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https://www.readbyqxmd.com/read/28223071/therapeutic-antibody-targeting-of-indoleamine-2-3-dioxygenase-ido2-inhibits-autoimmune-arthritis
#1
Lauren M F Merlo, Samantha Grabler, James B DuHadaway, Elizabeth Pigott, Kaylend Manley, George C Prendergast, Lisa D Laury-Kleintop, Laura Mandik-Nayak
Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease with no known cure. Recently, we identified the immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2) as an essential mediator of autoreactive B and T cell responses driving RA. However, therapeutically targeting IDO2 has been challenging given the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1. In this study, we develop a novel monoclonal antibody (mAb)-based approach to therapeutically target IDO2...
February 18, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28214225/a-relay-pathway-between-arginine-and-tryptophan-metabolism-confers-immunosuppressive-properties-on-dendritic-cells
#2
Giada Mondanelli, Roberta Bianchi, Maria Teresa Pallotta, Ciriana Orabona, Elisa Albini, Alberta Iacono, Maria Laura Belladonna, Carmine Vacca, Francesca Fallarino, Antonio Macchiarulo, Stefano Ugel, Vincenzo Bronte, Federica Gevi, Lello Zolla, Auke Verhaar, Maikel Peppelenbosch, Emilia Maria Cristina Mazza, Silvio Bicciato, Yasmina Laouar, Laura Santambrogio, Paolo Puccetti, Claudia Volpi, Ursula Grohmann
Arginase 1 (Arg1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunoregulatory enzymes catalyzing the degradation of l-arginine and l-tryptophan, respectively, resulting in local amino acid deprivation. In addition, unlike Arg1, IDO1 is also endowed with non-enzymatic signaling activity in dendritic cells (DCs). Despite considerable knowledge of their individual biology, no integrated functions of Arg1 and IDO1 have been reported yet. We found that IDO1 phosphorylation and consequent activation of IDO1 signaling in DCs was strictly dependent on prior expression of Arg1 and Arg1-dependent production of polyamines...
February 13, 2017: Immunity
https://www.readbyqxmd.com/read/28212884/desipramine-decreases-expression-of-human-and-murine-indoleamine-2-3-dioxygenases
#3
Alexandra K Brooks, Tiffany M Janda, Marcus A Lawson, Jennifer L Rytych, Robin A Smith, Cecilia Ocampo-Solis, Robert H McCusker
Abundant evidence connects depression symptomology with immune system activation, stress and subsequently elevated levels of kynurenine. Anti-depressants, such as the tricyclic norepinephrine/serotonin reuptake inhibitor desipramine (Desip), were developed under the premise that increasing extracellular neurotransmitter level was the sole mechanism by which they alleviate depressive symptomologies. However, evidence suggests that anti-depressants have additional actions that contribute to their therapeutic potential...
February 14, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28201999/effect-of-myeloid-differentiation-primary-response-gene-88-on-expression-profiles-of-genes-during-the-development-and-progression-of-helicobacter-induced-gastric-cancer
#4
Ivonne Lozano-Pope, Arnika Sharma, Michael Matthias, Kelly S Doran, Marygorret Obonyo
BACKGROUND: Gastric cancer is one of the most common and lethal type of cancer worldwide. Infection with Helicobacter pylori (H. pylori) is recognized as the major cause of gastric cancer. However, it remains unclear the mechanism by which Helicobacter infection leads to gastric cancer. Furthermore, the underlying molecular events involved during the progression of Helicobacter infection to gastric malignancy are not well understood. In previous studies, we demonstrated that that H. felis-infected Myd88 (-/-) mice exhibited dramatic pathology and an accelerated progression to gastric dysplasia; however, the MyD88 downstream gene targets responsible for this pathology have not been described...
February 15, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28191010/role-of-dietary-metabolites-in-regulating-the-host-immune-response-in-gastrointestinal-disease
#5
REVIEW
Mohamad El-Zaatari, John Y Kao
The host immune response to gastrointestinal (GI) infections, hypersensitivity reactions, or GI cancers comprises numerous pathways that elicit responses on different host cells. Some of these include (1) the stimulation of mast cells via their IgE receptor, (2) the production of antibodies leading to antibody-mediated cytotoxic T/natural killer cell killing, (3) the activation of the complement pathway, and (4) the activation of the adaptive immune response via antigen-presenting cell, T cell, and B cell interactions...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28181858/evaluation-of-immunomodulatory-properties-of-feline-mesenchymal-stem-cells
#6
Maciej Parys, John M Kruger, Vilma Yuzbasiyan-Gurkan
Mesenchymal stem cells (MSC) offer a novel approach to treatment of inflammatory disorders in humans and companion animals. Cats spontaneously develop a wide variety of inflammatory disorders and may potentially benefit from MSC-based therapies. Multiple genes are involved in immunomodulation by MSC and interspecies differences between expressions of these genes exist. The goals of the study were to characterize the expression of genes known to be involved in MSC-based immunomodulation and determine the effect of MSC on proliferation of T-cells in co-culture experiments with PBMC...
