Relationship between the monoamine oxidase gene overactivity and the other pathophysiological and behavioral parameters implicated in memory deficiency in albino Winstar rats as Alzheimer’s disease model

The current study aimed to assess the pathophysiology mechanisms that mediate the effect on albin winstar rats' memory induced by the co -administration of fluoride and aluminum sulfate, as a model of Alzheimer's disease. This was done by assessing monoamine oxidase-A (MAO-A) activity, antioxidant activity, H2O2 and amyloid-β concentration in the hippocampus, embedded deep into the brain's temporal lobe, and level of cytokines in serum. The polymerase chain reaction approach was used to genotyping MAO-A, followed by single -stranded conformational polymorphism (SSCP) coupled with sequencing technique. The experimental animals were divided into two groups: control and treated groups. The uptake of heavy metals led to significantly increased MAO-A activity, amyloid -β deposition, H2O2 and cytokines levels in the treated group. However, the finding showed a significant decrease in antioxidant activity in the treated group. The results indicated that metals caused memory and learning impairments. PCR -SSCP genotyping showed many SNPs and haplotypes of the MAO-A exon 2 region, which showed the MAO-A gene polymorphism changes associated with Alzheimer's disease. The overall results indicated a role of metals to induce oxidative stress stimulating pathophysiological hallmarks in the hippocampus due to an increase in the influx of monoamine oxidase expression, which has been implicated in impaired memory, this study focused on the genetic variation of the exon 2 in monoamine oxidase-A gene and its relationship to Alzheimer's disease with the presence of several single nucleotide polymorphisms that may be related to Alzheimer's disease model in rats.

Tobacco Smoke Extract Modulates Activity and Expression of Monoamine Oxidase and μ Opioid Receptor in Cultured Human Neuroblastoma Cells

<p>Tobacco addiction is a major public health concern and is responsible for approximately five million deaths globally each year. Although most current smokers express a desire to quit, few are successful in their attempts. Nicotine is the primary neurobiologically active component in tobacco smoke and acts through the nicotinic acetylcholine receptor (nAChR) to sustain addiction. However, nicotine replacement therapies have proven to be remarkably ineffective at helping smokers quit. This indicates that nicotine alone cannot fully account for the intense and enduring nature of tobacco addiction. Previous research has provided strong evidence that monoamine oxidase (MAO) enzymes and the endogenous opioid system may also play a role in tobacco dependence. The present study compared and contrasted the influence of nicotine and the non-nicotine components of tobacco smoke on the enzyme activity of MAO-A and MAO-B. Gene expression of MAO and the mu opioid receptor (MOR) in SH-SY5Y human neuroblastoma and U-118 MG glioma cell lines was also investigated. Using a kynuramine-based enzymatic assay adapted and optimised for this study, the MAO inhibitory activity of tobacco-based samples were tested, including total particulate matter (TPM) extracts from a range of New Zealand tobacco products, Quest(R) nicotine-free cigarettes, and fluid from the RUYAN(R) Electronic cigarette. TPM from both standard tobacco and Quest(R) significantly inhibited MAO-A and MAO-B activity in vitro and in cultured cells. Differences between the types and brands of tobacco products were observed. TPM derived from loose-leaf tobacco inhibited MAO enzymes more potently than samples from manufactured cigarettes. This difference was attributed to a significantly higher tar:nicotine ratio in loose-leaf tobacco. Standard TPM and Quest(R) TPM also inhibited total MAO activity in SH-SY5Y cells treated for 24 hours; whereas the weak activity in U-118 MG remained unchanged. However, MAO activity was highly dependent on the cell culture conditions, with activity increasing in SH-SY5Y cells when treated with a 5-day exposure regimen. This finding was unique to the present study. The gene expression of MAO-A, MAO-B, and MOR was examined using a qRT-PCR assay. All three genes were significantly up-regulated by standard and denicotinized TPM extracts after a 5-day treatment regimen. This finding was correlated with an increase in protein abundance for MOR, but not MAO-A or MAO-B, as assayed by Western blot. Up-regulation of MAO and MOR gene expression was abolished when cells were treated with TPM extracts in conjunction with the nAChR antagonist mecamylamine, suggesting that up-regulation of MAO and MOR genes was dependent, at least in part, on nAChR signalling. Both standard TPM and TPM from denicotinized Quest(R) cigarettes induced inhibition of MAO and up-regulation of MAO and MOR gene expression. This demonstrates that non-nicotine compounds within tobacco smoke can significantly influence the behaviour of cultured neuronal cells. Further research is required to fully elucidate the mechanisms behind the MAO and MOR gene response, and a better understanding of these mechanisms may provide a framework for the development of novel smoking cessation therapies.</p>

