Piperine mitigates behavioral impairments and provides neuroprotection against 3-nitropropinoic acid-induced Huntington disease-like symptoms.

Background: Piperine (PIP) is a powerful anti-oxidant and anti-inflammatory alkaloid which has been widely used in the treatment of various pathological conditions. However, few studies have clearly discussed the protective effects and potential mechanism of PIP in different neurological diseases. The aim of this study was to investigate the neuroprotective effect of PIP against 3-nitropropioninc acid (3-NP) induced neurobehavioral, biochemical and histopathological alterations in animals.Methods: Adult male Wistar rats were randomly divided into three groups. Group 1, the vehicle administered control group, received normal saline (p.o.). Group 2 received 3-NP (20 mg/kg.b.wt., i.p.) for 4 consecutive days. Group 3 received PIP (10 mg/kg.b.wt., p.o.) twice daily for a period of 4 days, 30 min before and 6 h after the 3-NP injection. Upon termination of treatment schedule, behavioral experiments were performed to access the behavioral outcomes. The brain striatal tissue was used for the estimation of monoamine oxidase activity and serotonin level. In addition, astrocytes activation was observed by GFAP immunostaining.Results: Our results showed that 3-NP induced behavioral impairments are attenuated by PIP co-treatment. Next, the extent of neuronal loss and astrocytes activation was reduced in the striatal brain region in PIP treated rats. Finally, it was observed that PIP alleviated the behavioral, biochemical, immunohistochemical and histological alterations.Conclusion: The results of the current study reveal the neuroprotective competency of PIP against Huntington disease like symptoms in rats.

In vitro and in vivo evaluation of fluorinated indanone derivatives as potential positron emission tomography agents for the imaging of monoamine oxidase B in the brain.

Monoamine oxidases (MAOs) play a key role in the metabolism of major monoamine neurotransmitters. In particular, the upregulation of MAO-B in Parkinson's disease, Alzheimer's disease and cancer augmented the development of selective MAO-B inhibitors for diagnostic and therapeutic purposes, such as the anti-parkinsonian MAO-B irreversible binder l-deprenyl (Selegiline®). Herein we report on the synthesis of novel fluorinated indanone derivatives for PET imaging of MAO-B in the brain. Out of our series, the derivatives 6, 8, 9 and 13 are amongst the most affine and selective ligands for MAO-B reported so far. For the derivative 6-((3-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (6) exhibiting an outstanding affinity (KiMAO-B = 6 nM), an automated copper-mediated radiofluorination starting from the pinacol boronic ester 17 is described. An in vitro screening in different species revealed a MAO-B region-specific accumulation of [18F]6 in rats and piglets in comparison to L-[3H]deprenyl. The pre-clinical in vivo assessment of [18F]6 in mice demonstrated the potential of indanones to readily cross the blood-brain barrier. Nonetheless, parallel in vivo metabolism studies indicated the presence of blood-brain barrier metabolites, thus arguing for further structural modifications. With the matching analytical profiles of the radiometabolite analysis from the in vitro liver microsome studies and the in vivo evaluation, the structure's elucidation of the blood-brain barrier penetrant radiometabolites is possible and will serve as basis for the development of new indanone derivatives suitable for the PET imaging of MAO-B.

Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis.

Monoamine oxidase (MAO) is believed to mediate the degradation of monoamine neurotransmitters, including dopamine, in the brain. Between the two types of MAO, MAO-B has been believed to be involved in dopamine degradation, which supports the idea that the therapeutic efficacy of MAO-B inhibitors in Parkinson's disease can be attributed to an increase in extracellular dopamine concentration. However, this belief has been controversial. Here, by utilizing in vivo phasic and basal electrochemical monitoring of extracellular dopamine with fast-scan cyclic voltammetry and multiple-cyclic square wave voltammetry and ex vivo fluorescence imaging of dopamine with GRABDA2m, we demonstrate that MAO-A, but not MAO-B, mainly contributes to striatal dopamine degradation. In contrast, our whole-cell patch-clamp results demonstrated that MAO-B, but not MAO-A, was responsible for astrocytic GABA-mediated tonic inhibitory currents in the rat striatum. We conclude that, in contrast to the traditional belief, MAO-A and MAO-B have profoundly different roles: MAO-A regulates dopamine levels, whereas MAO-B controls tonic GABA levels.

Norepinephrine Enhances Aerobic Glycolysis and May Act as a Predictive Factor for Immunotherapy in Gastric Cancer.

