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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
Development of Novel Fluorine-18 Labeled PET Radioligands for Monoamine Oxidase B (MAO-B)
No full textMonoamine oxidases (MAO-A and MAO-B) are important enzymes regulating the levels of monoaminergic neurotransmitters. Selective and irreversible MAO-B inhibitors such as L-deprenyl and rasagiline are clinically used for the treatment of psychiatric and neurological disorders. Positron emission tomography (PET) is a noninvasive imaging technique which has been utilized to visualize the localization of MAO-B in monkey and human brain and thereby has potential for studying neurodegenerative diseases and epilepsy. This thesis deals with the synthesis and evaluation of novel fluorine-18 labeled PET radioligands for detection of MAO-B activity.
The present thesis demonstrates that nine fluorinated propargyl amines were synthesized and tested for inhibition of MAO-B. In order to label those compounds with fluorine-18 seven chloro-precursors and two sulphamidate-precursors were also synthesized by multi step organic synthesis. Radiolabeling of six chloro-precursors with fluorine-18 was accomplished by a one-step nucleophilic substitution reaction. Radiolabeling of two sulphamidate-precursors with fluorine-18 was performed in two steps, compromising a nucleophilic substitution followed by the removal of the protecting group. The incorporation yield of the fluorination reactions varied from 40- 70%. The radiochemical purity was >99% and the specific radioactivities were in a range of 190-240 GBq/μmol at the time of administration.
In vitro MAO inhibition and/or autoradiography (ARG) experiments demonstrated a high selectivity for MAO-B over MAO-A for five of the compounds namely [18F]fluorodeprenyl, [18F]fluororasagiline, [18F]fluoro-N,4-dimethyl-N-(prop-2-ynyl) pentan-2-amine, [18F]fluorodeprenyl-D2 and [18F]fluororasagiline-D2. All five compounds were examined by PET and showed a high initial brain uptake in known MAO-B rich regions in cynomolgus monkey. [18F]Fluorodeprenyl showed a kinetic behavior similar to [11C]deprenyl where its fast irreversible binding to the enzyme renders the distribution of this radioligand in tissue limited by blood flow rather than the MAO-B enzyme concentration. [18F]Fluororasagiline and [18F]fluoro-N,4-dimethyl-N-(prop-2-ynyl)pentan-2-amine showed continuous increase of the radioactivity throughout the PET measurement that might be an indication of a blood-brain barrier penetrating radiometabolite which might in turn complicate a reliable quantification. Only [18F]fluorodeprenyl-D2 and [18F]fluororasagiline-D2 showed fast wash-out from the brain and less accumulation in cortical and sub-cortical regions. Radiometabolite studies demonstrated that both deuterated analogues were more stable measured in monkey plasma when compared to the non-deuterated analogues.
