Does Cell-Type-Specific Silencing of Monoamine Oxidase B Interfere with the Development of Right Ventricle (RV) Hypertrophy or Right Ventricle Failure in Pulmonary Hypertension?

Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). ROS molecules are produced in different compartments within the cell, with mitochondria known to produce the strongest ROS signal. Among ROS-forming mitochondrial proteins, outer-mitochondrial-membrane-located monoamine oxidases (MAOs, type A or B) are capable of degrading neurotransmitters, thereby producing large amounts of ROS. In mice, MAO-B is the dominant isoform, which is present in almost all cell types within the heart. We analyzed the effect of an inducible cardiomyocyte-specific knockout of MAO-B (cmMAO-B KO) for the development of RVH and RVF in mice. Right ventricular hypertrophy was induced by pulmonary artery banding (PAB). RV dimensions and function were measured through echocardiography. ROS production (dihydroethidium staining), protein kinase activity (PamStation device), and systemic hemodynamics (in vivo catheterization) were assessed. A significant decrease in ROS formation was measured in cmMAO-B KO mice during PAB compared to Cre-negative littermates, which was associated with reduced activity of protein kinases involved in hypertrophic growth. In contrast to littermates in which the RV was dilated and hypertrophied following PAB, RV dimensions were unaffected in response to PAB in cmMAO-B KO mice, and no decline in RV systolic function otherwise seen in littermates during PAB was measured in cmMAO-B KO mice. In conclusion, cmMAO-B KO mice are protected against RV dilatation, hypertrophy, and dysfunction following RV pressure overload compared to littermates. These results support the hypothesis that cmMAO-B is a key player in causing RV hypertrophy and failure during PH.

Kidney-Targeted Renalase Agonist Prevents Cisplatin-Induced Chronic Kidney Disease by Inhibiting Regulated Necrosis and Inflammation.

BACKGROUND: Repeated administration of cisplatin causes CKD. In previous studies, we reported that the kidney-secreted survival protein renalase (RNLS) and an agonist peptide protected mice from cisplatin-induced AKI. METHODS: To investigate whether kidney-targeted delivery of RNLS might prevent cisplatin-induced CKD in a mouse model, we achieved specific delivery of a RNLS agonist peptide (RP81) to the renal proximal tubule by encapsulating the peptide in mesoscale nanoparticles (MNPs). We used genetic deletion of RNLS, single-cell RNA sequencing analysis, and Western blotting to determine efficacy and to explore underlying mechanisms. We also measured plasma RNLS in patients with advanced head and neck squamous cell carcinoma receiving their first dose of cisplatin chemotherapy. RESULTS: In mice with CKD induced by cisplatin, we observed an approximate 60% reduction of kidney RNLS; genetic deletion of RNLS was associated with significantly more severe cisplatin-induced CKD. In this severe model of cisplatin-induced CKD, systemic administration of MNP-encapsulated RP81 (RP81-MNP) significantly reduced CKD as assessed by plasma creatinine and histology. It also decreased inflammatory cytokines in plasma and inhibited regulated necrosis in kidney. Single-cell RNA sequencing analyses revealed that RP81-MNP preserved epithelial components of the nephron and the vasculature and suppressed inflammatory macrophages and myofibroblasts. In patients receiving their first dose of cisplatin chemotherapy, plasma RNLS levels trended lower at day 14 post-treatment. CONCLUSIONS: Kidney-targeted delivery of RNLS agonist RP81-MNP protects against cisplatin-induced CKD by decreasing cell death and improving the viability of the renal proximal tubule. These findings suggest that such an approach might mitigate the development of CKD in patients receiving cisplatin cancer chemotherapy.

Brunner syndrome associated MAOA mutations result in NMDAR hyperfunction and increased network activity in human dopaminergic neurons.

