Antiapoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindan5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor.

Abstract The anti Parkinson drug, rasagiline [R-(þ)-N-propargyl-1-aminoindan], an inhibitor of type B monoamine oxidase, has been shown to suppress apoptosis induced by neurotoxins and oxidative stress. A series of novel propargylaminoindans with a carbamate moiety to inhibit cholinesterase were developed from phamacophore of rasagiline to protect or rescue deteriorated neurons in Alzheimer's and Lewy Body disease and provide a beneficial effect on the cognitive deficits. Rasagiline analogues were found to protect dopaminergic SH-SY5Y cells against apoptosis induced by peroxynitrite donor. -(3R)-aminoindan-5-yl]-ethyl methyl carbamate, was as effective as rasagiline in preventing apoptosis, followed by its S-enantiomer, TV3279. The anti-apoptotic-neuroprotective activity was shown to reside in the propargylamine and not the carbamate moiety. This resulted in stabilization of the mitochondrial membrane potential, the collapse of which initiates the apoptotic cascade. q 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Propargylamines; Anti-apoptotic activity; Mitochondrial membrane potential; Monoamine oxidase inhibitor; Cholinesterase inhibitor; Parkinson's disease; Alzheimer's disease; Lewy Body disease; Peroxynitrite; Rasagiline; TV3326 Neurodegenerative disorders, such as Parkinson's (PD) and Alzheimer's disease (AD), are characterized by progressive cell death of selective neurons in the brain. Apoptosis is considered to be a common type of neuronal cell death in neurodegenerative diseases that may be induced by various environmental and genetic factors. The apoptotic cascade is activated by tightly controlled step-wise processes and has been proposed to be a target of neurorescue or neuroprotective strategies A series of analogues were synthesized with a carbamate cholinesterase inhibitory moiety in the aminoindan structure of rasagiline with the purpose of preserving its neuroprotective activity Rasagiline and derivatives ( SH-SY5Y cells were incubated with 0.01 -10 mM of propargylamine derivatives for 20 min, then cultured for 18 h in the presence of 250 mM SIN-1, and the morphological changes in the cells were observed by phase-contrast and fluorescence microscopy after staining with PI and Hoechst 33342 The effects of SIN-1 with and without propargylamines were examined on mitochondrial permeability transition pore by measurement of DCm, as reported previously The chemical structures of rasagiline and its derivatives, TV3326, TV3279, TV3218 a (3SR)-aminoindan-5-yl]-ethyl methyl carbamate, without the propargyl moiety and TV 3294 (6-hydroxy-rasagiline), a propargylaminoindan metabolite of TV3326 without a carbamate moiety are shown in The effects of TV3326 and rasagiline on DCm were examined by measurement of the reduction in Rhodamin 123 fluorescence. SIN-1 (250 mM) reduced the fluorescence to 28.3% of control, and the pre-treatment with TV3326 or rasagiline (0.1 -10 mM) prevented the fluorescence reduction, as summarized in The present study on the structure-activity relationship among propargylamines studied shows that the propargyl moiety is responsible for the anti-apoptotic activity. The presence of the carbamate moiety in TV3326 and TV3279, did not affect the antiapoptotic function associated with rasagilin

Correlation between frontal lobe oxy-hemoglobin and severity of depression assessed using near-infrared spectroscopy

AbstractIntroductionThe search for objective biomarkers of psychiatric disorders has a long history. Despite this, no universally accepted instruments or methods to detect biomarkers have been developed. One potential exception is near-infrared spectroscopy, although interpreting the measures of blood flow recorded with this technique remains controversial. In this study, we aimed to investigate the relationship between recorded blood flow and depression severity assessed using the Hamilton depression scale in patients with various psychiatric disorders.MethodsEnrolled patients (n=43) had DSM-IV diagnoses of major depressive disorder (n=25), bipolar disorder I (n=5), schizophrenia (n=3), dysthymic disorder (n=3), psychotic disorder (n=3), panic disorder (n=2), and Obsessive Compulsive Disorder (n=2). The verbal fluency task was administered during blood flow recording from the frontal and temporal lobes.ResultsWe found that severity of depression was negatively correlated with the integral value of blood flow in the frontal lobe, irrespective of psychiatric diagnosis (F=5.94, p=0.02).DiscussionOur results support blood flow in the frontal lobe as a potential biomarker of depression severity across various psychiatric disorders.LimitationLimited sample size, no replication in the second set

