belonging to the default mode network (DMN). Larger DMN suppression in MAOA-L carriers might represent a compensation mechanism for impaired cognitive control.
Assuntos
Agressão/fisiologia , Genótipo , Inibição Psicológica , Monoaminoxidase/fisiologia , Análise e Desempenho de Tarefas , Adolescente , Alelos , Giro do Cíngulo/fisiologia , Humanos , Masculino , Córtex Pré-Frontal/fisiologiaRESUMO
Monoamine oxidase A (MAO-A) is a mitochondrial flavoenzyme implicated in the pathogenesis of atherosclerosis and inflammation and also in many neurological disorders. MAO-A also has been reported as a potential therapeutic target in prostate cancer. However, the regulatory mechanisms controlling cytokine-induced MAO-A expression in immune or cancer cells remain to be identified. Here, we show that MAO-A expression is co-induced with 15-lipoxygenase (15-LO) in interleukin 13 (IL-13)-activated primary human monocytes and A549 non-small cell lung carcinoma cells. We present evidence that MAO-A gene expression and activity are regulated by signal transducer and activator of transcription 1, 3, and 6 (STAT1, STAT3, and STAT6), early growth response 1 (EGR1), and cAMP-responsive element-binding protein (CREB), the same transcription factors that control IL-13-dependent 15-LO expression. We further established that in both primary monocytes and in A549 cells, IL-13-stimulated MAO-A expression, activity, and function are directly governed by 15-LO. In contrast, IL-13-driven expression and activity of MAO-A was 15-LO-independent in U937 promonocytic cells. Furthermore, we demonstrate that the 15-LO-dependent transcriptional regulation of MAO-A in response to IL-13 stimulation in monocytes and in A549 cells is mediated by peroxisome proliferator-activated receptor γ (PPARγ) and that signal transducer and activator of transcription 6 (STAT6) plays a crucial role in facilitating the transcriptional activity of PPARγ. We further report that the IL-13-STAT6-15-LO-PPARγ axis is critical for MAO-A expression, activity, and function, including migration and reactive oxygen species generation. Altogether, these results have major implications for the resolution of inflammation and indicate that MAO-A may promote metastatic potential in lung cancer cells.
Assuntos
Interleucina-13/fisiologia , Monoaminoxidase/metabolismo , Monócitos/metabolismo , Células A549 , Araquidonato 15-Lipoxigenase/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Inflamação , Neoplasias Pulmonares/patologia , Monoaminoxidase/fisiologia , Metástase Neoplásica , PPAR gama/metabolismo , Fator de Transcrição STAT6/metabolismo , Células U937RESUMO
ãIntrinsic serotonin (5-hydroxytryptamine; 5-HT) synthesized within the mammary epithelium has an important physiological role in milk volume homeostasis in many species including mice, cows, and humans. During lactation, mammary epithelial cells activate 5-HT synthesis by tryptophan hydroxylase 1 (TPH1). TPH1 catalyzes the rate-limiting step in 5-HT biosynthesis within mammary glands. 5-HT synthesized in mammary glands is released into both the apical (milk) and basolateral spaces by a vesicular monoamine transporter. 5-HT released into milk is incorporated by the apical membrane-expressed serotonin reuptake transporter and degraded by the monoamine oxidase A enzyme. Suckling maintains 5-HT at low levels in milk. When the mammary gland becomes filled with milk, 5-HT provides a negative feedback signal that suppresses further milk synthesis in the mammary epithelium. Our research, using human mammary epithelial MCF-12A cells, shows that the expression of ß-casein, a differentiation marker, is suppressed via 5-HT-mediated inhibition of signal transducer and activator of transcription 5. Additionally, our results show that reduced ß-casein expression in MCF-12A cells is associated with 5-HT7 receptor expression. Furthermore, we show that 5-HT7 receptor-mediated suppression of ß-casein expression is involved in the activation of protein kinase A and protein-tyrosine phosphatase 1B. Thus, this mechanism might be associated with the feedback signals by 5-HT within the mammary epithelium. Hence, further research that builds on our findings should include the elucidation of the physiological roles of 5-HT present in milk synthesized by mammary epithelial cells in vivo and its effects on nursing infants.