METHODS: Monoamine neurotransmitters were detected in gastric cancer tissue and paired normal tissue, and The Cancer Genome Atlas was used to identify differentially expressed norepinephrine-degrading and synthetic enzymes. Quantitative real-time PCR and the Seahorse assay were used to determine the effect of norepinephrine on gastric cancer cell glycolysis. MAOA expression in cancer tissues was analyzed by immunohistochemistry and was compared with the patient SUVmax value of PET-CT and other clinicopathological characteristics. RESULTS: The norepinephrine levels were markedly high in gastric cancer tissue, while the norepinephrine-degrading enzymes MAOA and MAOB showed low expression. High norepinephrine levels were associated with activated glycolysis. The MAOA or MAOB expression levels in tumor tissue were closely correlated with the patient SUV max values of PET-CT and immunotherapy evaluation indices, such as PD-L1 and the microsatellite status. CONCLUSIONS: Norepinephrine shows relatively higher expression in gastric cancer tissue than in normal tissue, and its expression level is associated with the glycolysis levels in patients. The norepinephrine-degrading enzymes MAOA and MAOB have significant expression differences in cancer and normal tissue, and their missing or low expression may predict immune therapy outcomes for gastric cancer patients. High norepinephrine levels with metabolic abnormalities may be more suitable for metabolic targeted therapy or immunotherapy.

[6]-Gingerol Ameliorates Cisplatin-Induced Pica by Regulating the TPH/MAO-A/SERT/5-HT/5-HT3 Receptor System in Rats.

PURPOSE: [6]-gingerol is a bioactive compound extracted from ginger, a traditional anti-emetic herb in Chinese medicine. Previous studies have demonstrated that [6]-gingerol can ameliorate chemotherapy-induced pica in rats, although the underlying mechanism has not been elucidated. This study is designed to investigate [6]-gingerol's antiemetic mechanism focusing on the 5-hydroxytryptamine (serotonin, 5-HT) system by evaluating the synthesis, metabolism and reuptake of 5-HT, as well as the mechanism of 5-hydroxytryptamine type 3 receptor (5-HT3 receptor), in a cisplatin-induced pica model of rats. METHODS: Rats were randomly divided into control group (vehicle + saline, Con), [6]-gingerol control group (50 mg/kg [6]-gingerol + saline, G-con), ondansetron control group (2.6 mg/kg ondansetron + saline, O-con), cisplatin model group (vehicle + cisplatin, Model), ondansetron-treated group (2.6 mg/kg ondansetron + cisplatin, O-treated), high dosage of [6]-gingerol-treated group (100 mg/kg [6]-gingerol + cisplatin, GH-treated), and low dosage of [6]-gingerol-treated group (50 mg/kg [6]-gingerol + cisplatin, GL-treated). The rats were administered with [6]-gingerol, ondansetron, and vehicle (3% Tween-80) by gavage twice (7:00 AM and 7:00 PM). One hour after the first treatment (8:00 AM), rats in groups Model, O-treated, GH-treated and GL-treated were injected intraperitoneally (i.p.) with 6 mg/kg cisplatin, and the other groups were injected i.p. with saline of equal volume. The consumption of kaolin of the rats were measured. All the rats were anesthetized by i.p. injection of pentobarbital sodium at 24 h post-cisplatin. After blood samples were taken, medulla oblongata and ileum were removed. The levels of 5-HT and its metabolite 5-HIAA in ileum, medulla oblongata and serum were determined using high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The mRNA expression levels of 5-HT3 receptor, tryptophan hydroxylase (TPH), monoamine oxidase A (MAO-A) and serotonin reuptake transporter (SERT) were detected by real-time PCR. The protein expression levels and distribution of 5-HT3 receptor, TPH and MAO-A in the medulla oblongata and ileum were measured by Western blotting and immunohistochemistry, respectively. RESULTS: [6]-gingerol treatment significantly reduced the kaolin ingestion and the increase in 5-HT concentration in rats induced by cisplatin. TPH, MAO-A, SERT, and 5-HT3 receptor are important in 5-HT metabolism, and cisplatin-induced alterations in the associated protein/mRNA levels were restored when treated with [6]-gingerol. CONCLUSION: This suggests that the antiemetic effect of [6]-gingerol against cisplatin-induced emesis may be due to 5-HT attenuation via modulating the TPH/MAO-A/SERT/5-HT/5-HT3 receptor system.

