International congress series最新文献

{"title":"X-ray structure and reaction mechanism of human indoleamine 2,3-dioxygenase","authors":"Hiroshi Sugimoto ,&nbsp;Shun-ichiro Oda ,&nbsp;Takashi Otsuki ,&nbsp;Keiko Yotsuya ,&nbsp;Tomoya Hino ,&nbsp;Tadashi Yoshida ,&nbsp;Yoshitsugu Shiro","doi":"10.1016/j.ics.2007.07.049","DOIUrl":"10.1016/j.ics.2007.07.049","url":null,"abstract":"<div><p>The oxidative cleavage of the pyrrole ring<span><span> of indoleamines by the insertion of molecular oxygen is catalyzed by indoleamine 2,3-dioxygenase (IDO). The reaction involves the addition of both atoms of a molecule of oxygen to break the C2–C3 double bond in the </span>indole<span><span> moiety of the substrate. We analyzed the X-ray crystal structure of human IDO in complex with the ligand inhibitor 4-phenylimidazole and cyanide. IDO folds into two alpha-helical domains with the heme between them. The conserved Ala of the flexible loop in the heme distal side is in close proximity to the iron. A mutant analysis suggests that, unlike the heme-containing monooxygenases or </span>peroxidases, no protein side chain of IDO is essential in dioxygen activation or proton abstraction. The characteristics of the IDO structure provide support for a reaction mechanism involving the abstraction of a proton from the substrate by iron-bound dioxygen.</span></span></p></div>","PeriodicalId":84918,"journal":{"name":"International congress series","volume":"1304 ","pages":"Pages 85-97"},"PeriodicalIF":0.0,"publicationDate":"2007-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ics.2007.07.049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"95587546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mental stress-induced changes in plasma serotonin, tryptophan, kynurenine concentrations in healthy participants","authors":"R. Teradaira ,&nbsp;Y. Itoh ,&nbsp;K. Kawai ,&nbsp;H. Ishikawa ,&nbsp;K. Ohashi ,&nbsp;Y. Nagamura","doi":"10.1016/j.ics.2007.07.006","DOIUrl":"10.1016/j.ics.2007.07.006","url":null,"abstract":"<div><p><span><span>In order to investigate the effect of mental stress on the tryptophan metabolism, a stress model of visual display terminals work was loaded on healthy students. Before and just after stress, plasma samples were collected and serotonin, tryptophan and </span>kynurenine were assayed. The plasma concentration of serotonin was increased by visual display terminals work. Both Trp and Kyn concentrations were decreased after stress load. These results suggest that serotonin formation from tryptophan may be accelerated, resulting in the suppressing of kynurenine metabolism from tryptophan. Furthermore, when these subjects were divided into two groups, one group of those accustomed to the personal computer and another group of those not accustomed, the changes of above amines and scores of </span>Profile of Mood States in the latter group were larger than that in the former group. These results also suggest that the activation of the person with a strong psychological load is larger than that of a weak person.</p></div>","PeriodicalId":84918,"journal":{"name":"International congress series","volume":"1304 ","pages":"Pages 175-179"},"PeriodicalIF":0.0,"publicationDate":"2007-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ics.2007.07.006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"103302146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of quinolinic acid on gene expression in human astrocytes: Implications for Alzheimer's disease","authors":"Ka Ka Ting ,&nbsp;Bruce J. Brew ,&nbsp;Gilles J. Guillemin","doi":"10.1016/j.ics.2007.07.010","DOIUrl":"10.1016/j.ics.2007.07.010","url":null,"abstract":"<div><p><span><span>Activated microglia and astrocytes play a key role in the neuroinflammatory response during </span>Alzheimer's disease (AD). The </span>kynurenine<span><span> pathway (KP) of tryptophan degradation is activated and production of the </span>excitotoxin<span> quinolinic acid<span> (QUIN) by monocytic cells is increased. We studied here the effects of QUIN in pathophysiological concentrations on the expression of genes including IL-1β, IL-6, S100β, Glutamate synthetase<span> (GS) glial fibrillary acidic protein<span> (GFAP) that are commonly associated with astrocytes in the development of neuroinflammation in AD. We found that IL-6, S100β and GS genes were constitutively expressed in human adult astrocytes (HAA) and only with TNFα, but not QUIN, IL-6 and S100β expression were increased compared with controls in HAA. IL-1β expression was increased by IFN-γ, TNFα and QUIN in HAA. These preliminary results suggest that QUIN's role in astroglial inflammatory response is mediated by increase of IL-1β expression. Therefore, QUIN is likely to play a role in astroglial inflammatory response that may contribute to the pathogenesis of AD.