Assuntos
Lactação/efeitos dos fármacos , Serotonina/fisiologia , Animais , Caseínas/metabolismo , Feminino , Homeostase , Humanos , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Humanas/metabolismo , Monoaminoxidase/fisiologia , Receptores de Serotonina/fisiologia , Serotonina/biossíntese , Triptofano Hidroxilase/fisiologiaRESUMO
Psychopathy is characterized by callous affect, interpersonal manipulation, a deviant lifestyle, and antisocial behavior. Previous research has linked psychopathic traits to childhood trauma, but also to the upstream variable number tandem repeat (uVNTR) polymorphism of the monoamine oxidase A (MAOA) gene. An interaction between childhood trauma and MAOA genotype has been associated with antisocial behavior, but so far little is known about interaction effects of childhood trauma and the MAOA uVNTR on psychopathy. In order to bridge this gap, we used data of 1531 male and 1265 female twins and their siblings from a Finnish community sample to estimate structural equation models. The psychopathy and childhood trauma constructs were conceptualized as bifactor models with one general and two orthogonal group factors. Data comprised self-reports on childhood trauma and psychopathic traits as well as MAOA uVNTR genotype. In both genders, childhood trauma was associated with the general factor that represents the overarching psychopathy construct, and with the group factor that captures social deviance, but not with the group factor capturing psychopathic core personality traits. Women with a low activity variant of the MAOA uVNTR reported slightly higher levels of psychopathy than those with a high activity allele, but only with respect to the general psychopathy factor. There was no evidence for an interaction effect between MAOA uVNTR genotype and childhood trauma on psychopathy in either gender. Our results suggest that psychopathy in general and social deviance in particular are associated with childhood trauma in men and women, and that psychopathic traits are subject to variation in the MAOA uVNTR genotype in women.
Assuntos
Transtorno da Personalidade Antissocial/genética , Adolescente , Adulto , Experiências Adversas da Infância , Alelos , Transtorno da Personalidade Antissocial/psicologia , Feminino , Finlândia , Frequência do Gene/genética , Genótipo , Humanos , Acontecimentos que Mudam a Vida , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites/genética , Monoaminoxidase/genética , Monoaminoxidase/fisiologia , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Autorrelato , Comportamento Social , Transtornos do Comportamento Social/genética , GêmeosRESUMO
It would not be practical to attempt to deal with all the advances that have informed our understanding of the behavior and functions of this enzyme over the past 90 years. This account concentrates key advances that explain why the monoamine oxidases remain of pharmacological and biochemical interest and on some areas of continuing uncertainty. Some issues that remain to be understood or are in need of further clarification are highlighted.
Assuntos
Monoaminoxidase/história , Monoaminoxidase/fisiologia , Animais , História do Século XX , História do Século XXI , Humanos , Neurologia/históriaRESUMO
Spermatozoa and neurones share similar membrane characteristics and features. Associations of multiple polymorphisms traditionally related to neurotransmission were investigated. Infertile men were grouped into controls with normospermia (n = 182) and idiopathic infertile men with asthenozoospermia (n = 103), and analysed as a case-control study and as a quantitative association of each genotype. Ten neurotransmission-associated genetic variants were mapped by SNP analysis using quantitative polymerase chain reaction with TaqMan probes. Men with HTR2A rs6313 had a higher risk of asthenozoospermia (OR = 2.14; P = 0.04). MAOA rs3788862 G carriers displayed an increased risk of asthenozoospermia (OR = 2.29; P = 0.02). The SLC18A1 rs1390938 G allele was more frequent among such cases (0.75 versus 0.87; P < 0.01 and P < 0.01 for Armitage trend test); for SLC18A1 rs2270641 P = 0.02 (case-control frequency) and P = 0.01 (Armitage trend test). MAOA rs3788862 was correlated with sperm motility (Spearman ρ = 0.14; P = 0.02); SLC18A1 rs1390938 was correlated with sperm count and motility (Spearman ρ = 0.20; P < 0.01). Gene polymorphisms of HTR2A, MAOA and SLC18A1, related to neurotransmission, are individually associated with asthenozoospermia through variation in sperm count and motility, without detectable allelic or genotype interaction.