The clinical value and potential molecular mechanism of the downregulation of MAOA in hepatocellular carcinoma tissues.

BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide and tends to be detected at an advanced stage. More effective biomarkers for HCC screening and prognosis assessment are needed and the mechanisms of HCC require further exploration. The role of MAOA in HCC has not been intensively investigated. METHODS: In-house tissue microarrays, genechips, and RNAsequencing datasets were integrated to explore the expression status and the clinical value of MAOA in HCC. Immunohistochemical staining was utilized to determine MAOA protein expression. Intersection genes of MAOA related co-expressed genes and differentially expressed genes were obtained to perform functional enrichment analyses. In vivo experiment was conducted to study the impact of traditional Chinese medicine nitidine chloride (NC) on MAOA in HCC. RESULTS: MAOA was downregulated and possessed an excellent discriminatory capability in HCC patients. Decreased MAOA correlated with poor prognosis in HCC patients. Downregulated MAOA protein was relevant to an advanced TNM stage in HCC patients. Co-expressed genes that positively related to MAOA were clustered in chemical carcinogenesis, where CYP2E1 was identified as the hub gene. In vivo experiment showed that nitidine chloride significantly upregulated MAOA in a nude mouse HCC model. CONCLUSIONS: A decreased MAOA level is not only correlated with aggressive behaviors in males but also serves as a promising biomarker for the diagnosis and prognosis of HCC patients. Moreover, MAOA may play a role in AFB1 toxic transformation through its synergistic action with co-expressed genes, especially CYP3A4. MAOA also serves as a potential therapy target of NC in HCC patients.

Piperazine multi-substituted triarylphosphine oxide compound as an instant "light-up" fluorescent probe for monoamine oxidase.

Monoamine oxidase (MAOs) is involved in several psychiatric and neurological disorders. The specific detection of MAOs is of great significance to elucidate their functions in various biological processes. Currently, however, fast detection of MAOs remains a great challenge. It is, therefore, important to develop novel fluorescent probes for the monitoring of intracellular MAO activity. In this study, we synthesized OTPP-3-Piperazine and OTNP-3-Piperazine by functionalizing triarylphosphine with piperazine groups for MAO detection, using the rational design ofmolecular structures. OTNP-3-Piperazine demonstrated higher sensitivity to MAOs than OTPP-3-Piperazine because MAOs induced an AIE process via oxidation to produce water-insoluble oxidation products in OTNP-3-Piperazine. Such a recognition mechanism instantly responded to MAOs. OTNP-3-Piperazine was also introduced into different cells to explore its application as a biological probe. These results showed that it differentiated MAO-overexpressing cells from other cells, which demonstrated its promise as a biological fluorescent probe.

Monoamine oxidase-A activity is required for clonal tumorsphere formation by human breast tumor cells.

BACKGROUND: Breast tumor growth and recurrence are driven by an infrequent population of breast tumor-initiating cells (BTIC). We and others have reported that the frequency of BTIC is orders of magnitude higher when breast tumor cells are propagated in vitro as clonal spheres, termed tumorspheres, by comparison to adherent cells. We exploited the latter to screen > 35,000 small molecules to identify agents capable of targeting BTIC. We unexpectedly discovered that selective antagonists of serotonin signaling were among the hit compounds. To better understand the relationship between serotonin and BTIC we expanded our analysis to include monoamine oxidase-A (MAO-A), an enzyme that metabolizes serotonin. METHODS: We used the Nanostring technology and Western blotting to determine whether MAO-A is expressed in human breast tumor cell lines cultured as tumorspheres by comparison to those grown as adherent cells. We then determined whether MAO-A activity is required for tumorsphere formation, a surrogate in vitro assay for BTIC, by assessing whether selective MAO-A inhibitors affect the frequency of tumorsphere-forming cells. To learn whether MAO-A expression in breast tumor cells is associated with other reported properties of BTIC such as anticancer drug resistance or breast tumor recurrence, we performed differential gene expression analyses using publicly available transcriptomic datasets. RESULTS: Tumorspheres derived from human breast tumor cell lines representative of every breast cancer clinical subtype displayed increased expression of MAO-A transcripts and protein by comparison to adherent cells. Surprisingly, inhibition of MAO-A activity with selective inhibitors reduced the frequency of tumorsphere-forming cells. We also found that increased MAO-A expression is a common feature of human breast tumor cell lines that have acquired anticancer drug resistance and is associated with poor recurrence-free survival (RFS) in patients that experienced high-grade, ER-negative (ER-) breast tumors. CONCLUSIONS: Our data suggests that MAO-A activity is required for tumorsphere formation and that its expression in breast tumor cells is associated with BTIC-related properties. The discovery that a selective MAO-A inhibitor targets tumorsphere-forming cells with potencies in the nanomolar range provides the first evidence of this agent's anticancer property. These data warrant further investigation of the link between MAO-A and BTIC.