</span></span></span></span></span></p></div>","PeriodicalId":84918,"journal":{"name":"International congress series","volume":"1304 ","pages":"Pages 384-388"},"PeriodicalIF":0.0,"publicationDate":"2007-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ics.2007.07.010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"96479630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of increased indoleamine 2,3-dioxygenase activity exacerbates neuronal cell death in various CNS disorders","authors":"Hidetsugu Fujigaki,&nbsp;Kuniaki Saito","doi":"10.1016/j.ics.2007.07.050","DOIUrl":"10.1016/j.ics.2007.07.050","url":null,"abstract":"<div><p><span><span>Increased levels of several tryptophan metabolites have been demonstrated in various </span>neurological disorders<span> and were postulated to be secondary to induction of indoleamine 2,3-dioxygenase (IDO) and other enzymes of the </span></span><span>l</span>-tryptophan-kynurenine pathway. Previous reports have proposed that <span>l</span><span>-tryptophan metabolites (e.g., kynurenine, 3-hydroxykynurenine, quinolinic acid) may be involved in mediating neuronal damage in certain CNS disorders. On the other hand, recent studies have suggested that marked increases in IDO could suppress immune response by locally depleting </span><span>l</span><span>-tryptophan and/or accumulation of kynurenine pathway metabolites in various immune-related diseases. In fact, accumulation of kynurenine pathway metabolites in experimental autoimmune encephalomyelitis<span> has been considered to relate to the onset of symptoms; however, recent studies demonstrated that inhibition of IDO by 1-methyl-tryptophan significantly exacerbated disease scores. Furthermore, our study demonstrates that inhibition of IDO significantly exacerbated the loss of pyramidal neurons in the hippocampus<span> following transient ischemia<span>. In this review, the role of IDO and kynurenine pathway metabolites in the pathogenesis of various CNS diseases, especially both beneficial and deleterious effects, were discussed.</span></span></span></span></p></div>","PeriodicalId":84918,"journal":{"name":"International congress series","volume":"1304 ","pages":"Pages 314-323"},"PeriodicalIF":0.0,"publicationDate":"2007-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ics.2007.07.050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"103952951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tryptophan metabolism and non-hypoxic induction of hypoxia-inducible factor (HIF)","authors":"P. Fardin ,&nbsp;M.B Manzari ,&nbsp;A. Petretto ,&nbsp;A. Ricciardi ,&nbsp;L. Varesio","doi":"10.1016/j.ics.2007.07.039","DOIUrl":"10.1016/j.ics.2007.07.039","url":null,"abstract":"<div><p>We studied the response of macrophages to activation of Hypoxia inducible factor 1<span><span><span><span><span><span> pathway triggered by hypoxia<span><span> or, under normoxic conditions by Picolinic, a metabolite of tryptophan. We analyzed the expression of Glutamine: fructose-6-phosphate amidotransferase (GFAT), the rate-limiting </span>enzyme in the </span></span>hexosamine </span>biosynthetic pathway controlling </span>protein glycosylation. We obtained the first evidence that the GFAT mRNA and protein are constitutively present in mouse macrophages and we demonstrated that the expression is inducible by hypoxia and by the hypoxia-related stimuli </span>picolinic acid (PA). The promoter of GFAT contains the consensus sequence of the Hypoxia responsive element (HRE) in position −74/−65 and we studied the role of HRE on the activation of the promoter by transfecting the </span>macrophage cell lines<span><span> with appropriate expression vectors containing fragments of the GFAT promoter. We found that GFAT HRE is essential for the </span>transcriptional activation<span> by hypoxia or PA and that HIF1α can augment this response activate GFAT expression. Moreover, we demonstrated that PA is a potent inducer of HIF 1 and HIF2. Comparison of the gene expression profile induced by hypoxia or PA revealed that only a small number of genes are induced by both stimuli like GFAT, despite the activation of HIF-dependent pathways by both stimuli.