Tobacco Smoke Extract Modulates Activity and Expression of Monoamine Oxidase and μ Opioid Receptor in Cultured Human Neuroblastoma Cells

<p>Tobacco addiction is a major public health concern and is responsible for approximately five million deaths globally each year. Although most current smokers express a desire to quit, few are successful in their attempts. Nicotine is the primary neurobiologically active component in tobacco smoke and acts through the nicotinic acetylcholine receptor (nAChR) to sustain addiction. However, nicotine replacement therapies have proven to be remarkably ineffective at helping smokers quit. This indicates that nicotine alone cannot fully account for the intense and enduring nature of tobacco addiction. Previous research has provided strong evidence that monoamine oxidase (MAO) enzymes and the endogenous opioid system may also play a role in tobacco dependence. The present study compared and contrasted the influence of nicotine and the non-nicotine components of tobacco smoke on the enzyme activity of MAO-A and MAO-B. Gene expression of MAO and the mu opioid receptor (MOR) in SH-SY5Y human neuroblastoma and U-118 MG glioma cell lines was also investigated. Using a kynuramine-based enzymatic assay adapted and optimised for this study, the MAO inhibitory activity of tobacco-based samples were tested, including total particulate matter (TPM) extracts from a range of New Zealand tobacco products, Quest(R) nicotine-free cigarettes, and fluid from the RUYAN(R) Electronic cigarette. TPM from both standard tobacco and Quest(R) significantly inhibited MAO-A and MAO-B activity in vitro and in cultured cells. Differences between the types and brands of tobacco products were observed. TPM derived from loose-leaf tobacco inhibited MAO enzymes more potently than samples from manufactured cigarettes. This difference was attributed to a significantly higher tar:nicotine ratio in loose-leaf tobacco. Standard TPM and Quest(R) TPM also inhibited total MAO activity in SH-SY5Y cells treated for 24 hours; whereas the weak activity in U-118 MG remained unchanged. However, MAO activity was highly dependent on the cell culture conditions, with activity increasing in SH-SY5Y cells when treated with a 5-day exposure regimen. This finding was unique to the present study. The gene expression of MAO-A, MAO-B, and MOR was examined using a qRT-PCR assay. All three genes were significantly up-regulated by standard and denicotinized TPM extracts after a 5-day treatment regimen. This finding was correlated with an increase in protein abundance for MOR, but not MAO-A or MAO-B, as assayed by Western blot. Up-regulation of MAO and MOR gene expression was abolished when cells were treated with TPM extracts in conjunction with the nAChR antagonist mecamylamine, suggesting that up-regulation of MAO and MOR genes was dependent, at least in part, on nAChR signalling. Both standard TPM and TPM from denicotinized Quest(R) cigarettes induced inhibition of MAO and up-regulation of MAO and MOR gene expression. This demonstrates that non-nicotine compounds within tobacco smoke can significantly influence the behaviour of cultured neuronal cells. Further research is required to fully elucidate the mechanisms behind the MAO and MOR gene response, and a better understanding of these mechanisms may provide a framework for the development of novel smoking cessation therapies.</p>

Tobacco smoke extract modulates activity and expression of monoamine oxidase and μ opioid receptor in cultured human neuroblastoma cells

<p>Tobacco addiction is a major public health concern and is responsible for approximately five million deaths globally each year. Although most current smokers express a desire to quit, few are successful in their attempts. Nicotine is the primary neurobiologically active component in tobacco smoke and acts through the nicotinic acetylcholine receptor (nAChR) to sustain addiction. However, nicotine replacement therapies have proven to be remarkably ineffective at helping smokers quit. This indicates that nicotine alone cannot fully account for the intense and enduring nature of tobacco addiction. Previous research has provided strong evidence that monoamine oxidase (MAO) enzymes and the endogenous opioid system may also play a role in tobacco dependence. The present study compared and contrasted the influence of nicotine and the non-nicotine components of tobacco smoke on the enzyme activity of MAO-A and MAO-B. Gene expression of MAO and the mu opioid receptor (MOR) in SH-SY5Y human neuroblastoma and U-118 MG glioma cell lines was also investigated. Using a kynuramine-based enzymatic assay adapted and optimised for this study, the MAO inhibitory activity of tobacco-based samples were tested, including total particulate matter (TPM) extracts from a range of New Zealand tobacco products, Quest(R) nicotine-free cigarettes, and fluid from the RUYAN(R) Electronic cigarette. TPM from both standard tobacco and Quest(R) significantly inhibited MAO-A and MAO-B activity in vitro and in cultured cells. Differences between the types and brands of tobacco products were observed. TPM derived from loose-leaf tobacco inhibited MAO enzymes more potently than samples from manufactured cigarettes. This difference was attributed to a significantly higher tar:nicotine ratio in loose-leaf tobacco. Standard TPM and Quest(R) TPM also inhibited total MAO activity in SH-SY5Y cells treated for 24 hours; whereas the weak activity in U-118 MG remained unchanged. However, MAO activity was highly dependent on the cell culture conditions, with activity increasing in SH-SY5Y cells when treated with a 5-day exposure regimen. This finding was unique to the present study. The gene expression of MAO-A, MAO-B, and MOR was examined using a qRT-PCR assay. All three genes were significantly up-regulated by standard and denicotinized TPM extracts after a 5-day treatment regimen. This finding was correlated with an increase in protein abundance for MOR, but not MAO-A or MAO-B, as assayed by Western blot. Up-regulation of MAO and MOR gene expression was abolished when cells were treated with TPM extracts in conjunction with the nAChR antagonist mecamylamine, suggesting that up-regulation of MAO and MOR genes was dependent, at least in part, on nAChR signalling. Both standard TPM and TPM from denicotinized Quest(R) cigarettes induced inhibition of MAO and up-regulation of MAO and MOR gene expression. This demonstrates that non-nicotine compounds within tobacco smoke can significantly influence the behaviour of cultured neuronal cells. Further research is required to fully elucidate the mechanisms behind the MAO and MOR gene response, and a better understanding of these mechanisms may provide a framework for the development of novel smoking cessation therapies.</p>