Monoamine oxidase-A targeting probe for prostate cancer imaging and inhibition of metastasis.

Mitochondrial enzyme monoamine oxidase (MAO-A) is known to be overexpressed in prostate cancer (PCa) cells. Herein, we have developed a two-photon probe (PCP-1) for selectively targeting and imaging the MAO-A in PCa. Supported by enzymatic docking and in vitro experiments, PCP-1 showed efficiency to visualize MAO-A overexpressing cells and inhibit their growth and metastasis potential.

Identification of genes related to mental disorders by text mining.

Mental disorders are important diseases with a high prevalence rate in the general population. Common mental disorders are complex diseases with high heritability, and their pathogenesis is the result of interactions between genetic and environmental factors. However, the relationship between mental disorders and genes is complex and difficult to evaluate. Additionally, some mental disorders involve numerous genes, and a single gene can also be associated with different types of mental disorders.This study used text mining (including word frequency analysis, cluster analysis, and association analysis) of the PubMed database to identify genes related to mental disorders.Word frequency analysis revealed 52 high-frequency genes important in studies of mental disorders. Cluster analysis showed that 5-HTT, SLC6A4, and MAOA are common genetic factors in most mental disorders; the intra-group genes in each cluster were highly correlated. Some mental disorders may have common genetic factors; for example, there may be common genetic factors between 'Affective Disorders' and 'Schizophrenia.' Association analysis revealed 35 frequent itemsets and 25 association rules, indicating close associations among genes. The results of association rules showed that CCK, MAOA, and 5-HTT are the most closely related.We used text mining technology to analyze genes related to mental disorders to further summarize and clarify the relationships between mental disorders and genes as well as identify potential relationships, providing a foundation for future experiments. The results of the associative analysis also provide a reference for multi-gene studies of mental disorders.

An Endeavor in the Reaction-Based Approach to Fluorescent Probes for Biorelevant Analytes: Challenges and Achievements.

The promising features of fluorescence spectroscopy have inspired a quest for fluorescent probes for analysis and monitoring of molecular interactions in biochemical, medical, and environmental sciences. To overcome the competitive supramolecular interactions in aqueous media encountered with conventional molecular-recognition-based probes, the use of reaction-based probes that involve making or breaking of covalent bonds has emerged as a complementary sensing strategy to realize higher selectivity and sensitivity with larger spectroscopic changes. In spite of the enormous efforts, the development of reaction-based fluorescent probes meets with certain challenges in terms of their practical applications, demanding "intelligent design" of probes with an appropriate fluorophore attached to an efficient reactive moiety at the right place. This Account summarizes the results of our efforts made in the development and fine-tuning of reaction-based fluorescent probes toward those goals, classified by the type of analyte (anions, metal cations, and biomolecules) with notes on the challenges and achievements. The reaction-based approach was demonstrated to be powerful for the selective sensing of anions (cyanide and (amino)carboxylates) for the first time, and later it was extended to develop two-photon probes for bisulfite and fluoride ions. The reaction-based approach also enabled selective sensing of noble metal ions such as silver, gold, and palladium along with toxic (methyl)mercury species and paramagnetic copper ions. Furthermore, microscopic imaging and monitoring of biologically relevant species with reaction-based two-photon probes were explored for hydrogen sulfide, hypochlorous acid, formaldehyde, monoamine oxidase enzyme, and ATP.

Cerebral MAO Activity Is Not Altered by a Novel Herbal Antidepressant Treatment.