</span></span></span></p></div>","PeriodicalId":84918,"journal":{"name":"International congress series","volume":"1304 ","pages":"Pages 241-249"},"PeriodicalIF":0.0,"publicationDate":"2007-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ics.2007.07.039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"99040134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phthalate esters enhance quinolinate production by inhibiting amino-carboxymuconate-semialdehyde decarboxylase (ACMSD), a key enzyme of the tryptophan-niacin pathway","authors":"K. Shibata,&nbsp;T. Fukuwatari,&nbsp;R. Sasaki","doi":"10.1016/j.ics.2007.07.018","DOIUrl":"10.1016/j.ics.2007.07.018","url":null,"abstract":"<div><p><span><span><span>We investigated the effects of dietary phthalic acid<span> diesters (PAEs) on the metabolism of Trp-niacin in rats. The administration of PAEs increased the formation of Trp metabolites beyond </span></span>QA such as </span>nicotinamide and </span><em>N</em>¹-methylnicotinamide, <em>N</em>¹-methyl-2-pyridone-5-carboxamide and <em>N</em>¹<span><span>-methyl-4-pyridone-3-carboxamide. In other words, the intake of PAEs gave the increase in the conversion ratio of Trp to niacin<span>. Then, we investigated the effects of dietary PAEs on major enzyme activities involved in the metabolism of Trp-niacin. Based on the findings that the formation of QA and its metabolites significantly increased with PAEs administration, we proposed that the activity of </span></span>ACMSD<span> (EC 4.1.1.45) would be inhibited by PAEs intake. However, we did not find that the activity decreased in the rats fed with PAEs containing diet. To assess the effects of various PAEs on the metabolites of the Trp-niacin pathway, rats were fed with a diet containing dimethylphthalate<span>, diethylphthalate, di-</span></span></span><em>n</em>-butylphthalate, di-<em>n</em>-octyl phthalate, and di-2-ethylhexylphtahlate (DEHP). The results showed that the length and structure of side chains in the esters appeared to be crucial for the formation of Trp metabolites. DEHP that has long and branched side chains was the most powerful disruptor of Trp metabolism. Because the PAE-induced effects may be due to the monoesters that are produced in the digestive organs, we also examined phthalate monoesters. Rats were fed with a diet containing mono-<em>n</em>-butylphthalate, mono-<em>n</em>-hexylphthalate, mono-2-ethylhexylphthalate (MEHP). The results were very similar to those when the diesters were used. There is the possibility that direct effect of DEHP and MEHP on the <em>in vitro</em> activity of ACMSD and QPRT were tested. Although DEHP could not be tested because of its low solubility, MEHP reversibly inhibited ACMSD. In contrast, neither QPRT was affected by any of the phthalate monoesters. Correlation between inhibition of ACMSD by PAEs with different side chains and the formation of QA supports the notion that PAEs perturb Trp metabolism by inhibiting ACMSD.</p></div>","PeriodicalId":84918,"journal":{"name":"International congress series","volume":"1304 ","pages":"Pages 184-194"},"PeriodicalIF":0.0,"publicationDate":"2007-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ics.2007.07.018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"99090757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hemin-mediated fluorometric determination of melatonin by high-performance liquid chromatography","authors":"H. Iizuka,&nbsp;K. Someya,&nbsp;T. Yajima","doi":"10.1016/j.ics.2007.07.047","DOIUrl":"10.1016/j.ics.2007.07.047","url":null,"abstract":"<div><p><span><span>A new fluorometric method for the determination of </span>melatonin<span> using a reversed-phase high-performance liquid chromatography was developed. Melatonin, by heating in the presence of hemin<span><span> and sodium percarbonate<span> at 100 °C for 15 min, gave a strong fluorescent product (Ex. 247 nm, Em. 384 nm). Employing a solid phase extraction prior to </span></span>HPLC, the level of linear range reached to between 5 to 100 pmol/l (</span></span></span><em>R</em>² <!-->=<!--> <!-->0.9906).</p></div>","PeriodicalId":84918,"journal":{"name":"International congress series","volume":"1304 ","pages":"Pages 409-414"},"PeriodicalIF":0.0,"publicationDate":"2007-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ics.2007.07.047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"110572212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential targeting of tryptophan catabolism in tumors and in tumor-draining lymph nodes by stereoisomers of the IDO inhibitor 1-methyl-tryptophan","authors":"Alexander J. Muller ,&nbsp;Richard Metz ,&nbsp;George C. Prendergast","doi":"10.1016/j.ics.2007.07.042","DOIUrl":"10.1016/j.ics.2007.07.042","url":null,"abstract":"<div><p><span><span>Increased activity of the tryptophan-catabolizing enzyme </span>indoleamine 2.3-dioxygenase (IDO), encoded by the </span><em>INDO</em><span> gene, has been associated with a broad spectrum of cancers and is implicated in the pathophysiological process of tumoral immune escape. Our interest in IDO grew out of the finding that disruption of the </span><em>Bin1</em> anti-cancer gene in oncogenically transformed mouse cells can lead to elevated interferon-γ mediated induction of <em>Indo</em><span><span><span><span> gene expression that is associated with immune escape. Using the prototypical IDO inhibitor 1-methyl-tryptophan (1MT), we demonstrated synergistic cooperativity