Monoamine neurotransmitter abundance affects motor control, emotion, and cognitive function and is regulated by monoamine oxidases. Among these, Monoamine oxidase A (MAOA) catalyzes the degradation of dopamine, norepinephrine, and serotonin into their inactive metabolites. Loss-of-function mutations in the X-linked MAOA gene have been associated with Brunner syndrome, which is characterized by various forms of impulsivity, maladaptive externalizing behavior, and mild intellectual disability. Impaired MAOA activity in individuals with Brunner syndrome results in bioamine aberration, but it is currently unknown how this affects neuronal function, specifically in dopaminergic (DA) neurons. Here we generated human induced pluripotent stem cell (hiPSC)-derived DA neurons from three individuals with Brunner syndrome carrying different mutations and characterized neuronal properties at the single cell and neuronal network level in vitro. DA neurons of Brunner syndrome patients showed reduced synaptic density but exhibited hyperactive network activity. Intrinsic functional properties and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission were not affected in DA neurons of individuals with Brunner syndrome. Instead, we show that the neuronal network hyperactivity is mediated by upregulation of the GRIN2A and GRIN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), resulting in increased NMDAR-mediated currents. By correcting a MAOA missense mutation with CRISPR/Cas9 genome editing we normalized GRIN2A and GRIN2B expression, NMDAR function and neuronal population activity to control levels. Our data suggest that MAOA mutations in Brunner syndrome increase the activity of dopaminergic neurons through upregulation of NMDAR function, which may contribute to the etiology of Brunner syndrome associated phenotypes.

Hepatic monoamine oxidase B is involved in endogenous geranylgeranoic acid synthesis in mammalian liver cells.

Geranylgeranoic acid (GGA) originally was identified in some animals and has been developed as an agent for preventing second primary hepatoma. We previously have also identified GGA as an acyclic diterpenoid in some medicinal herbs. Recently, we reported that in human hepatoma-derived HuH-7 cells, GGA is metabolically labeled from 13C-mevalonate. Several cell-free experiments have demonstrated that GGA is synthesized through geranylgeranial by oxygen-dependent oxidation of geranylgeraniol (GGOH), but the exact biochemical events giving rise to GGA in hepatoma cells remain unclear. Monoamine oxidase B (MOAB) has been suggested to be involved in GGOH oxidation. Here, using two human hepatoma cell lines, we investigated whether MAOB contributes to GGA biosynthesis. Using either HuH-7 cell lysates or recombinant human MAOB, we found that: 1) the MAO inhibitor tranylcypromine dose-dependently downregulates endogenous GGA levels in HuH-7 cells; and 2) siRNA-mediated MAOB silencing reduces intracellular GGA levels in HuH-7 and Hep3B cells. Unexpectedly, however, CRISPR/Cas9-generated MAOB-KO human hepatoma Hep3B cells had GGA levels similar to those in MAOB-WT cells. A sensitivity of GGA levels to siRNA-mediated MAOB downregulation was recovered when the MAOB-KO cells were transfected with a MAOB-expression plasmid, suggesting that MAOB is the enzyme primarily responsible for GGOH oxidation and that some other latent metabolic pathways may maintain endogenous GGA levels in the MAOB-KO hepatoma cells. Along with the previous findings, these results provide critical insights into the biological roles of human MAOB and provide evidence that hepatic MAOB is involved in endogenous GGA biosynthesis via GGOH oxidation.

Monoamine Oxidase Deficiency Causes Prostate Atrophy and Reduces Prostate Progenitor Cell Activity.

