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Marcele F Bastos, Ana Carolina A V Kayano, João Luiz Silva-Filho, João Conrado K Dos-Santos, Carla Judice, Yara C Blanco, Nathaniel Shryock, Michelle K Sercundes, Luana S Ortolan, Carolina Francelin, Juliana A Leite, Rafaella Oliveira, Rosa M Elias, Niels O S Câmara, Stefanie C P Lopes, Letusa Albrecht, Alessandro S Farias, Cristina P Vicente, Claudio C Werneck, Selma Giorgio, Liana Verinaud, Sabrina Epiphanio, Claudio R F Marinho, Pritesh Lalwani, Rogerio Amino, Julio Aliberti, Fabio T M Costa
Cerebral malaria (CM) is a multifactorial syndrome involving an exacerbated proinflammatory status, endothelial cell activation, coagulopathy, hypoxia, and accumulation of leukocytes and parasites in the brain microvasculature. Despite significant improvements in malaria control, 15% of mortality is still observed in CM cases, and 25% of survivors develop neurologic sequelae for life-even after appropriate antimalarial therapy. A treatment that ameliorates CM clinical signs, resulting in complete healing, is urgently needed...
March 20, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Stacy A Voils, Mohamed H Shahin, Timothy J Garrett, Reginald F Frye
OBJECTIVE: Incidence of venous thromboembolism (VTE) in critically ill patients remains unacceptably high despite widespread use of thromboprophylaxis. A systems biology approach may be useful in understanding disease pathology and predicting response to treatment. Metabolite profile under specific environmental conditions provides the closest link to phenotype, but the relationship between metabolomics and risk of VTE in critically ill patients is unknown. In this study, metabolomics signatures are compared in patients with and without VTE...
March 8, 2018: Thrombosis Research
Gayan S Jayawickrama, Alireza Nematollahi, Guanchen Sun, W Bret Church
Kynurenine aminotransferase-II (KAT-II) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that acts in the tryptophan metabolic pathway by catalyzing the transamination of kynurenine into kynurenic acid (KYNA). It is one of four isoforms in the KAT family, of which it is the primary homologue responsible for KYNA production in the mammalian brain. KAT-II is targeted for inhibition as KYNA is implicated in diseases such as schizophrenia, where it is found in elevated concentrations. Previously, many different approaches have been taken to develop KAT-II inhibitors, and herein fragment-based drug design (FBDD) approaches have been exploited to provide further lead compounds that can be designed into novel inhibitors...
March 1, 2018: SLAS Discovery
Yuying Liu, Xiaoyu Liang, Wenqian Dong, Yi Fang, Jiadi Lv, Tianzhen Zhang, Roland Fiskesund, Jing Xie, Jinyan Liu, Xiaonan Yin, Xun Jin, Degao Chen, Ke Tang, Jingwei Ma, Huafeng Zhang, Jing Yu, Jun Yan, Huaping Liang, Siqi Mo, Feiran Cheng, Yabo Zhou, Haizeng Zhang, Jing Wang, Jingnan Li, Yang Chen, Bing Cui, Zhuo-Wei Hu, Xuetao Cao, F Xiao-Feng Qin, Bo Huang
Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8+ T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8+ T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8+ T cells via the transporters SLC7A8 and PAT4...
March 12, 2018: Cancer Cell
Peter Hertelendy, Jozsef Toldi, Ferenc Fulop, Laszlo Vecsei
Ischemic stroke is one of the leading causes of mortality and permanent disability in developed countries. Stroke induces massive glutamate release, which in turn causes N-Methyl-D-aspartate (NMDA) receptor over-excitation and thus calcium overload in neurons leading to cell death via apoptotic cascades. The kynurenine pathway is a complex enzymatic cascade of tryptophan catabolism, generating various neuroactive metabolites. One metabolite, kynurenic acid (KYNA), is a potent endogenous NMDA glutamate receptor antagonist, making it a possible therapeutic tool to decrease excitotoxicity and neuroinflammation...
March 12, 2018: Current Medicinal Chemistry
Micah T Nelp, Patrick A Kates, John T Hunt, John A Newitt, Aaron Balog, Derrick Maley, Xiao Zhu, Lynn Abell, Alban Allentoff, Robert Borzilleri, Hal A Lewis, Zeyu Lin, Steven P Seitz, Chunhong Yan, John T Groves
For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N -formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Johanna M Gostner, Eva Obermayr, Ioana E Braicu, Nicole Concin, Sven Mahner, Adriaan Vanderstichele, Jalid Sehouli, Ignace Vergote, Dietmar Fuchs, Robert Zeillinger
OBJECTIVE: Circulating tumor cells (CTCs) may represent a chronic stimulus for the immune system. In the present study we investigated the potential association of CTCs, the immune activation marker neopterin, and the ratio of kynurenine to tryptophan (Kyn/Trp) as a measure for tryptophan breakdown. METHODS: Neopterin, tryptophan and kynurenine levels were measured in plasma samples from patients with benign gynecological diseases (n=65) and with primary advanced epithelial ovarian cancer (EOC) at diagnosis (n=216) and six months after adjuvant platinum-based chemotherapy (n=45) by an enzyme-linked immunosorbent assay and high performance liquid chromatography...
