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OPA1 silencing in AC16: a model to study MAO A upregulation and autophagy dysregulation
No full textreservedHeart failure and cardiovascular disease are becoming a worldwide health crisis, they are often characterized by profound alterations in cardiomyocyte function and energy metabolism, in this context mitochondrial dysfunction plays a crucial role. Cellular quality control mechanisms such as autophagy and its selective form, mitophagy, have important functions in maintaining homeostasis and degrading damaged organelles. Monoamine oxidase A is one of the primary sources of oxidative stress in the mitochondria, being responsible for the deamination of neurotransmitters such as norepinephrine and serotonin, it generates reactive oxygen species. These toxic byproducts in the heart could be one of the causes of mitochondrial dysfunction, affecting the myocardium and leading to cardiovascular disease. OPA1 is a protein involved in mitochondrial fusion and cristae remodelling, which regulates mitochondrial dynamics. Previous studies from a murine model with cardiac downregulation of OPA1 was characterized by an impairment in autophagy, it also exhibited a marked upregulation of MAO A. The objective of the study was to generate a cellular model characterized by OPA1 downregulation that could be used to investigate the possible relationship between MAO A, OPA1 and autophagy in cardiomyocytes. The model was generated employing a human cardiomyocyte cell line AC16 derived from the adult ventricular tissue and it confirmed the same MAO A upregulation as the previous murine model.Heart failure and cardiovascular disease are becoming a worldwide health crisis, they are often characterized by profound alterations in cardiomyocyte function and energy metabolism, in this context mitochondrial dysfunction plays a crucial role. Cellular quality control mechanisms such as autophagy and its selective form, mitophagy, have important functions in maintaining homeostasis and degrading damaged organelles. Monoamine oxidase A is one of the primary sources of oxidative stress in the mitochondria, being responsible for the deamination of neurotransmitters such as norepinephrine and serotonin, it generates reactive oxygen species. These toxic byproducts in the heart could be one of the causes of mitochondrial dysfunction, affecting the myocardium and leading to cardiovascular disease. OPA1 is a protein involved in mitochondrial fusion and cristae remodelling, which regulates mitochondrial dynamics. Previous studies from a murine model with cardiac downregulation of OPA1 was characterized by an impairment in autophagy, it also exhibited a marked upregulation of MAO A. The objective of the study was to generate a cellular model characterized by OPA1 downregulation that could be used to investigate the possible relationship between MAO A, OPA1 and autophagy in cardiomyocytes. The model was generated employing a human cardiomyocyte cell line AC16 derived from the adult ventricular tissue and it confirmed the same MAO A upregulation as the previous murine model
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Expression regulation of MAO isoforms in monocytic cells in response to Th2 cytokines
No full textBackground: Th2-cytokines, such as interleukins-4 and –13 (IL-4, IL-13), have been identified as alternative stimuli of monocytes/macrophages. We have recently profiled the gene-expression pattern of IL-4-teated human peripheral monocytes and found that 15-lipoxygenase-1 (15-LOX1) and monoamine oxidase A (MAO-A) are among the five most strongly upregulated gene products in IL-4-treated cells. Transfection of monocytic cells (U937) with 15-LOX1 also induced MAO-A expression. These data suggested that 15-LOX1 products might play a role in the IL4-induced signaling cascade leading to expression of MAO-A in human monocytes. Material/Methods: To test this hypothesis we incubated wild-type and 15-LOX1-transfected U937 cells with different concentrations of either IL-4 or 15-LOX-products [13S-H(p)ODE, 15S-H(p)ETE] and quantified the expression of 15-LOX1, MAO-A, and MAO-B by activity assays and real-time RT-PCR. Results: Wild-type U937 cells express neither MAO-A nor MAO-B, but after three days of IL4 treatment, MAO-A mRNA was detected. A similar isoform-specific expression of MAO-A mRNA was observed when U937 cells were transfected with 15-LOX1 or when the cells were incubated with primary 15-LOX1 products (hydroperoxy fatty acids) or H2O2. In contrast, the corresponding hydroxy fatty acids were ineffective. Conclusions: These data indicate that increased intracellular peroxide concentrations (oxidative stress) induce MAO-A expression in monocytes/macrophages, which normally do not express the enzyme. Our findings also suggest that IL-4-induced upregulation of MAO-A expression in human peripheral monocytes may proceed via 15-LOX1-dependent and 15-LOX1-independent pathways. The biological role of MAO-A expression for monocyte function is discussed
Combined treatment with MAO-A inhibitor and MAO-B inhibitor increases extracellular noradrenaline levels more than MAO-A inhibitor alone through increases in β-phenylethylamine