Monoamine oxidases (MAOs) degrade a number of biogenic and dietary amines, including monoamine neurotransmitters, and play an essential role in many biological processes. Neurotransmitters and related neural events have been shown to participate in the development, differentiation, and maintenance of diverse tissues and organs by regulating the specialized cellular function and morphological structures of innervated organs such as the prostate. Here we show that mice lacking both MAO isoforms, MAOA and MAOB, exhibit smaller prostate mass and develop epithelial atrophy in the ventral and dorsolateral prostates. The cellular composition of prostate epithelium showed reduced CK5+ or p63+ basal cells, accompanied by lower Sca-1 expression in p63+ basal cells, but intact differentiated CK8+ luminal cells in MAOA/B-deficient mouse prostates. MAOA/B ablation also decreased epithelial cell proliferation without affecting cell apoptosis in mouse prostates. Using a human prostate epithelial cell line, we found that stable knockdown of MAOA and MAOB impaired the capacity of prostate stem cells to form spheres, coinciding with a reduced CD133+ /CD44+ /CD24- stem cell population and less expression of CK5 and select stem cell markers, including ALDH1A1, TROP2, and CD166. Alternative pharmacological inhibition of MAOs also repressed prostate cell stemness. In addition, we found elevated expression of MAOA and MAOB in epithelial and/or stromal components of human prostate hyperplasia samples compared with normal prostate tissues. Taken together, our findings reveal critical roles for MAOs in the regulation of prostate basal progenitor cells and prostate maintenance. Stem Cells 2018;36:1249-1258.

New insights into Brunner syndrome and potential for targeted therapy.

We report two families with Brunner syndrome living in one state of Australia. The first family had a predicted protein-truncating variant of monoamine oxidase A (MAOA) (p.S251KfsX2). Affected males had mild intellectual disability (ID), obsessive behaviour, limited friendships and were introverted and placid during clinical interview. The family disclosed episodic explosive aggression after a diagnosis was made. The second family had a missense variant in MAOA (p.R45W). Affected males had borderline-mild ID, attention deficit disorder and limited friendships. One had a history of explosive aggression in childhood and episodic symptoms of flushing, headaches and diarrhoea. Their carrier mother had normal intelligence but similar episodic symptoms. Characteristic biochemical abnormalities included high serum serotonin and urinary metanephrines and low urinary 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA). Symptomatic individuals in the second family had particularly high serotonin levels, and treatment with a serotonin reuptake inhibitor and dietary modification resulted in reversal of biochemical abnormalities, reduction of 'serotonergic' symptoms and behavioural improvement. Brunner syndrome should be considered as a cause of mild ID with paroxysmal behavioural symptoms. It can be screened for with serum/urine metanephrine and serotonin measurement. Cautious treatment with a serotonin reuptake inhibitor, dietary modifications and avoidance of medications contraindicated in patients on monoamine oxidase inhibitors can improve symptoms.

Monoamine Oxidase A is Required for Rapid Dendritic Remodeling in Response to Stress.

BACKGROUND: Acute stress triggers transient alterations in the synaptic release and metabolism of brain monoamine neurotransmitters. These rapid changes are essential to activate neuroplastic processes aimed at the appraisal of the stressor and enactment of commensurate defensive behaviors. Threat evaluation has been recently associated with the dendritic morphology of pyramidal cells in the orbitofrontal cortex (OFC) and basolateral amygdala (BLA); thus, we examined the rapid effects of restraint stress on anxiety-like behavior and dendritic morphology in the BLA and OFC of mice. Furthermore, we tested whether these processes may be affected by deficiency of monoamine oxidase A (MAO-A), the primary enzyme catalyzing monoamine metabolism. METHODS: Following a short-term (1-4h) restraint schedule, MAO-A knockout (KO) and wild-type (WT) mice were sacrificed, and histological analyses of dendrites in pyramidal neurons of the BLA and OFC of the animals were performed. Anxiety-like behaviors were examined in a separate cohort of animals subjected to the same experimental conditions. RESULTS: In WT mice, short-term restraint stress significantly enhanced anxiety-like responses, as well as a time-dependent proliferation of apical (but not basilar) dendrites of the OFC neurons; conversely, a retraction in BLA dendrites was observed. None of these behavioral and morphological changes were observed in MAO-A KO mice. CONCLUSIONS: These findings suggest that acute stress induces anxiety-like responses by affecting rapid dendritic remodeling in the pyramidal cells of OFC and BLA; furthermore, our data show that MAO-A and monoamine metabolism are required for these phenomena.