Inhibition of monoamine oxidase (MAO)-A/B can ameliorate depressive- and anxiety-related symptoms via increase of monoamine extracellular levels. However, such inhibition can also instigate hypertensive response following exposure to dietary tyramine (i.e., "the cheese effect"). Novel herbal treatment (NHT) is an herbal formula that has been demonstrated to reduce depressive- and anxiety-like symptoms in pre-clinical studies. The aim of the current study was to examine whether the therapeutic potential of NHT is underlain by inhibition of MAO-A/B and whether NHT poses a risk for tyramine hyper-potentiation. Unpredictable chronic mild stress (UCMS)-exposed mice and naïve mice were treated for 3 weeks with NHT (30 mg/kg; i.p.), the selective serotonin reuptake inhibitor (SSRI) escitalopram (15 mg/kg; i.p.), or saline. Subsequently, MAO-A/B activities in the hypothalamus, striatum, and prefrontal cortex (PFC) were assessed. Exposure to UCMS led to significant increases in both MAO-A and MAO-B activities in the hypothalamus (p < 0.001) and in the PFC (p < 0.01 for MAO-A; p < 0.001 for MAO-B). Neither NHT nor escitalopram had any notable effects. Treatment with NHT was supported as safe in terms of risk for inducing a hypertensive response. The antidepressant- and anxiolytic-like effects of NHT are mediated via pathways other than MAO-A/B inhibition.

Brain region specific methylation and Sirt1 binding changes in MAOA promoter is associated with sexual dimorphism in early life stress induced aggressive behavior.

The maladaptive form of aggressive behavior confers risk for violence and criminal incidences with profound impact on society. Although considerable research has been devoted to elucidate the etiology of aggression, molecular correlates of sex differences remains largely unexplored. Also, little attention has been given to whether males and females respond differently to similar causal factor of aggression. Here, we show the possible association of brain region specific neural activity (c-Fos expression) and monoamine oxidase A (MAOA) epigenetic state with sexual dimorphism in peripubertal stress (PPS) induced adulthood aggression. While PPS adult males exhibited escalated aggression, females spent maximal time in social exploration. c-Fos expression was brain region and sex specific. In the PPS adult cohort, only males showed elevated c-Fos expression in the prefrontal cortex, indicative of their hyper-responsive behavior. MAOA expression and enzyme activity was reduced in hypothalamus and increased in prefrontal cortex of hyper-aggressive male mice. Investigation into the underlying mechanisms revealed hypomethylation in prefrontal cortex and hypermethylation in hypothalamus of MAOA promoter negatively correlating with the expression pattern. On the other hand, binding of Sirt1 to MAOA promoter was diametrically opposite being increased in prefrontal cortex and reduced in hypothalamus. In females, neither expression nor epigenetic state of MAOA gene was significantly altered between control and PPS adult mice. Our study revealed novel epigenetic correlates of sexual dimorphism in stress induced aggressive psychopathology. However, given the multi-factorial nature with environmental influences, further studies are warranted to uncover the biological hub.

Recent advances in reaction-based fluorescent probes for detecting monoamine oxidases in living systems.

Monoamine oxidase (MAO) is a membrane-bound mitochondrial enzyme that plays an important role by catalyzing oxidative deamination to maintain the homeostasis of neurotransmitters and other biogenic amines in living systems. MAO activity is critical for the brain and central nervous system. Its dysfunction is closely related with many neurological and psychiatric disorders. Fluorescent probes provide a useful approach to accurately detect MAO activity and assist to better elucidate their biological functions. Herein, in this Minireview, we summarize the recent advances in reaction based MAO type fluorescent probes and their imaging applications in living systems.

Inhibitor structure-guided design and synthesis of near-infrared fluorescent probes for monoamine oxidase A (MAO-A) and its application in living cells and in vivo.

A series of near-infrared fluorescent probes based on inhibitor (clorgyline) structure-guided design were synthesized for the specific detection of MAO-A in cells and in vivo. Moreover, we have successfully used the high specificity of one of the probes to visualize MAO-A activity in zebrafish and tumor tissue for the first time.

Classics in Neuroimaging: Development of PET Tracers for Imaging Monoamine Oxidases.

In this Viewpoint, we highlight the history of positron emission tomography (PET) radiotracer development to quantify changes in monoamine oxidase (MAO)-A and -B enzyme expression or activity. MAO-A and MAO-B are critical for understanding monoaminergic pathways in psychiatric addiction disorders, and more recently in neurodegenerative disorders with MAO-B expression in astrogliosis. Unique radiochemical innovations have been shown for neuroimaging of MAOs including the clinical translation of irreversible propargylamine-based suicide inhibitors, application of deuterium-substitution to slow down metabolism, development of trapped metabolite imaging agents, and unique 11C-carbonylation chemistry toward novel high-affinity reversibly binding inhibitors.