Get PDFMonoamine oxidase inhibitors (MAO inhibitors) have been widely used as antidepressants. However, it remains unclear whether a difference exists between non-selective MAO inhibitors and selective MAO-A inhibitors in terms of their antidepressant effects. Using in vivo microdialysis methods, we measured extracellular noradrenaline and serotonin levels following administration of Ro 41-1049, a reversible MAO-A inhibitor and/or lazabemide, a reversible MAO-B inhibitor in the medial prefrontal cortex (mPFC) of rats. We examined the effect of local infusion of β-phenylethylamine to the mPFC of rats on extracellular noradrenaline and serotonin levels. Furthermore, the concentrations of β-phenylethylamine in the tissue of the mPFC after combined treatment with Ro 41-1049 and lazabemide were measured. The Ro 41-1049 alone and the combined treatment significantly increased extracellular noradrenaline levels compared with vehicle and lazabemide alone. Furthermore, the combined treatment increased noradrenaline levels significantly more than Ro 41-1049 alone did. The Ro 41-1049 alone and the combined treatment significantly increased extracellular serotonin levels compared with vehicle and lazabemide alone, but no difference in serotonin levels was found between the combined treatment group and the Ro 41-1049 group. Local infusion of low-dose β-phenylethylamine increased extracellular noradrenaline levels, but not that of serotonin. Only the combined treatment significantly increased β-phenylethylamine levels in tissues of the mPFC. Our results suggest that the combined treatment with a MAO-A inhibitor and a MAO-B inhibitor strengthens antidepressant effects because the combined treatment increases extracellular noradrenaline levels more than a MAO-A inhibitor alone through increases in β-phenylethylamine
Evidence that brain MAO A activity does not correspond to MAO A genotype in healthy male subjects
No full textBackground: A functional polymorphism in the promoter region of the monoamine oxidase A (MAO A) gene has two common alleles that are referred to as the high and low MAO A genotypes. We report the first in vivo human study to determine whether there is an association between MAO A genotype and brain MAO A activity in healthy male subjects. Methods: Brain MAO A activity was measured with positron emission tomography and [C-11]clorgyline in 38 healthy adult male nonsmokers genotyped for MAO A polymorphism. Results: There was no significant difference in brain MAO A activity between the high (n = 26) and low (n = 12) MAO A genotypes. Conclusions: The lack of an association between the high and low MAO A genotype and brain MAO A activity suggests that this polymorphism by itself does not contribute to differences in brain MAO A activity in healthy adult male subject
Calcium ions alter monoamine oxidase A activity
No full textS. Armstrong graduated from the University of St Andrews in 2011Activation of the flavoprotein monoamine oxidase A (MAO A) by calcium ions has been reported in isolated mitochondria, in cell lines, and in vivo. Enhanced MAO A activity has been associated with a rise in oxidative damage (1,2), and with apoptosis in a neuronal cell line (5). Here, purified human MAO A and membrane-bound MAO A and B were used to investigate the direct regulation of MAO activity by Ca2+ ions. At fixed substrate concentration the activity of purified MAO A was stimulated (<20%) by Ca2+ over a physiological range, a much smaller effect than observed in cells; Mg2+ and Mn2+ had no effect. However, when chelating agents (EDTA or EGTA) were added to remove divalent ions present in the water, MAO A activity was increased, but addition of 1 mM Ca2+ to the chelating buffer resulted in inhibition of activity requiring 10 min to reach the minimum. When assayed in HEPES buffer (50 mM, pH 7.4) without chelator, Ca2+ caused mixed-type inhibition of kynuramine oxidation with a Ki of 0.3 mM for binding to free enzyme. We conclude that Ca2+ (but not Mg2+ or Mn2+) interacts directly with purified MAO A to change the kinetic parameters resulting in decreased activity. In contrast, with membrane-bound MAO A (but not membrane-bound MAO B), Ca2+ enhances activity by doubling the Vmax without a change in KM. Recently, molecular dynamics simulations suggested that membrane attachment altered the conformational dynamics of MAO A and facilitated the opening of the substrate tunnel. The data here are consistent with a conformational change induced by Ca2+, the effect of which is different when the enzyme is stabilised in the membrane
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Differential expression of MAO A.
No full text<p>Photomicrographs showing MAO A immunostaining. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075062#pone-0075062-g003" target="_blank">Figure 3A</a> shows brain tissue from <i>M. velifer</i> used as a positive control for this technique. The inset shows the mammary gland of <i>M. velifer</i> as a negative control when slides were incubated with pre-immune serum. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075062#pone-0075062-g003" target="_blank">Figures 3B, 3C and 3D</a> show MAO A differential expression during lactation, involution and the resting phase, respectively. Longitudinal sections. Scale: A: 20 µm; B, C, D: 100 µm.</p
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