Tobacco smoke extract modulates activity and expression of monoamine oxidase and μ opioid receptor in cultured human neuroblastoma cells

<p>Tobacco addiction is a major public health concern and is responsible for approximately five million deaths globally each year. Although most current smokers express a desire to quit, few are successful in their attempts. Nicotine is the primary neurobiologically active component in tobacco smoke and acts through the nicotinic acetylcholine receptor (nAChR) to sustain addiction. However, nicotine replacement therapies have proven to be remarkably ineffective at helping smokers quit. This indicates that nicotine alone cannot fully account for the intense and enduring nature of tobacco addiction. Previous research has provided strong evidence that monoamine oxidase (MAO) enzymes and the endogenous opioid system may also play a role in tobacco dependence. The present study compared and contrasted the influence of nicotine and the non-nicotine components of tobacco smoke on the enzyme activity of MAO-A and MAO-B. Gene expression of MAO and the mu opioid receptor (MOR) in SH-SY5Y human neuroblastoma and U-118 MG glioma cell lines was also investigated. Using a kynuramine-based enzymatic assay adapted and optimised for this study, the MAO inhibitory activity of tobacco-based samples were tested, including total particulate matter (TPM) extracts from a range of New Zealand tobacco products, Quest(R) nicotine-free cigarettes, and fluid from the RUYAN(R) Electronic cigarette. TPM from both standard tobacco and Quest(R) significantly inhibited MAO-A and MAO-B activity in vitro and in cultured cells. Differences between the types and brands of tobacco products were observed. TPM derived from loose-leaf tobacco inhibited MAO enzymes more potently than samples from manufactured cigarettes. This difference was attributed to a significantly higher tar:nicotine ratio in loose-leaf tobacco. Standard TPM and Quest(R) TPM also inhibited total MAO activity in SH-SY5Y cells treated for 24 hours; whereas the weak activity in U-118 MG remained unchanged. However, MAO activity was highly dependent on the cell culture conditions, with activity increasing in SH-SY5Y cells when treated with a 5-day exposure regimen. This finding was unique to the present study. The gene expression of MAO-A, MAO-B, and MOR was examined using a qRT-PCR assay. All three genes were significantly up-regulated by standard and denicotinized TPM extracts after a 5-day treatment regimen. This finding was correlated with an increase in protein abundance for MOR, but not MAO-A or MAO-B, as assayed by Western blot. Up-regulation of MAO and MOR gene expression was abolished when cells were treated with TPM extracts in conjunction with the nAChR antagonist mecamylamine, suggesting that up-regulation of MAO and MOR genes was dependent, at least in part, on nAChR signalling. Both standard TPM and TPM from denicotinized Quest(R) cigarettes induced inhibition of MAO and up-regulation of MAO and MOR gene expression. This demonstrates that non-nicotine compounds within tobacco smoke can significantly influence the behaviour of cultured neuronal cells. Further research is required to fully elucidate the mechanisms behind the MAO and MOR gene response, and a better understanding of these mechanisms may provide a framework for the development of novel smoking cessation therapies.</p>

Near-Infrared MAO A Inhibitor (NMI) Outperformed FDA-Approved Chemotherapeutic Agents in Brain and Other Cancers: A Bioinformatic Analysis of NCI60 Screening Data

