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Kynurenin

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https://www.readbyqxmd.com/read/28336141/the-discovery-of-potent-and-selective-kynurenine-3-monooxygenase-inhibitors-for-the-treatment-of-acute-pancreatitis
#1
John Liddle, Benjamin Beaufils, Margaret Binnie, Anne Bouillot, Alexis A Denis, Michael M Hann, Carl P Haslam, Duncan S Holmes, Jon P Hutchinson, Michael Kranz, Andrew McBride, Olivier Mirguet, Damian J Mole, Christopher G Mowat, Sandeep Pal, Paul Rowland, Lionel Trottet, Iain J Uings, Ann L Walker, Scott P Webster
A series of potent, competitive and highly selective kynurenine monooxygenase inhibitors have been discovered via a substrate-based approach for the treatment of acute pancreatitis. The lead compound demonstrated good cellular potency and clear pharmacodynamic activity in vivo.
March 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28329310/immunologic-pathways-that-predict-mortality-in-hiv-infected-ugandans-initiating-art
#2
Sulggi Lee, Helen Byakwaga, Yap Boum, Tricia H Burdo, Kenneth C Williams, Michael M Lederman, Yong Huang, Russell P Tracy, Huyen Cao, Jessica E Haberer, Annet Kembabazi, David R Bangsberg, Jeffrey N Martin, Peter W Hunt
Plasma kynurenine/tryptophan (KT) ratio, a marker of adaptive immune defects, strongly predicts mortality during treated HIV disease in Ugandans compared to U.S.-based populations, Here, KT ratio, and T cell and plasma biomarkers of immune activation were measured among 535 HIV-infected Ugandans prior to ART initiation and at month 6 of viral suppression. Month 6 KT ratio (aHR=2.74), sCD14 (aHR=2.32), IL-6 (aHR=2.34), and D dimer (aHR=1.95) were associated with mortality occurring ≥6 months after ART initiation, KT ratio remained significantly predictive of mortality even after adjustment for the additional biomarkers, suggesting an independent contribution to clinical outcomes in resource-limited settings...
March 1, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28325761/the-aryl-hydrocarbon-receptor-governs-epithelial-cell-invasion-during-oropharyngeal-candidiasis
#3
Norma V Solis, Marc Swidergall, Vincent M Bruno, Sarah L Gaffen, Scott G Filler
Oropharyngeal candidiasis (OPC), caused predominantly by Candida albicans, is a prevalent infection in patients with advanced AIDS, defects in Th17 immunity, and head and neck cancer. A characteristic feature of OPC is fungal invasion of the oral epithelial cells. One mechanism by which C. albicans hyphae can invade oral epithelial cells is by expressing the Als3 and Ssa1 invasins that interact with the epidermal growth factor receptor (EGFR) on epithelial cells and stimulate endocytosis of the organism. However, the signaling pathways that function downstream of EGFR and mediate C...
March 21, 2017: MBio
https://www.readbyqxmd.com/read/28320838/early-immune-regulatory-changes-in-a-primary-controlled-human-plasmodium-vivax-infection-cd1c-mdc-maturation-arrest-induction-of-the-kynurenine-pathway-and-regulatory-t-cell-activation
#4
Tonia Woodberry, Jessica R Loughland, Gabriela Minigo, Julie G Burel, Fiona H Amante, Kim A Piera, Yvette McNeil, Tsin W Yeo, Michael F Good, Denise L Doolan, Christian R Engwerda, James S McCarthy, Nicholas M Anstey
Plasmodium vivax malaria remains a major public health problem. The requirements for acquisition of protective immunity to this species are not clear. Dendritic cells (DC) are essential for immune cell priming, but also perform immune-regulatory functions, along with regulatory T cells (Treg). An important function of DC involves activation of the kynurenine pathway via indoleamine 2,3-dioxygenase (IDO). Using a controlled human experimental infection study with blood-stage P. vivax, we characterised plasmacytoid DC (pDC) and myeloid DC (mDC) subset maturation, CD4(+)CD25(+)CD127(lo) Treg activation and IDO activity...
March 20, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28319697/genetic-variants-of-the-kynurenine-3-monooxygenase-and-postpartum-depressive-symptoms-after-cesarean-section-in-chinese-women
#5
Sai-Ying Wang, Kai-Ming Duan, Xiao-Fang Tan, Ji-Ye Yin, Xiao-Yuan Mao, Wei Zheng, Chun-Yan Wang, Mi Yang, Cheng Peng, Hong-Hao Zhou, Zhao-Qian Liu
BACKGROUND: New conceptualizations of depression have emphasized the role of the kynurenine pathway (KP) in the pathogenesis of postpartum depressive symptoms (PDS). Kynurenine 3-monooxygenase (KMO) is a rate-limiting enzyme of the KP, where it catalyzes the conversion of kynurenine (KYN) to 3-hydroxykynurenine (3-HK). Previous work indicates that KMO is closely linked to the pathophysiology of depressive disorders. The purpose of this study is to investigate whether variations in the KMO gene affect PDS development after cesarean section...