語りかける書きことばの表現

国立国語研究所 コーパス開発センター プロジェクト研究員国立国語研究所 言語資源研究系国立国語研究所 コーパス開発センター 技術補佐員国立国語研究所 言語資源研究系Postdoctoral Research Fellow, Center for Corpus Development, NINJALDepartment of Corpus Studies, NINJALTechnical Assistant, Center for Corpus Development, NINJALDepartment of Corpus Studies, NINJAL書籍テキストに見られる「語りかける」という文体の特徴を報告する。調査対象には,『現代日本語書き言葉均衡コーパス』(BCCWJ)に収録されている図書館サブコーパスを使用した。コーパスを用いた文体分析を行うにあたっては,語や文脈的な語の結びつきなどの頻度情報のほか,コーパスに付与された書誌情報やアノテーターによる作業コメントなどを用いた。「語りかける」という文体は,エッセイやブログなどのくだけたテキストにのみ出現しやすく,直接的に読み手へ呼びかけや問いかけを行うなどの表現を有すると考えられてきた。しかし,書籍においては,いわゆるハウツー本をはじめとするような教示的な態度を示すテキストに出現しやすい傾向があり,必ずしも直感的に「語りかける」ととらえられる表現が多く含まれるばかりではないことがわかった。本稿は,テキストが「語りかける」と読み手が判断した際に,文脈に依存した表現や,テキストに向かう読み手の前提的態度などが影響していたことを示す。In this paper, we report the characteristics of the writing style called "addressing the reader" found in books. For this study, we used the Library Sub-corpus contained in the Balanced Corpus of Contemporary Written Japanese (BCCWJ). In performing a stylistic analysis of the corpus, we used the information annotated in the corpus and the comments of the annotators (namely, readers), as well as the word frequencies and contextual connections between words. We found that the "addressive" style is more common in texts written in a casual style, such as essays and blogs, and contains phrases used to address readers directly or ask them questions (as if the writer and the readers are having a dialogue). In books, however, this writing style can be found in instructive texts, mainly in so-called how-to or enlightening books. Therefore, expressions that readers intuitively consider "addressive" in nature are not always encountered in these texts. In this paper, we will show that when readers find that the text is "addressing" them, they are influenced by context-dependent expressions and their own presuppositions as participants

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Neuroprotective Function of Rasagiline and Selegiline, Inhibitors of Type B Monoamine Oxidase, and Role of Monoamine Oxidases in Synucleinopathies

Synucleinopathies are a group of neurodegenerative disorders caused by the accumulation of toxic species of α-synuclein. The common clinical features are chronic progressive decline of motor, cognitive, behavioral, and autonomic functions. They include Parkinson’s disease, dementia with Lewy body, and multiple system atrophy. Their etiology has not been clarified and multiple pathogenic factors include oxidative stress, mitochondrial dysfunction, impaired protein degradation systems, and neuroinflammation. Current available therapy cannot prevent progressive neurodegeneration and “disease-modifying or neuroprotective” therapy has been proposed. This paper presents the molecular mechanisms of neuroprotection by the inhibitors of type B monoamine oxidase, rasagiline and selegiline. They prevent mitochondrial apoptosis, induce anti-apoptotic Bcl-2 protein family, and pro-survival brain- and glial cell line-derived neurotrophic factors. They also prevent toxic oligomerization and aggregation of α-synuclein. Monoamine oxidase is involved in neurodegeneration and neuroprotection, independently of the catalytic activity. Type A monoamine oxidases mediates rasagiline-activated signaling pathways to induce neuroprotective genes in neuronal cells. Multi-targeting propargylamine derivatives have been developed for therapy in various neurodegenerative diseases. Preclinical studies have presented neuroprotection of rasagiline and selegiline, but beneficial effects have been scarcely presented. Strategy to improve clinical trials is discussed to achieve disease-modification in synucleinopathies

Mitochondria in Neuroprotection by Phytochemicals: Bioactive Polyphenols Modulate Mitochondrial Apoptosis System, Function and Structure