Renalase protects against ischemic AKI.

Elevated levels of plasma catecholamines accompany ischemic AKI, possibly contributing the inflammatory response. Renalase, an amine oxidase secreted by the proximal tubule, degrades circulating catecholamines and reduces myocardial necrosis, suggesting that it may protect against renal ischemia reperfusion injury. Here, mice subjected to renal ischemia reperfusion injury had significantly lower levels of renalase in the plasma and kidney compared with sham-operated mice. Consistent with this, plasma NE levels increased significantly after renal ischemia reperfusion injury. Furthermore, renal tubular inflammation, necrosis, and apoptosis were more severe and plasma catecholamine levels were higher in renalase-deficient mice subjected to renal ischemia reperfusion compared with wild-type mice. Administration of recombinant human renalase reduced plasma catecholamine levels and ameliorated ischemic AKI in wild-type mice. Taken together, these data suggest that renalase protects against ischemic AKI by reducing renal tubular necrosis, apoptosis, and inflammation, and that plasma renalase might be a biomarker for AKI. Recombinant renalase therapy may have potential for the prevention and treatment of AKI.

Tyrosinase deficiency impairs social novelty preference in mice.

OBJECTIVE: Tyrosinase is a rate-limiting enzyme for the biosynthesis of melanin pigment in peripheral tissues, such as skin and the retina. We recently reported the expression and enzymatic activity of tyrosinase as well as its protective effects against oxidative stress-induced protein damage in the mouse brain. The functional role of tyrosinase in the central nervous system, however, remains largely unknown. In the present study, we investigated the involvement of tyrosinase in social behavior in mice. METHODS: Pigmented C57BL/10JMsHir (B10) and tyrosinase-deficient albino B10.C- Tyr c /Hir (B10-c) mice were subjected to the three-chamber sociability test to assess sociability and social novelty preference. In addition, we measured the mRNA expression of genes involved in catecholamine metabolism in the hippocampus by real-time quantitative PCR analysis. RESULTS: The results obtained showed that tyrosinase deficiency impaired social novelty preference, but not sociability in mice. We also found that the hippocampal expression of genes involved in catecholamine metabolism, such as monoamine oxidase A and catechol-O-methyltransferase , were significantly decreased in tyrosinase-deficient B10-c mice. CONCLUSION: These results suggest that tyrosinase activity is functionally involved in the phenotypic expression of social behavior, particularly social novelty preference, in mice. The present study will advance our understanding of the functional role of tyrosinase in the central nervous system.

Monoamine oxidase A and A/B knockout mice display autistic-like features.

Converging lines of evidence show that a sizable subset of autism-spectrum disorders (ASDs) is characterized by increased blood levels of serotonin (5-hydroxytryptamine, 5-HT), yet the mechanistic link between these two phenomena remains unclear. The enzymatic degradation of brain 5-HT is mainly mediated by monoamine oxidase (MAO)A and, in the absence of this enzyme, by its cognate isoenzyme MAOB. MAOA and A/B knockout (KO) mice display high 5-HT levels, particularly during early developmental stages. Here we show that both mutant lines exhibit numerous behavioural hallmarks of ASDs, such as social and communication impairments, perseverative and stereotypical responses, behavioural inflexibility, as well as subtle tactile and motor deficits. Furthermore, both MAOA and A/B KO mice displayed neuropathological alterations reminiscent of typical ASD features, including reduced thickness of the corpus callosum, increased dendritic arborization of pyramidal neurons in the prefrontal cortex and disrupted microarchitecture of the cerebellum. The severity of repetitive responses and neuropathological aberrances was generally greater in MAOA/B KO animals. These findings suggest that the neurochemical imbalances induced by MAOA deficiency (either by itself or in conjunction with lack of MAOB) may result in an array of abnormalities similar to those observed in ASDs. Thus, MAOA and A/B KO mice may afford valuable models to help elucidate the neurobiological bases of these disorders and related neurodevelopmental problems.