These results together suggest that both [18F]fluorodeprenyl-D2 and [18F]fluororasagiline-D2 may be improved PET radioligands and potential molecular imaging biomarker candidates for PET studies in neuroinflammation and neurodegeneration, accompanied with astrocyte activation
The portrayal of women in Mao Dun's early fiction 1927-1932
No full textIt is the prevailing critical assessment of Mao Dun's early creative writing that he displays a singular insight in his portrayal of women. This thesis seeks not only to challenge this assessment by a predominantly male body of criticism but also the assumptions on which it is based, namely that an intellectual sympathy for the women’s cause necessarily implies a transcendence of the patriarchal attitudes with which society is imbued. The major short stories and novellas written between 1927 and 1932 are analysed systematically to identify Mao Dun's underlying attitudes towards women. His portrayal of women is assessed from the following perspectives:~ his autobiographical accounts of his encounters with women in his political and personal life and his deliberate association of his female comrades with his creative inspiration;- traditional Chinese perceptions of women and gender roles as these are manifested in the classical tradition;-- Mao Dun's numerous articles and essays on the women's question written during the nineteen twenties and his work in the women's section of the Party in Shanghai;- Mao Dun's attempt to reconcile his conflicting sympathies for feminism and socialism. This thesis relies for its methodology on Western feminist criticism. While the approach is maintained, in its application to the context of early twentieth century China, its eurocentrism in terms of cultural assumptions and perceptions of gender has been replaced by a definition of Chinese values. Since a fundamental prerequisite, of feminist criticism is the assessment of the writer in his/her own cultural context, a historical survey of the portrayal of women in traditional literature is provided to serve as a standard against which to measure Mao Dun’s portrayal
Nietzsche y mao
No full textNietzsche tiene que ver con una represión espectacular de su obra por parte de la Razón Occidental en sus diversas formas y en el interior (Kant, Hegel) de la Metafísica Occidental, cuando no en sus límites (Heidegger). Si la Razón Occidental ha reprimido, tergiversado y deformado una obra como la de Nietzsche, su ensañamiento alcanza su máximo apogeo con relación a la obra de Mao, puesto que es allí dondedescubre y redescubre la fascinación de su propia muerte (la de la Razón Occidental), puesto que su entraña secreta y su sensibilidad fulgurante son tocadas por Mao en su punta más vulnerable: el de la práctica y las condiciones de la lucha de c1ases. De ahí, su encarnizamiento sordo contra Mao y los intentos fraudulentos de reducir su obra, sea a una simple herencia del Hegelianismo o de su "crítico" de turno, Feuerbach; sea a una variante más de la fenomenología o de la "Razón Critica" Kantiana, cuando no del historicismo, positivismo, o inc1uso y sobre todo del empirismo vulgar
Platelet monoamine oxidase activity in alcoholics with and without a family history of alcoholism
No full textA number of studies point at platelet monoamine oxidase (MAO) activity being reduced in alcoholics with a family history of drinking, this being a possible vulnerability marker for alcoholism. To test this hypothesis, we examined a group of recently detoxified alcoholics with high (n = 25) and low genetic loading for alcoholism (n = 28) and a group of healthy controls (n = 21). Clinical assessments were made using the SCID II interview for psychiatric disorders, the Family History Assessment Module and the Semi-Structural Assessment of Genetics in Alcoholism, a questionnaire especially designed for genetic studies. Platelet MAO activity with and without ethanol stimulation and the percentage of MAO activity with ethanol did not differ between groups. The only significant difference was a lower inhibition of MAO activity with ethanol in alcoholics both with and without a family history compared to controls. In patients with antisocial personality traits, platelet MAO activity was also not found to be different from other alcoholics. Our findings question the hypothesis of reduced platelet MAO activity to be a possible vulnerability marker for alcoholism. Copyright (C) 2000 S. Karger AG. Basel
Los daños del rey sabio: Mao y China.