Assuntos
Astenozoospermia/genética , Monoaminoxidase/genética , Receptor 5-HT2A de Serotonina/genética , Contagem de Espermatozoides , Motilidade dos Espermatozoides/genética , Proteínas Vesiculares de Transporte de Monoamina/genética , Estudos de Casos e Controles , Genótipo , Humanos , Masculino , Monoaminoxidase/fisiologia , Polimorfismo Genético , Receptor 5-HT2A de Serotonina/fisiologia , Proteínas Vesiculares de Transporte de Monoamina/fisiologiaRESUMO
Background: Aggression is a behaviour with evolutionary origins, but in today's society it is often both destructive and maladaptive. Increase of aggressive behaviour has been observed in a number of serious mental illnesses, and it represents a clinical challenge for mental healthcare provider. These phenomena can lead to harmful behaviours, including violence, thus representing a serious public health concern. Aggression is often a reason for psychiatric hospitalization, and it often leads to prolonged hospital stays, suffering by patients and their victims, and increased stigmatization. Moreover, it has an effect on healthcare use and costs in terms of longer length of stay, more readmissions and higher drug use. Materials and methods: In this review, based on a selective search of 2010-2016 pertinent literature on PubMed, we analyze and summarize information from original articles, reviews, and book chapters about aggression and psychiatric disorders, discussing neurobiological basis and therapy of aggressive behaviour. Results: A great challenge has been revealed regarding the neurobiology of aggression, and an integration of this body of knowledge will ultimately improve clinical diagnostics and therapeutic interventions. The great heterogeneity of aggressive behaviour still hampers our understanding of its causal mechanisms. Still, over the past years, the identification of specific subtypes of aggression has released possibilities for new and individualized treatment approaches. Conclusions: Neuroimaging studies may help to further elucidate the interrelationship between neurocognitive functioning, personality traits, and antisocial and violent behaviour. Recent studies point toward manipulable neurobehavioral targets and suggest that cognitive, pharmacological, neuromodulatory, and neurofeedback treatment approaches can be developed to ameliorate urgency and aggression in schizophrenia. These combined approaches could improve treatment efficacy. As current pharmacological and therapeutic interventions are effective but imperfect, new insights into the neurobiology of aggression will reveal novel avenues for treatment of this destructive and costly behaviour.
Assuntos
Agressão/fisiologia , Transtornos Mentais/fisiopatologia , Fatores Etários , Agressão/classificação , Agressão/efeitos dos fármacos , Agressão/psicologia , Transtornos Induzidos por Álcool/fisiopatologia , Aminas Biogênicas/fisiologia , Catecol O-Metiltransferase/fisiologia , Predisposição Genética para Doença , Humanos , Transtornos Mentais/genética , Transtornos Mentais/psicologia , Monoaminoxidase/fisiologia , Neuroimagem , Neurotransmissores/fisiologia , Agitação Psicomotora/tratamento farmacológico , Agitação Psicomotora/fisiopatologia , Psicotrópicos/uso terapêutico , Fatores de Risco , Transtornos do Sono-Vigília/fisiopatologia , Transtornos do Sono-Vigília/psicologiaRESUMO
Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6. MAOA inhibitor treatment effectively reduces metastasis and prolongs mouse survival by disengaging the Shh-IL6-RANKL signaling network in stromal cells in the tumor microenvironment. These findings provide a rationale for targeting MAOA and its associated molecules to treat PCa metastasis.