Our previous work has shown that monoamine oxidase A (MAO A) is overexpressed in glioma and prostate cancer. Near-infrared dye conjugate MAO A Inhibitor (NMI) inhibited the growth of these cancers. This study investigated the effects of NMI on other cancers by NCI60 screening. Our results showed that 48 out of 59 screened cell lines from nine types of cancer had 100% growth inhibition at 10 μM NMI treatment. The in vitro efficacy of NMI determined by growth inhibition (GI50 and TGI) and lethal doses (LC50) has been further studied in various cell lines of CNS cancer, prostate cancer, and non-small cell lung cancer (NSCLC), these three cancers showed increased MAO A expression in tumors compared to normal tissues. Based on the waterfall plots and the 3D scatter plot of GI50, TGI, and LC50 data, NMI showed higher potency to several CNS cancer and NSCLC cell lines than prostate cancer cell lines. In vitro efficacy of NMI outperformed FDA-approved drugs for CNS cancer, prostate cancer, and NSCLC, respectively. The Pairwise Pearson Correlation Coefficient (PCC) showed that NMI has a unique mechanism compared to the existing anticancer drugs. This study shows that NMI is a novel theragnostic drug with high potency and unique mechanisms for brain, prostate, NSCLC, and other cancers.

Monoamine oxidase contributes to the valvular oxidative stress in patients with mitral valve regurgitation

Background Oxidative stress plays a central role in the pathogenesis of cardiovascular diseases but the role of enzymatic sources of reactive oxygen species (ROS) remains elusive. There is scarce information in the literature regarding valvular oxidative stress. Monoamine oxidases (MAOs), with 2 isoforms, A and B, have emerged as important sources of oxidative stress in the cardiovascular system. Purpose To assess whether MAOs-related oxidative stress occurs in the pathological valves in patients with severe mitral regurgitation (due to valve degeneration and chordae rupture) and surgical indication and its interference with the activation of the renin-angiotensin aldosterone (RAAS) system. Material and methods Samples of mitral valve (n=17) were harvested during the valvular replacement procedure and used for reactive oxygen species (ROS) assessment (immune-fluorescence, spectrophotometry) and MAO mRNA and protein expression (qPCR and immune-fluorescence) measurement. Inflammatory markers, biochemical parameters and echocardiography (GE, Vivid 9, Vivid E95) data were also collected. Results Both MAO isoforms are expressed in the diseased mitral valves, with a predominance of MAO-A isoform. Ex vivo incubation with angiotensin 2 (12 h, 100 nM) of samples obtained from patients without RAAS medication lead to MAO upregulation and high ROS production. MAO-related oxidative stress was mitigated by MAO inhibition with clorgyline (MAO-A inhibitor, 10 microM) and selegyline (MAO-B inhibitor, 10 microM) and also by the angiotensin II receptor type 1 (AT1) antagonist, irbersartan (10 microM). Conclusions Monoamine oxidase is expressed in the pathological mitral valves, regardless the etiology. Its expression and the related-oxidative stress are modulated by angiotensin 2, irbesartan. Whether the latter effect is present in valvular patients treated with RAAS inhibitors is currently under investigation. FUNDunding Acknowledgement Type of funding sources: None.

Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors

A series of dietary flavonoid acacetin 7-O-methyl ether derivatives were computationally designed aiming to improve the selectivity and potency profiles against monoamine oxidase (MAO) B. The designed compounds were evaluated for their potential to inhibit human MAO-A and -B. Compounds 1c, 2c, 3c, and 4c were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds 1c–4c displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds 1c and 2c showed reversible inhibition of MAO-B. These results provide a basis for further studies on the potential application of these modified flavonoids for the treatment of Parkinson’s Disease and other neurological disorders.

Calocybe indicia extract modifies GABA and Serotonin levels to Alleviate anxiety in experimental adult Zebrafish models

Zebrafish (Danio rerio) was used as a model to study anxiety due to its physiological homology to humans. The pathophysiology of anxiety, even though still unclear, has been extensively studied in Zebrafish. Anxiety was induced by withdrawal after exposure to 0.5% ethanol, which proved to be anxiogenic, validated through the novel tank test. The light/dark test revealed that exposure to 0.5% ethanol had anxiolytic effects. The milky mushroom, Calocybe indica was used to treat anxiety since its anti-hypertensive effects have already been reported. Biochemical parameters such as GABA and MAO (A&B) were measured before and after treatment with different concentrations of C. indica and standard anxiolytic drug, Fluoxetine to compare and confirm the anxiolytic effect. The GABA content was found to be 119.9±1.99 mmoles/g tissue weight after treatment with 50 µg C. indica which was comparable to the normal group values (100±4.12). MAO (A&B) activity decreased which in turn increased serotonin levels with 25µg of C. indica. 25µg and 100µg concentration of the extract of C. indica was found to be optimum in reducing the level of anxiety.