Increased stress response and beta-phenylethylamine in MAOB-deficient mice.

MAOA and MAOB are key iso-enzymes that degrade biogenic and dietary amines. MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, or 5-HT) and norepinephrine (NE), whereas MAOB preferentially oxidizes beta-phenylethylamine (PEA). Both forms can oxidize dopamine (DA). A mutation in MAOA results in a clinical phenotype characterized by borderline mental retardation and impaired impulse control. X-chromosomal deletions which include MAOB were found in patients suffering from atypical Norrie's disease, which is characterized by blindness and impaired hearing. Reduced MAOB activity has been found in type-II alcoholism and in cigarette smokers. Because most alcoholics smoke, the effects of alcohol on MAOB activity remain to be determined. Here we show that targetted inactivation of MAOB in mice increases levels of PEA but not those of 5-HT, NE and DA, demonstrating a primary role for MAOB in the metabolism of PEA. PEA has been implicated in modulating mood and affect. Indeed, MAOB-deficient mice showed an increased reactivity to stress. In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson's disease.

Polymorphism of the renalase gene in end-stage renal disease patients affected by hypertension.

BACKGROUND: Renalase is a novel flavin adenine dinucleotide-dependent amine oxidase that is secreted by the kidney. It circulates in the blood and modulates the cardiac function and systemic blood pressure. Insufficiency of renalase in patients with chronic kidney disease may explain the frequent occurrence of hypertension among patients with end-stage renal disease (ESRD) and an increased risk of cardiovascular events in this group. The aim of the study was to assess the relationship of two renalase gene polymorphisms with hypertension in dialysed patients. METHODS: Rs2576178 polymorphism was genotyped in 369 patients, rs10887800 polymorphism was genotyped in 421 dialysed patients, using polymerase chain reaction (PCR) and subsequent cleavage with Msp I and Pst I restriction endonucleases. RESULTS: Genotype distribution and allele frequencies of rs2576178 polymorphism were compared in the following subgroups of patients: dialysed patients with hypertension: ESRD HY + (n = 200) and dialysed patients without hypertension: ESRD HY - (n = 169). There was a significant difference in the frequency of the G allele carriers. G allele carriers were associated with a 1.55 times higher risk of hypertension [odds ratio (OR) = 1.55; 95% confidence interval (CI): 1.023-2.357, P = 0.039]. Distribution of genotypes and frequencies of alleles of rs10887800 polymorphism were compared in the following subgroups of patients: ESRD HY + (n = 278) and ESRD HY - (n = 143). The G allele carriers were recognized with a significantly higher frequency in ESRD HY + patients (0.46 in ESRD HY + versus 0.37 in ESRD HY - ) [OR = 1.76; 95% CI: (1.159-2.667, P = 0.008)]. CONCLUSIONS: Our results are the first to suggest an association between renalase gene polymorphisms analysed and hypertension in dialysed patients. It may be an important step towards gaining a deeper insight into cardiovascular pathophysiology. Furthermore, it might provide an optimal treatment and better prognosis for patients with chronic kidney disease.

Monoamine oxidases regulate telencephalic neural progenitors in late embryonic and early postnatal development.