Sex-Related Effects of Prenatal Stress on Region-Specific Expression of Monoamine Oxidase A and β Adrenergic Receptors in Rat Hearts / Efeitos Sexo-Específicos de Estresse Pré-Natal na Expressão Região-Específica de Monoamina Oxidase A e Receptores Adrenérgicos Β no Coração de Ratos

Abstract Background: Prenatal stress may increase risk of developing cardiovascular disorders in adulthood. The cardiotoxic effects of catecholamines are mediated via prolonged adrenergic receptor stimulation and increased oxidative stress upon their degradation by monoamine oxidase A (MAO-A). Objectives: We investigated long-term effects of prenatal stress on β (1, 2, 3) adrenergic receptors and MAO-A gene expression in the hearts of adult rat offspring. Methods: Pregnant rats were exposed to unpredictable mild stress during the third week of gestation. RNA was isolated from left ventricular apex and base of adult offspring. Quantitative PCR was used to measure gene expression in collected ventricular tissue samples. The level of significance was set to p < 0.05. Results: β3 adrenergic receptor mRNA was undetectable in rat left ventricle. β1 adrenergic receptor was the predominantly expressed subtype at the apical and basal left ventricular myocardium in the control females. Male offspring from unstressed mothers displayed higher apical cardiac β1 than β2 adrenergic receptor mRNA levels. However, β1 and β2 adrenergic receptor mRNAs were similarly expressed at the ventricular basal myocardium in males. Unlike males, prenatally stressed females exhibited decreased β1 adrenergic receptor mRNA expression at the apical myocardium. Prenatal stress did not affect cardiac MAO-A gene expression. Conclusions: Collectively, our results show that prenatal stress may have exerted region- and sex-specific β1 and β2 adrenergic receptor expression patterns within the left ventricle.

Resumo Fundamento: Estresse pré-natal pode aumentar os riscos de desenvolver doenças cardiovasculares na idade adulta. Os efeitos cardiotóxicos de catecolaminas são mediados pela estimulação prolongada dos receptores adrenérgicos e pelo aumento do estresse oxidativo após sua degradação pela monoamina oxidase A (MAO-A). Objetivos: Investigamos os efeitos a longo prazo de estresse pré-natal nos receptores β (1, 2, 3) adrenérgicos e na expressão do gene MAO-A nos corações da prole adulta de ratos. Método: Ratas prenhes foram expostas a estresse crônico moderado imprevisível durante a terceira semana de gestação. O RNA foi isolado do ápice e da base do ventrículo esquerdo da prole adulta. Utilizou-se PCR quantitativa em tempo real para medir a expressão gênica nas amostras de tecido ventricular coletadas. O nível de significância foi estabelecido em p < 0,05. Resultados: Foi indetectável o mRNA do receptor adrenérgico β3 no ventrículo esquerdo dos ratos. O receptor adrenérgico β1 foi o subtipo mais expresso no miocárdio ventricular esquerdo apical e basal nas fêmeas controle. A prole masculina das mães não estressadas apresentou níveis cardíacos apicais de mRNA do receptor adrenérgico β1 mais altos do que os de β2. Porém, mRNAs dos receptores adrenérgicos β1 e β2 foram expressos de forma semelhante no miocárdio basal ventricular na prole masculina em geral. Ao contrário da prole masculina, a prole feminina exposta ao estresse pré-natal exibiu uma expressão diminuída do mRNA do receptor adrenérgico β1 no miocárdio apical. O estresse pré-natal não afetou a expressão gênica de MAO-A cardíaca. Conclusões: Coletivamente, nossos resultados mostram que estresse pré-natal pode ter exercido padrões de expressão região- e sexo-específica dos receptores adrenérgicos β1 e β2 no ventrículo esquerdo.

Sex-Related Effects of Prenatal Stress on Region-Specific Expression of Monoamine Oxidase A and ß Adrenergic Receptors in Rat Hearts.