March 10, 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/28314892/abnormal-kynurenine-pathway-of-tryptophan-catabolism-in-cardiovascular-diseases
#6
REVIEW
Ping Song, Tharmarajan Ramprasath, Huan Wang, Ming-Hui Zou
Kynurenine pathway (KP) is the primary path of tryptophan (Trp) catabolism in most mammalian cells. The KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and 3-hydroxyanthranilic acid (3-HAA). Increased catabolite concentrations in serum are associated with several cardiovascular diseases (CVD), including heart disease, atherosclerosis, and endothelial dysfunction, as well as their risk factors, including hypertension, diabetes, obesity, and aging...
March 17, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28303855/expression-and-prognostic-value-of-indoleamine-2-3-dioxygenase-in-pancreatic-cancer
#7
Tao Zhang, Xiang-Long Tan, Yong Xu, Zi-Zheng Wang, Chao-Hui Xiao, Rong Liu
BACKGROUND: Indoleamine 2,3-dioxygenase (IDO), an enzyme for tryptophan metabolism through the kynurenine pathway, exhibits an immunosuppressive effect and induces immune tolerance in tumor cells. The effects of IDO on pancreatic cancer are poorly understood. This study aimed to investigate the expression and prognostic significance of IDO in pancreatic cancer. METHODS: We evaluated the protein expression of IDO in PANC-1, CFPAC-1, and BxPC-3 cell lines with or without 48 h treatment by 500 U/ml interferon-γ (IFN-γ)...
March 20, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28302400/substrate-and-inhibitor-specificity-of-kynurenine-monooxygenase-from-cytophaga-hutchinsonii
#8
Robert S Phillips, Andrew D Anderson, Harvey G Gentry, Osman F Güner, J Phillip Bowen
Kynurenine monooxygenase (KMO) is a potential drug target for treatment of neurodegenerative disorders such as Huntington's and Alzheimer's diseases. We have evaluated substituted kynurenines as substrates or inhibitors of KMO from Cytophaga hutchinsonii. Kynurenines substituted with a halogen at the 5-position are excellent substrates, with values of kcat and kcat/Km comparable to or higher than kynurenine. However, kynurenines substituted in the 3-position are competitive inhibitors, with KI values lower than the Km for kynurenine...
March 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28290151/deficit-schizophrenia-is-characterized-by-defects-in-igm-mediated-responses-to-tryptophan-catabolites-trycats-a-paradigm-shift-towards-defects-in-natural-self-regulatory-immune-responses-coupled-with-mucosa-derived-trycat-pathway-activation
#9
Buranee Kanchanatawan, Sunee Sirivichayakul, Kiat Ruxrungtham, André F Carvalho, Michel Geffard, George Anderson, Michael Maes
Deficit schizophrenia is accompanied by mucosa-associated activation of the tryptophan catabolite (TRYCAT) pathway, as indicated by increased IgA responses to noxious (NOX) TRYCATs, but not regulatory or protective (PRO) TRYCATs, suggesting increased neurotoxic, excitotoxic, inflammatory, and oxidative potential. No previous studies examined IgM-mediated autoimmune responses to the TRYCAT pathway in deficit versus nondeficit schizophrenia. We measured IgM responses to NOX TRYCATs, namely, quinolinic acid (QA), 3-OH-kynurenine (3HK), picolinic acid (PA), and xanthurenic (XA) acid, and PRO TRYCATs, including kynurenic acid (KA) and anthranilic acid (AA), in 40 healthy controls and 40 deficit and 40 nondeficit schizophrenic patients...
March 14, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28285566/involvement-of-the-cytokine-ido1-ahr-loop-in-zinc-oxide-nanoparticle-induced-acute-pulmonary-inflammation
#10
Chia-Chi Ho, Hui-Ling Lee, Chao-Yu Chen, Yueh-Hsia Luo, Ming-Hsien Tsai, Hui-Ti Tsai, Pinpin Lin
Zinc oxide nanoparticles (ZnONPs) are widely used in our daily life, such as in sunscreens and electronic nanodevices. However, pulmonary exposure to ZnONPs causes acute pulmonary inflammation, which is considered as an initial event for various respiratory diseases. Thus, elucidation of the underlying cellular mechanisms of ZnONPs can help us in predicting their potential effects in respiratory diseases. In this study, we observed that ZnONPs increased proinflammatory cytokines, accompanied with an increased expression of aryl hydrocarbon receptor (AhR) and its downstream target cytochrome P450 1A1 (CYP1A1) in macrophages in vitro and in mouse lung epithelia in vivo...