with cytotoxic chemotherapy in an autochthonous mouse breast cancer model. Of the two </span>stereoisomers<span> of 1MT, the D isomer has been demonstrated to be a substantially less potent inhibitor of the IDO enzyme. However, in tolerogenic, IDO-expressing dendritic cells (DCs), D-1MT is as effective as L-1MT at blocking tryptophan catabolism and is actually superior at abrogating </span></span>T cell suppression. This is consistent with data obtained in two mouse breast cancer models in which IDO is predominantly expressed in DCs within the tumor-draining </span>lymph nodes. In both of these models D-1MT was more effective than L-1MT as an anti-tumor agent. We have recently discovered that a previously undocumented, IDO-related enzyme, referred to here as IDO2, is preferentially inhibited by D-1MT. The relative importance of targeting IDO versus IDO2 with inhibitory compounds and the possibility of cross-talk between these two enzymes is currently being evaluated.</span></p></div>","PeriodicalId":84918,"journal":{"name":"International congress series","volume":"1304 ","pages":"Pages 250-261"},"PeriodicalIF":0.0,"publicationDate":"2007-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ics.2007.07.042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"102321788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of Huntington's disease transgenic mice based on “Quinolinate Hypothesis”","authors":"T. Imai ,&nbsp;K. Kobayashi ,&nbsp;Y. Arii ,&nbsp;E. Sugimoto ,&nbsp;A. Okuno ,&nbsp;K. Shibata ,&nbsp;S.-I. Fukuoka","doi":"10.1016/j.ics.2007.07.025","DOIUrl":"10.1016/j.ics.2007.07.025","url":null,"abstract":"<div><p>Enzymes<span><span> related to quinolinate metabolism in the brain of </span>Huntington's disease<span> transgenic mice were investigated. Elevated levels of quinolinate were suggested in the diseased brains, supporting quinolinate hypothesis.</span></span></p></div>","PeriodicalId":84918,"journal":{"name":"International congress series","volume":"1304 ","pages":"Pages 377-379"},"PeriodicalIF":0.0,"publicationDate":"2007-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ics.2007.07.025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"96116431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mass spectrometric detection of quinolinic acid in microdissected Alzheimer's disease plaques","authors":"Gilles J. Guillemin ,&nbsp;Bruce J. Brew ,&nbsp;Claire E. Noonan ,&nbsp;Toby G. Knight ,&nbsp;George A. Smythe ,&nbsp;Karen M. Cullen","doi":"10.1016/j.ics.2007.07.012","DOIUrl":"10.1016/j.ics.2007.07.012","url":null,"abstract":"<div><p><span><span><span>Inflammation, chiefly in the form of activated microglia, is a feature of </span>Alzheimer's disease (AD) pathology. The </span>kynurenine<span><span><span> pathway of tryptophan degradation is activated in inflammation. One of the end products of the pathway, </span>quinolinic acid<span><span> (QUIN), is a potent excitotoxin and is produced by macrophages and microglia. In our study of AD post-mortem </span>brain tissue, we investigated the presence of QUIN in plaques. We used QUIN </span></span>immunohistochemistry<span> in 45-μm sections of AD and control brain tissue. Then, to confirm the immunohistochemical findings, plaques were isolated using laser capture microdissection<span> and analysed for QUIN using mass spectroscopy. In AD tissue, QUIN-immunoreactivity was detected in cortical microglia, astrocytes and neurons, with microglial and astrocytic expression of QUIN highest in the perimeter of </span></span></span></span>senile plaques<span><span>. Whole brain extracts of AD have not previously shown a significant up-regulation of QUIN, however, the lesions of AD are microlocal and evolve over time. To confirm the presence of QUIN in senile plaques and provide some quantitative estimates, we microdissected lesions from AD hippocampus<span> using light microscopy and laser capture and then used gas chromatography-mass spectroscopy for QUIN. QUIN was enriched in plaques but was not detected in periplaque regions or in control brain tissue free from plaques. These results provide a platform on which to assay the evolving presence of QUIN in the plaque. Our data show that QUIN is a candidate factor in the complex and multi-factorial cascade of AD </span></span>neurodegeneration. Tempering the action of this excitotoxin with kynurenine pathway inhibitors may open a therapeutic door for patients in active stages of the disease.</span></p></div>","PeriodicalId":84918,"journal":{"name":"International congress series","volume":"1304 ","pages":"Pages 404-408"},"PeriodicalIF":0.0,"publicationDate":"2007-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ics.2007.07.012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"97685124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}