BACKGROUND: Prenatal stress may increase risk of developing cardiovascular disorders in adulthood. The cardiotoxic effects of catecholamines are mediated via prolonged adrenergic receptor stimulation and increased oxidative stress upon their degradation by monoamine oxidase A (MAO-A). OBJECTIVES: We investigated long-term effects of prenatal stress on ß (1, 2, 3) adrenergic receptors and MAO-A gene expression in the hearts of adult rat offspring. METHODS: Pregnant rats were exposed to unpredictable mild stress during the third week of gestation. RNA was isolated from left ventricular apex and base of adult offspring. Quantitative PCR was used to measure gene expression in collected ventricular tissue samples. The level of significance was set to p < 0.05. RESULTS: ß3 adrenergic receptor mRNA was undetectable in rat left ventricle. ß1 adrenergic receptor was the predominantly expressed subtype at the apical and basal left ventricular myocardium in the control females. Male offspring from unstressed mothers displayed higher apical cardiac ß1 than ß2 adrenergic receptor mRNA levels. However, ß1 and ß2 adrenergic receptor mRNAs were similarly expressed at the ventricular basal myocardium in males. Unlike males, prenatally stressed females exhibited decreased ß1 adrenergic receptor mRNA expression at the apical myocardium. Prenatal stress did not affect cardiac MAO-A gene expression. CONCLUSIONS: Collectively, our results show that prenatal stress may have exerted region- and sex-specific ß1 and ß2 adrenergic receptor expression patterns within the left ventricle.

Distribution of oxidized DJ-1 in Parkinson's disease-related sites in the brain and in the peripheral tissues: effects of aging and a neurotoxin.

DJ-1 plays an important role in antioxidant defenses, and a reactive cysteine at position 106 (Cys106) of DJ-1, a critical residue of its biological function, is oxidized under oxidative stress. DJ-1 oxidation has been reported in patients with Parkinson's disease (PD), but the relationship between DJ-1 oxidation and PD is still unclear. In the present study using specific antibody for Cys106-oxidized DJ-1 (oxDJ-1), we analyzed oxDJ-1 levels in the brain and peripheral tissues in young and aged mice and in a mouse model of PD induced using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). OxDJ-1 levels in the brain, heart, and skeletal muscle were high compared with other tissues. In the brain, oxDJ-1 was detected in PD-related brain sites such as the substantia nigra (SN) of the midbrain, olfactory bulb (OB), and striatum. In aged wild-type mice, oxDJ-1 levels in the OB, striatum, and heart tended to decrease, while those in the skeletal muscle increased significantly. Expression of dopamine-metabolizing enzymes significantly increased in the SN and OB of aged DJ-1-/- mice, accompanied by a complementary increase in glutathione peroxidase 1. MPTP treatment concordantly changed oxDJ-1 levels in PD-related brain sites and heart. These results indicate that the effects of physiological metabolism, aging, and neurotoxin change oxDJ-1 levels in PD-related brain sites, heart, and skeletal muscle where mitochondrial load is high, suggesting a substantial role of DJ-1 in antioxidant defenses and/or dopamine metabolism in these tissues.

Ratiometric Near-Infrared Fluorescent Probe for Synergistic Detection of Monoamine Oxidase B and Its Contribution to Oxidative Stress in Cell and Mice Aging Models.

As new biomarkers, monoamine oxidases (MAOs) play important roles in maintaining the homeostasis of biogenic amines via catalyzing the oxidation of biogenic amines to corresponding aldehydes with the generation of reactive oxygen species (ROS). MAOs have two isoforms, MAO-A and MAO-B. MAO-A is considered to be a major factor of neuropsychiatric and depressive disorders. However, MAO-B is thought to be involved in several neurodegenerative diseases. Therefore, to explore their distinct roles in different diseases, the selective detection of MAOs is essential. Herein, two new types of near-infrared (NIR) fluorescent probes, MitoCy-NH2 and MitoHCy-NH2, are provided for synergistic imaging of MAO-B and its contribution to oxidative stress in cells and in mice aging models. These probes are composed of three moieties: heptamethine cyanine as fluorophore, propanamide as recognition group, and triphenylphosphonium cation as mitochondrial targeting group. The amine oxidation and ß-elimination reaction can lead to obvious fluorescence increase and color changes from green to blue. The probe MitoHCy-NH2 can be used to synergistically detect MAO-B and its contribution to oxidative stress in the replicative senescence model. And the probe MitoCy-NH2 can offer ratiometric near-infrared fluorescence for the selective detection of MAO-B in the H2O2-induced cell aging model and in mice aging models. The results reveal that there are different MAO-B levels in different ages of mice models. MitoCy-NH2 also can evaluate therapeutic effects of pargyline and selegiline in mice models. The desirable analytical behaviors of our probes make them useful chemical tools for the selective detection of MAO-B and its contribution to oxidative stress in biosystems.