In aging and neurodegenerative diseases, loss of distinct type of neurons characterizes disease-specific pathological and clinical features, and mitochondria play a pivotal role in neuronal survival and death. Mitochondria are now considered as the organelle to modulate cellular signal pathways and functions, not only to produce energy and reactive oxygen species. Oxidative stress, deficit of neurotrophic factors, and multiple other factors impair mitochondrial function and induce cell death. Multi-functional plant polyphenols, major groups of phytochemicals, are proposed as one of most promising mitochondria-targeting medicine to preserve the activity and structure of mitochondria and neurons. Polyphenols can scavenge reactive oxygen and nitrogen species and activate redox-responsible transcription factors to regulate expression of genes, coding antioxidants, anti-apoptotic Bcl-2 protein family, and pro-survival neurotrophic factors. In mitochondria, polyphenols can directly regulate the mitochondrial apoptosis system either in preventing or promoting way. Polyphenols also modulate mitochondrial biogenesis, dynamics (fission and fusion), and autophagic degradation to keep the quality and number. This review presents the role of polyphenols in regulation of mitochondrial redox state, death signal system, and homeostasis. The dualistic redox properties of polyphenols are associated with controversial regulation of mitochondrial apoptosis system involved in the neuroprotective and anti-carcinogenic functions. Mitochondria-targeted phytochemical derivatives were synthesized based on the phenolic structure to develop a novel series of neuroprotective and anticancer compounds, which promote the bioavailability and effectiveness. Phytochemicals have shown the multiple beneficial effects in mitochondria, but further investigation is required for the clinical application

SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation.

Senescent cells develop a pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). As many SASP components affect surrounding cells and alter their microenvironment, SASP may be a key phenomenon in linking cellular senesence with individual aging and age-related diseases. We herein demonstrated that the expression of Sirtuin1 (SIRT1) was decreased and the expression of SASP components was reciprocally increased during cellular senescence. The mRNAs and proteins of SASP components, such as IL-6 and IL-8, quickly accumulated in SIRT1-depleted cells, and the levels of these factors were also higher than those in control cells, indicating that SIRT1 negatively regulated the expression of SASP factors at the transcriptional level. SIRT1 bound to the promoter regions of IL-8 and IL-6, but dissociated from them during cellular senescence. The acetylation of Histone H3 (K9) and H4 (K16) of the IL-8 and IL-6 promoter regions gradually increased during cellular senescence. In SIRT1-depleted cells, the acetylation levels of these regions were already higher than those in control cells in the pre-senescent stage. Moreover, these acetylation levels in SIRT1-depleted cells were significantly higher than those in control cells during cellular senescence. These results suggest that SIRT1 repressed the expression of SASP factors through the deacetylation of histones in their promoter regions

A complement component C1q-mediated mechanism of antibody-dependent enhancement of Ebola virus infection

Besides the common Fc receptor (FcR)-mediated mechanism of antibody-dependent enhancement (ADE), Ebola virus (EBOV) is known to utilize the complement component C1q for ADE of infection. This mechanism is FcR-independent and mediated by cross-linking of virus-antibody-C1q complexes to cell surface C1q receptors, leading to enhanced viral entry into cells. Using confocal microscopy, we found that virus-like particles (VLPs) consisting of EBOV glycoprotein, nucleoprotein, and matrix protein attached to the surface of human kidney 293 cells more efficiently in the presence of an ADE monoclonal antibody and C1q than with the antibody or C1q alone, and that there was no significant difference in the efficiency of VLP uptake into endosomes between the C1q-mediated ADE and non-ADE entry. Accordingly, both ADE and non-ADE infection were similarly decreased by inhibitors of the signaling pathways known to be required for endocytosis. These results suggest that C1q-mediated ADE of EBOV infection is simply caused by increased attachment of virus particles to the cell surface, which is distinct from the mechanism of FcR-mediated ADE requiring intracellular signaling to promote phagocytosis/macropinocytosis. Author summary Ebola virus (EBOV) utilizes the complement component C1q for antibody-dependent enhancement (ADE) of infection. We found that an ADE antibody increased viral attachment in the presence of C1q and that there was no significant difference in the efficiency of viral uptake into endosomes between the C1q-mediated ADE and non-ADE entry. Accordingly, both ADE and non-ADE infection were similarly decreased by inhibitors of the signaling pathways for endocytosis. These results suggest that C1q-mediated ADE of EBOV infection is simply caused by increased viral attachment to the cell surface, most likely via cross-linking of virus-antibody-C1q complexes to cellular C1q receptors