March 9, 2018: Gynecologic Oncology
Buranee Kanchanatawan, Sira Sriswasdi, Supaksorn Thika, Sunee Sirivichayakul, André F Carvalho, Michel Geffard, Marta Kubera, Michael Maes
Deficit schizophrenia is characterized by neurocognitive impairments and changes in the patterning of IgA/IgM responses to plasma tryptophan catabolites (TRYCATs). In the current study, supervised pattern recognition methods, including logistic regression analysis (LRA), Support Vector Machine (SVM), and Soft Independent Modeling of Class Analogy (SIMCA), were used to examine whether deficit schizophrenia is a discrete diagnostic class with respect to Consortium To Establish a Registry for Alzheimer's disease (CERAD) and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests and IgA/IgM responses to noxious (NOX) and generally more protective (PRO) TRYCATs...
March 11, 2018: Metabolic Brain Disease
Trevor W Stone, Megan McPherson, L Gail Darlington
Existing explanations of obesity-associated cancer emphasise direct mutagenic effects of dietary components or hormonal imbalance. Some of these hypotheses are reviewed briefly, but recent evidence suggests a major role for chronic inflammation in cancer risk, possibly involving dietary content. These ideas include the inflammation-induced activation of the kynurenine pathway and its role in feeding and metabolism by activation of the aryl hydrocarbon receptor (AHR) and by modulating synaptic transmission in the brain...
February 27, 2018: EBioMedicine
N J C Stapelberg, R Pratt, D L Neumann, D H K Shum, S Brandis, V Muthukkumarasamy, B Stantic, M Blumenstein, J P Headrick
BACKGROUND: Biological pathways underlying major depressive disorder (MDD) can be viewed as systems biology networks. The psycho-immune-neuroendocrine (PINE) network comprises central nervous, immune, endocrine and autonomic systems, integrating biological mechanisms of MDD. Such networks exhibit recurrent motifs with specific functions, including positive and negative feedback loops, and are subject to critical transitions, influenced by feedback loop transitions (FLTs). AIMS: We aim to identify critical feedback loops and their FLTs, as well sentinel network nodes (SNNs), key network nodes that drive FLTs, within the PINE network...
March 7, 2018: Neuroscience and Biobehavioral Reviews
Travis M Bettison, Christopher B Nahm, Anthony J Gill, Anubhav Mittal, Gin S Malhi, Jaswinder S Samra
BACKGROUND: Psychological distress is highly prevalent in patients with pancreatic cancer (PC), yet little is known about the pathophysiology underlying the relationship between these 2 diseases. Our aim was to systematically review the evidence examining the pathophysiological mechanisms of the association between PC and psychological distress. METHODS: A systematic review of the literature was conducted using MEDLINE, Embase, PsychINFO, and CINAHL databases and reported according to the preferred reporting items for systematic reviews and meta-analyses guidelines...
April 2018: Pancreas
Carlos R Dostal, Megan Carson Sulzer, Keith W Kelley, Gregory G Freund, Robert H McCusker
Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis and immune system eliciting changes in cognitive function, mood and anxiety. An important link between stress and altered behavior is stimulation of the Kynurenine Pathway which generates neuroactive and immunomodulatory kynurenines. Tryptophan entry into this pathway is controlled by rate-limiting indoleamine/tryptophan 2,3-dioxygenases (DOs: Ido1, Ido2, Tdo2). Although implicated as mediating changes in behavior, detecting stress-induced DO expression has proven inconsistent...
December 2017: Neurobiology of Stress
Joshua Chiappelli, Francesca M Notarangelo, Ana Pocivavsek, Marian A R Thomas, Laura M Rowland, Robert Schwarcz, L Elliot Hong
Abnormalities in the kynurenine pathway (KP) of tryptophan degradation, leading to the dysfunction of neuroactive KP metabolites in the brain, have been implicated in the pathophysiology of schizophrenia (SZ). One plausible mechanism involves dysregulation of various pro-inflammatory cytokines associated with the disease, which affect indoleamine-2,3-dioxygenase (IDO), a key enzyme for tryptophan to kynurenine conversion. In order to test this hypothesis directly, we measured plasma levels of the major KP metabolites kynurenine and kynurenic acid (KYNA), as well as four major cytokines, in a sample of 106 SZ patients and 104 control participants...