March 13, 2017: Nanotoxicology
https://www.readbyqxmd.com/read/28285360/kynurenic-acid-downregulates-il-17-1l-23-axis-in-vitro
#11
Sanam Salimi Elizei, Malihe-Sadat Poormasjedi-Meibod, Xia Wang, Maryam Kheirandish, Aziz Ghahary
Exploring the function of interleukin (IL) 17 and related cytokine interactions have been proven useful toward understanding the role of inflammation in autoimmune diseases. Production of the inflammatory cytokine IL-23 by dendritic cells (DC's) has been shown to promote IL-17 expression by Th17 cells. It is well established that Th17 cells play an important role in several autoimmune diseases including psoriasis and alopecia. Our recent investigations have suggested that Kynurenine-rich environment can shift a pro-inflammatory response to an anti-inflammatory response, as is the case in the presence of the enzyme Indoleamine 2,3 dioxygenase (IDO), the rate-limiting enzyme in tryptophan degradation and Kynurenine (Kyn) production...
March 11, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28284335/oxidative-modifications-of-blood-serum-proteins-in-myasthenia-gravis
#12
Monika Adamczyk-Sowa, Edyta Bieszczad-Bedrejczuk, Sabina Galiniak, Izabela Rozmiłowska, Damian Czyżewski, Grzegorz Bartosz, Izabela Sadowska-Bartosz
Myasthenia gravis (MG) is an autoimmune disease caused by production of antibodies against acetylcholine receptors of the neuromuscular junction (Ab). The aim of this study was to ascertain if oxidative stress accompanies MG by estimation of the several independent parameters of oxidative damage, mainly the levels of oxidative modifications of blood serum proteins. The group studied consisted of 50 MG patients (28 females and 22 males), 24 with ocular MG (OMG) and 26 with generalized MG (GMG), of mean age of 66...
April 15, 2017: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/28275903/correlations-of-kynurenic-acid-3-hydroxykynurenine-sil-2r-ifn-%C3%AE-and-il-4-with-clinical-symptoms-during-acute-relapse-of-schizophrenia
#13
Kinga Szymona, Barbara Zdzisińska, Hanna Karakuła-Juchnowicz, Tomasz Kocki, Martyna Kandefer-Szerszeń, Marta Flis, Wojciech Rosa, Ewa M Urbańska
Several lines of evidence suggest that up-regulation of immune response and alterations of kynurenine pathway function are involved in pathogenesis of schizophrenia. Correlations among clinical status (using PANNS, SANS and SAPS scales) and blood levels of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and levels of selected immunoactive molecules, soluble interleukin-2 receptor (sIL-2R), interferon-α (IFN-α) and IL-4 were analyzed in 51 chronic schizophrenia patients during acute relapse, after four weeks of therapy and at remission...
March 8, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28266612/microbiota-alteration-is-associated-with-the-development-of-stress-induced-despair-behavior
#14
Ioana A Marin, Jennifer E Goertz, Tiantian Ren, Stephen S Rich, Suna Onengut-Gumuscu, Emily Farber, Martin Wu, Christopher C Overall, Jonathan Kipnis, Alban Gaultier
Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. Here, we employed a combination of behavioral, molecular and computational techniques to test the role of the microbiota in mediating despair behavior. In chronically stressed mice displaying despair behavior, we found that the microbiota composition and the metabolic signature dramatically change. Specifically, we observed reduced Lactobacillus and increased circulating kynurenine levels as the most prominent changes in stressed mice...
March 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28262996/relationships-between-body-temperatures-and-inflammation-indicators-under-physiological-and-pathophysiological-conditions-in-pigs-exposed-to-systemic-lipopolysaccharide-and-dietary-deoxynivalenol
#15
T Tesch, E Bannert, J Kluess, J Frahm, L Hüther, S Kersten, G Breves, L Renner, S Kahlert, H-J Rothkötter, S Dänicke
We studied the constancy of the relationship between rectal and intraabdominal temperature as well as their linkage to inflammatory markers (leucocyte counts, kynurenine-to-tryptophan ratio (Kyn-Trp ratio), tumour necrosis factor alpha (TNF-α) in healthy and in pigs exposed to lipopolysaccharide (LPS) and/or deoxynivalenol (DON). Barrows (n = 44) were fed 4 weeks either a DON-contaminated (4.59 mg DON/kg feed) or a control (CON) diet and equipped with an intraabdominal temperature logger and a multicatheter system (V...