Monoamine neurotransmitters play major roles in regulating a range of brain functions in adults and increasing evidence suggests roles for monoamines in brain development. Here we show that mice lacking the monoamine metabolic enzymes MAO A and MAO B (MAO AB-deficient mice) exhibit diminished proliferation of neural stem cells (NSC) in the developing telencephalon beginning in late gestation [embryonic day (E) 17.5], a deficit that persists in neonatal and adult mice. These mice showed significantly increased monoamine levels and anxiety-like behaviors as adults. Assessments of markers of intermediate progenitor cells (IPC) and mitosis showed that NSC in the subventricular zone (SVZ), but not in the ventricular zone, are reduced in MAO AB-deficient mice. A developmental time course of monoamines in frontal cortical tissues revealed increased serotonin levels as early as E14.5, and a further large increase was found between E17.5 and postnatal day 2. Administration of an inhibitor of serotonin synthesis (parachlorophenylalanine) between E14.5 and E19.5 restored the IPC numbers and SVZ thickness, suggesting the role of serotonin in the suppression of IPC proliferation. Studies of neurosphere cultures prepared from the telencephalon at different embryonic and postnatal ages showed that serotonin stimulates proliferation in wild-type, but not in MAO AB-deficient, NSC. Together, these results suggest that a MAO-dependent long-lasting alteration in the proliferation capacity of NSC occurs late in embryonic development and is mediated by serotonin. Our findings reveal novel roles for MAOs and serotonin in the regulation of IPC proliferation in the developing brain.

Renalase deficiency aggravates ischemic myocardial damage.

Chronic kidney disease (CKD) leads to an 18-fold increase in cardiovascular complications not fully explained by traditional risk factors. Levels of renalase, a recently discovered oxidase that metabolizes catecholamines, are decreased in CKD. Here we show that renalase deficiency in a mouse knockout model causes increased plasma catecholamine levels and hypertension. Plasma blood urea nitrogen, creatinine, and aldosterone were unaffected. However, knockout mice had normal systolic function and mild ventricular hypertrophy but tolerated cardiac ischemia poorly and developed myocardial necrosis threefold more severe than that found in wild-type mice. Treatment with recombinant renalase completely rescued the cardiac phenotype. To gain insight into the mechanisms mediating this cardioprotective effect, we tested if gene deletion affected nitrate and glutathione metabolism, but found no differences between hearts of knockout and wild-type mice. The ratio of oxidized (NAD) to reduced (NADH) nicotinamide adenine dinucleotide in cardiac tissue, however, was significantly decreased in the hearts of renalase knockout mice, as was plasma NADH oxidase activity. In vitro studies confirmed that renalase metabolizes NADH and catecholamines. Thus, renalase plays an important role in cardiovascular pathology and its replacement may reduce cardiac complications in renalase-deficient states such as CKD.

Maladaptive defensive behaviours in monoamine oxidase A-deficient mice.

Rich evidence indicates that monoamine oxidase (MAO) A, the major enzyme catalysing the degradation of monoamine neurotransmitters, plays a key role in emotional regulation. Although MAOA deficiency is associated with reactive aggression in humans and mice, the involvement of this enzyme in defensive behaviour remains controversial and poorly understood. To address this issue, we tested MAOA knockout (KO) mice in a spectrum of paradigms and settings associated with variable degrees of threat. The presentation of novel inanimate objects induced a significant reduction in exploratory approaches and increase in defensive behaviours, such as tail-rattling, biting and digging. These neophobic responses were context-dependent and particularly marked in the home cage. In the elevated plus- and T-mazes, MAOA KO mice and wild-type (WT) littermates displayed equivalent locomotor activity and time in closed and open arms; however, MAOA KO mice featured significant reductions in risk assessment, as well as unconditioned avoidance and escape. No differences between genotypes were observed in the defensive withdrawal and emergence test. Conversely, MAOA KO mice exhibited a dramatic reduction of defensive and fear-related behaviours in the presence of predator-related cues, such as predator urine or an anaesthetized rat, in comparison with those observed in their WT littermates. The behavioural abnormalities in MAOA KO mice were not paralleled by overt alterations in sensory and microvibrissal functions. Collectively, these results suggest that MAOA deficiency leads to a general inability to appropriately assess contextual risk and attune defensive and emotional responses to environmental cues.