February 27, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Sudeep Chenna Narendra, Jaya Prakash Chalise, Sophie Biggs, Ulrich Kalinke, Mattias Magnusson
Objective: CD4+ FoxP3+ CD25+ regulatory T-cells (Tregs ) are important for preventing tissue destruction. Here, we investigate the role of Tregs for protection against experimental arthritis by IFN-α. Methods: Arthritis was triggered by intra-articular injection of methylated bovine serum albumin (mBSA) in wild-type mice, Foxp3DTReGFP+/- mice [allowing selective depletion of Tregs by diphtheria toxin (DT)] and CD4-Cre+/- IFNA1R flox/flox mice (devoid of IFNAR signaling in T-cells) earlier immunized with mBSA, with or without treatment with IFN-α or the indoleamine 2,3-dioxygenase (IDO)-metabolite kynurenine...
2018: Frontiers in Immunology
Fabio Marino
Mass spectrometry (MS)-based immunopeptidomics has developed as one of the leading methodologies for comprehensive characterization of in vivo presented Human Leukocyte Antigen (HLA)-bound peptides. Unveiling the identity of HLA-bound peptides derived from diseased cells is crucial to gain knowledge on the constitution of efficient disease-specific T cell responses. The HLA-presented peptidome reflects the status of the cellular proteome, hence disease-related aberrations of post-translational modifications (PTMs) might lead to presentation of peptides harboring PTMs...
March 7, 2018: Proteomics
Jan Hoffmann, Andrew Charles
There is substantial evidence indicating a role for glutamate in migraine. Levels of glutamate are higher in the brain and possibly also in the peripheral circulation in migraine patients, particularly during attacks. Altered blood levels of kynurenines, endogenous modulators of glutamate receptors, have been reported in migraine patients. Population genetic studies implicate genes that are involved with glutamate signaling in migraine, and gene mutations responsible for familial hemiplegic migraine and other familial migraine syndromes may influence glutamate signaling...
March 5, 2018: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Angelo Zinellu, Alessandro Giuseppe Fois, Elisabetta Zinellu, Elisabetta Sotgiu, Salvatore Sotgia, Dionigia Arru, Arduino A Mangoni, Ciriaco Carru, Pietro Pirina
AIM: Since an increase in kynurenine (Kyn) plasma concentrations has been proposed as marker of immune system activation, we studied the associations between the Kyn levels and presence and severity of chronic obstructive pulmonary disease (COPD). METHODS & RESULTS: Plasma Kyn, tryptophan (Trp) and Kyn/Trp ratio were measured in 43 COPD patients with clinically defined mild (n = 29) or moderate (n = 14) disease and 43 age- and sex-matched healthy controls...
March 6, 2018: Biomarkers in Medicine
Aaron T Wecksler, Jian Yin, Paula Lee Tao, Bruce Kabakoff, Alavattam Sreedhara, Galahad Deperalta
Photostability conditions as prescribed by ICH guidelines induced highly reduction-resistant scrambled disulfides that contribute to the population of apparent non-reducible aggregates induced by excessive light exposure. Photo-induced cross-linked species were isolated under reducing conditions using an organic phase size exclusion chromatography (SEC) method, followed by O18-labeling tryptic mapping to identify cross-linked peptides. Disulfide scrambling was observed within the IgG1 structurally conserved, intrachain cysteine-cysteine-tryptophan triads (Cys-Cys-Trp), and correlated with Trp-to-Kynurenine (Kyn) photo-degradation within these triads...
March 5, 2018: Molecular Pharmaceutics
Ying Xue, Han Xiao, Songhe Guo, Banglao Xu, Yuehua Liao, Yixian Wu, Ge Zhang
Fusobacterium nucleatum (Fn) is a tumor-associated obligate anaerobic bacterium, which has a role in the progression of colorectal cancer (CRC). Fn can invade and promote colon epithelial cells proliferation. However, how Fn survives and proliferates in its host cells remains largely unknown. In this study, we aimed to determine the molecular mechanisms underlying the morphology, survival, and proliferation of Fn in THP-1-derived macrophages (dTHP1). For the first time, we found that Fn is a facultative intracellular bacterium that can survive and limited proliferate in dTHP1 cells up to 72 h, and a live Fn infection can inhibit apoptosis of dTHP1 cells by activating the PI3K and ERK pathways...
March 2, 2018: Cell Death & Disease
Luke Carroll, David I Pattison, Justin B Davies, Robert F Anderson, Camilo Lopez-Alarcon, Michael J Davies
Oxidative damage is a common process in many biological systems and proteins are major targets for damage due to their high abundance and very high rate constants for reaction with many oxidants (both radicals and two-electron species). Tryptophan (Trp) residues on peptides and proteins are a major sink for a large range of biological oxidants as these side-chains have low radical reduction potentials. The resulting Trp-derived indolyl radicals (Trp● ) have long lifetimes in some circumstances due to their delocalized structures, and undergo only slow reaction with molecular oxygen, unlike most other biological radicals...
February 26, 2018: Free Radical Biology & Medicine
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