March 6, 2017: Journal of Animal Physiology and Animal Nutrition
https://www.readbyqxmd.com/read/28258445/physio-somatic-symptoms-in-schizophrenia-association-with-depression-anxiety-neurocognitive-deficits-and-the-tryptophan-catabolite-pathway
#16
Buranee Kanchanatawan, Sunee Sirivichayakul, Supaksorn Thika, Kiat Ruxrungtham, André F Carvalho, Michel Geffard, George Anderson, Cristiano Noto, Rada Ivanova, Michael Maes
To investigate the frequency of physio-somatic symptoms (PS) symptoms in schizophrenia and their relation to positive, negative and affective symptoms; neurocognitive deficits and impairments in the tryptophan catabolite (TRYCAT) pathway. Eighty four patients with schizophrenia and 40 healthy controls were assessed using the 12 item Fibromyalgia and Chronic Fatigue Syndrome Rating scale (FF) and scales for negative and positive symptoms, depression and anxiety. Cognitive functioning was tested using the Cambridge Neuropsychological Test Automated Battery (CANTAB)...
March 3, 2017: Metabolic Brain Disease
https://www.readbyqxmd.com/read/28250737/kynurenine-pathway-metabolism-and-neuroinflammatory-disease
#17
REVIEW
Nady Braidy, Ross Grant
Immune-mediated activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP) is a consistent finding in all inflammatory disorders. Several studies by our group and others have examined the neurotoxic potential of neuroreactive TRYP metabolites, including quinolinic acid (QUIN) in neuroinflammatory neurological disorders, including Alzheimer's disease (AD), multiple sclerosis, amylotropic lateral sclerosis (ALS), and AIDS related dementia complex (ADC). Our current work aims to determine whether there is any benefit to the affected individuals in enhancing the catabolism of TRYP via the KP during an immune response...
January 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28245765/kynurenines-and-pacap-in-migraine-medicinal-chemistry-and-pathogenetic-aspects
#18
János Tajti, Délia Szok, Gábor Nagy-Grócz, Bernadett Tuka, Anna Petrovics-Balog, József Toldi, László Vécsei
BACKGROUND: Migraine is a highly disabling neurovascular primary headache disorder, with its exact pathomechanism being still unrevealed. The current leading hypotheses are based on the sensitization and activation of the trigeminovascular system. OBJECTIVE: To review the literature with focus on the effects of kynurenines (L-kynurenine and kynurenic acid) and pituitary adenylate cyclase-activating polypeptide on the regulation of the trigeminovascular system. METHOD: A literature search was conducted to identify preclinical and clinical publications (198 references) by using the keywords 'kynurenines', 'pituitary adenylate cyclase-activating polypeptide', and 'migraine' in the database of MEDLINE/PubMed up to 10 September 2016for topical review...
February 27, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28243208/high-kynurenine-a-tryptophan-metabolite-predicts-remission-in-patients-with-major-depression-to-add-on-treatment-with-celecoxib
#19
Daniela Krause, Aye-Mu Myint, Christine Schuett, Richard Musil, Sandra Dehning, Anja Cerovecki, Michael Riedel, Volker Arolt, Markus J Schwarz, Norbert Müller
BACKGROUND: Signs of an inflammatory process have been described in major depression. METHODS: In a double-blind, randomized study of celecoxib or placebo add-on to reboxetine in 40 depressed patients, celecoxib treatment has beneficial effects. In order to evaluate the tryptophan/kynurenine metabolism and to identify predictors for remission, tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN) were estimated in the serum of 32 patients before and after treatment and in a group of 20 healthy controls...
2017: Frontiers in Psychiatry
https://www.readbyqxmd.com/read/28241062/increased-breakdown-of-kynurenine-towards-its-neurotoxic-branch-in-bipolar-disorder
#20
Armin Birner, Martina Platzer, Susanne Astrid Bengesser, Nina Dalkner, Frederike T Fellendorf, Robert Queissner, Rene Pilz, Philipp Rauch, Alexander Maget, Carlo Hamm, Simone Herzog-Eberhard, Harald Mangge, Dietmar Fuchs, Natalie Moll, Sieglinde Zelzer, Gregor Schütze, Markus Schwarz, Bernd Reininghaus, Hans-Peter Kapfhammer, Eva Z Reininghaus
INTRODUCTION: Bipolar disorder (BD) is a chronic psychiatric disease which can take most different and unpredictable courses. It is accompanied by unspecific brainstructural changes and cognitive decline. The neurobiological underpinnings of these processes are still unclear. Emerging evidence suggests that tryptophan catabolites (TRYCATs), which involve all metabolites of tryptophan towards the kynurenine (KYN) branch, are involved in the etiology as well as in the course of BD. They are proposed to be mediators of immune-inflammation and neurodegeneration...
2017: PloS One
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