Effects of renalase deficiency on liver fibrosis markers in a nonalcoholic steatohepatitis mouse model.

Progression of nonalcoholic steatohepatitis (NASH) is attributed to several factors, including inflammation and oxidative stress. In recent years, renalase has been reported to suppress oxidative stress, apoptosis and inflammation. A number of studies have suggested that renalase may be associated with protecting the liver from injury. The present study aimed to clarify the effects of renalase knockout (KO) in mice with NASH that were induced with a choline­deficient high­fat diet (CDAHFD) supplemented with 0.1% methionine. Wild type (WT) and KO mice (6­week­old) were fed a normal diet (ND) or CDAHFD for 6 weeks, followed by analysis of the blood liver function markers and liver tissues. CDAHFD intake was revealed to increase blood hepatic function markers, lipid accumulation and oxidative stress compared with ND, but no significant differences were observed between the WT and KO mice. However, in the KO­CDAHFD group, the Adgre1 and Tgfb1 mRNA levels were significantly higher, and α­SMA expression was significantly lower compared with the WT­CDAHFD group. Furthermore, the Gclc mRNA and phosphorylated protein kinase B (Akt) levels were significantly lower in the KO­ND group compared with the WT­ND group. The results of the current study indicated that as NASH progressed in the absence of renalase, oxidative stress, macrophage infiltration and TGF­ß expression were enhanced, while α­SMA expression in NASH may be partly suppressed due to the decreased phosphorylation of Akt level.

Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy.

Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.

Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 deficiency reduces leukocyte infiltration into adipose tissue and favors fat deposition.

Obesity is associated with low-grade inflammation and leukocyte infiltration in white adipose tissue (WAT) and is linked to diabetic complications. Semicarbazide-sensitive amine oxidase, also known as vascular adhesion protein-1 (SSAO/VAP-1), is a membrane protein that is highly expressed in adipocytes and is also present on the endothelial cell surface where it is involved in leukocyte extravasation. We studied fat deposition and leukocyte infiltration in WAT of mice with a null mutation in the amine oxidase copper-containing-3 (AOC3) gene encoding SSAO/VAP-1. Both epididymal and inguinal WATs were larger in 6-month-old AOC3-KO males than in age-matched wild-type controls. However, WAT from AOC3-KO mice contained lower CD45 mRNA levels and fewer CD45(+) leukocytes. Subpopulation analyses revealed a diminished infiltration of WAT by T cells, macrophages, natural killer, and natural killer T cells. A decrease in leukocyte content in WAT was also detected in female AOC3-KO mice as early as 2 months of age, whereas increased fat mass was evident by 6 months of age. Reduced CD45(+) populations in WAT of AOC3-KO mice was not rescued by human SSAO/VAP-1 expression on adipocytes under the control of aP2, suggesting the importance of vascular AOC3 in leukocyte entrance into fat. Our results indicate that SSAO/VAP-1 is instrumental for the presence of leukocytes in WAT. Therefore, AOC3-KO mice present a unique model of mild obesity, characterized by increased WAT devoid of low-grade inflammation.

Sympathetic activation in chronic renal failure.

The potential involvement of sympathetic overactivity has been neglected in this population despite accumulating experimental and clinical evidence suggesting a crucial role of sympathetic activation for both progression of renal failure and the high rate of cardiovascular events in patients with chronic kidney disease. The contribution of sympathetic neural mechanisms to the occurrence of cardiac arrhythmias, the development of hypertension, and the progression of heart failure are well established; however, the exact mechanisms contributing to heightened sympathetic tone in patients with chronic kidney disease are unclear. This review analyses potential mechanisms underlying sympathetic activation in chronic kidney disease, the range of adverse consequences associated with this activation, and potential therapeutic implications resulting from this relationship.

The role of monoamine oxidase A in the neurobiology of aggressive, antisocial, and violent behavior: A tale of mice and men.

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.