No full textThis essay is an attempt to reflect on the weight and the consequences of a central personified power without effective social or institutional controls. In the first three decades of People’s Republic of China, Mao was the promoter of two initiatives (the Great Leap forward and the Cultural revolution) that produced the worst economic setbacks, and with the Cultural revolution, an extended delegitimation of the Communist Party itself. After reconstructing the outgoing moments (from 1935 to 1949 and from 1958 to 1969) of Mao's influence in the contemporary history of his country, we argue that the last three decades of Chinese history would be incomprehensible without considering their nature of reaction to a long cycle of charismatic authority with imperial traits.Este ensayo es un intento de reflexión sobre el peso y las consecuencias de un poder central personificado y sin eficaces controles institucionales o sociales. En las primeras tres décadas de la República Popular China, Mao fue el promotor de las dos iniciativas (el Gran salto adelante y la Revolución cultural) que produjeron graves retrocesos económicos y, con la revolución cultural, una extendida deslegitimación del propio Partido Comunista. Después de reconstruir los momentos salientes (sobre todo en 1935-1949 y en 1958-1969) de la influencia de Mao en la historia contemporánea de su país, se sostiene aquí que las últimas tres décadas de la historia china serían incomprensibles sin considerar su componente de reacción a un largo ciclo de autoridad carismática con rasgos imperiales
Assay of MAO inhibition by chromatographic techniques (HPLC/HPLC-MS)
No full textMonoamine oxidase (MAO) enzymes (MAO A and B) catalyze the oxidative deamination of biogenic amines, neurotransmitters, and xenobiotic amines and contribute to the regulation of the content of these active substances in mammalian organisms. The oxidation of biogenic amines by MAO produces hydrogen peroxide (H2O2) and aldehydes that represent risk factors for oxidative injury. The inhibitors of MAO are useful as antidepressants and neuroprotective agents. Usually, the assays of MAO determine amine deamination products or measure the H2O2 released by using direct spectrophotometric or fluorimetric methods. Direct methods are more prone to interferences and can afford inaccurate results. Those limitations can be avoided by using chromatographic techniques. This work describes a chromatographic method to assay MAO A and MAO B activity by using kynuramine as a nonselective substrate and the subsequent analysis of 4-hydroxyquinoline by RP-HPLC-DAD-fluorescence and mass spectrometry (MS). Alternatively, the assay uses the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin as a substrate of MAO that is oxidized (bioactivated) to neurotoxic pyridinium cations which are analyzed by HPLC. These methods are applied to assess the inhibition of MAO by bioactive β-carboline alkaloids occurring in foods, plants, and biological systems.The author thank the Spanish Government-FEDER through projects RTI2018-093940-B-I00 and RTI2018-095544-B-I00.Peer reviewe
Nietzsche y Mao
No full textNietzsche tiene que ver con una represión espectacular de su obra por parte de la Razón Occidental en sus diversas formas y en el interior (Kant, Hegel) de la Metafísica Occidental, cuando no en sus límites (Heidegger). Si la Razón Occidental ha reprimido, tergiversado y deformado una obra como la de Nietzsche, su ensañamiento alcanza su máximo apogeo con relación a la obra de Mao, puesto que es allí donde
descubre y redescubre la fascinación de su propia muerte (la de la Razón Occidental), puesto que su entraña secreta y su sensibilidad fulgurante son tocadas por Mao en su punta más vulnerable: el de la práctica y las condiciones de la lucha de c1ases. De ahí, su encarnizamiento sordo contra Mao y los intentos fraudulentos de reducir su obra, sea a una simple herencia del Hegelianismo o de su "crítico" de turno, Feuerbach; sea a una variante más de la fenomenología o de la "Razón Critica" Kantiana, cuando no del historicismo, positivismo, o inc1uso y sobre todo del empirismo vulgar
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Monoamine oxidase in neuronal cell death
No full textMonoamine oxidase (MAO) is an oxidative enzyme that deaminates a variety of amine substrates, including the neurotransmitter dopamine. The enzymatic reaction requires molecular oxygen and produces hydrogen peroxide as a by-product. MAO is localised in the outer mitochondrial membrane and exists as two isoforms, MAO-A and MAO-B, which are differentially expressed in the body and differ in their substrate and inhibitor specificities. Previous studies have suggested that MAO-generated reactive oxygen species (ROS) contribute to oxidative stress in the cell and can directly inhibit electron transport, cause damage to mitochondrial DNA and enhance cell death signalling. In this study the role of MAO in cell death was investigated in dopaminergic neuroblastoma (SH-SY5Y) cells, in three diverse models of mitochondrially-mediated apoptosis. The relevance of MAO in cell death signalling was confirmed with the use of two unrelated MAO inhibitors and the creation of stable SH-SY5Y cell lines that either over express MAO-A or have reduced levels of MAO-A. The study is the first to over express MAO-A using recombinant technology and to use miRNA to stably knock-down MAO-A expression in human neuronal cells
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