February 9, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28179106/non-tumor-cell-ido1-predominantly-contributes-to-enzyme-activity-and-response-to-ctla-4-pd-l1-inhibition-in-mouse-glioblastoma
#7
Lijie Zhai, Erik Ladomersky, Carlos R Dostal, Kristen L Lauing, Kathleen Swoap, Leah K Billingham, Galina Gritsina, Meijing Wu, Robert H McCusker, David C Binder, Derek A Wainwright
Glioblastoma (GBM) is the most common malignant brain tumor in adults with a median survival of 14.6months. A contributing factor to GBM aggressiveness is the intratumoral expression of the potently immunosuppressive enzyme, indoleamine 2,3 dioxygenase 1 (IDO1). The enzymatic activity of IDO1 is associated with the conversion of tryptophan into downstream kynurenine (Kyn), which has previously been hypothesized to contribute toward the suppression of tumor immunity. Utilizing the syngeneic, immunocompetent, intracranial GL261 cell GBM model, we previously demonstrated that tumor cell, but not non-tumor cell IDO1, suppresses T cell-mediated brain tumor regression in mice...
February 4, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28159919/evaluation-of-radiofluorinated-carboximidamides-as-potential-ido-targeted-pet-tracers-for-cancer-imaging
#8
Xuan Huang, Zhongjie Pan, Michael L Doligalski, Xia Xiao, Epifanio Ruiz, Mikalai M Budzevich, Haibin Tian
IDO1 is an enzyme catalyzing the initial and rate-limiting step in the catabolism of tryptophan along the kynurenine pathway. IDO1 expression could suppress immune responses by blocking T-lymphocyte proliferation locally, suggesting a role of IDO in the regulation of immune responses. The goal of this study was to evaluate the potential of radiofluorinated carboximidamides as selective PET radioligands for IDO1. Specific binding correlated with IDO1 expression as measured through in vitro, microPET experiments...
January 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28141856/transcriptional-profiling-in-experimental-visceral-leishmaniasis-reveals-a-broad-splenic-inflammatory-environment-that-conditions-macrophages-toward-a-disease-promoting-phenotype
#9
Fanping Kong, Omar A Saldarriaga, Heidi Spratt, E Yaneth Osorio, Bruno L Travi, Bruce A Luxon, Peter C Melby
Visceral Leishmaniasis (VL), caused by the intracellular protozoan Leishmania donovani, is characterized by relentlessly increasing visceral parasite replication, cachexia, massive splenomegaly, pancytopenia and ultimately death. Progressive disease is considered to be due to impaired effector T cell function and/or failure of macrophages to be activated to kill the intracellular parasite. In previous studies, we used the Syrian hamster (Mesocricetus auratus) as a model because it mimics the progressive nature of active human VL...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28130499/amino-acid-catabolism-in-multiple-sclerosis-affects-immune-homeostasis
#10
Laura Negrotto, Jorge Correale
Amino acid catabolism has been implicated in immunoregulatory mechanisms present in several diseases, including autoimmune disorders. Our aims were to assess expression and activity of enzymes involved in Trp and Arg catabolism, as well as to investigate amino acid catabolism effects on the immune system of multiple sclerosis (MS) patients. To this end, 40 MS patients, 30 healthy control subjects, and 30 patients with other inflammatory neurological diseases were studied. Expression and activity of enzymes involved in Trp and Arg catabolism (IDO1, IDO2, Trp 2,3-dioxygenase [TDO], arginase [ARG] 1, ARG2, inducible NO synthetase) were evaluated in PBMCs...
January 27, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28123606/strong-correlation-of-indoleamine-2-3-dioxygenase-1-expression-with-basal-like-phenotype-and-increased-lymphocytic-infiltration-in-triple-negative-breast-cancer
#11
Sewha Kim, Sanghui Park, Min Sun Cho, Woosung Lim, Byung-In Moon, Sun Hee Sung
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme involved in tumor immune escape. Blockade of the IDO1 pathway is an emerging modality of cancer immunotherapy. Triple-negative breast cancer (TNBC) lacks established therapeutic targets and may be a good candidate for this novel immunotherapeutic agent. The purpose of this study was to evaluate the clinicopathologic characteristics of the IDO1-expressing TNBC subset. A tissue microarray was constructed from 200 patients with TNBC. Immunohistochemistry (IHC) for IDO1 and TNBC molecular subtype-surrogate markers (AR, GCDFP-15, claudin-3, E-cadherin, CK5/6, and EGFR) was performed using this tissue microarray...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28118532/regulating-the-balance-between-the-kynurenine-and-serotonin-pathways-of-tryptophan-metabolism
#12
Yang Li, Nan Hu, Dan Yang, Gregory Oxenkrug, Qing Yang
Tryptophan is metabolized along the kynurenine and serotonin pathways, resulting in formation of kynurenine metabolites, neuroactive serotonin and melatonin. Each pathway is critical for maintaining healthy homeostasis. However, the two pathways are extremely unequal in their ability to degrade tryptophan, and little is known about the mechanisms maintaining the balance between them. Here, we demonstrated that in PC12 cells, a change of expression of key genes of one pathway resulted in a change of expression of key genes of the other...
January 24, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28114346/hepatitis-c-virus-induces-mdscs-like-monocytes-through-tlr2-pi3k-akt-stat3-signaling
#13
Naicui Zhai, Haijun Li, Hongxiao Song, Yang Yang, An Cui, Tianyang Li, Junqi Niu, Ian Nicholas Crispe, Lishan Su, Zhengkun Tu
BACKGROUND AND AIMS: Recent studies reveal the accumulation of myeloid derived suppressor cells (MDSCs) in human peripheral blood mononuclear cells (PBMCs) following HCV infection, which may facilitate and maintain HCV persistent infection. The mechanisms by which HCV induces MDSCs are poorly understood. In the present study, we investigated the mechanisms by which HCV induces MDSCs that lead to suppression of T cell proliferation and expansion of CD4+Foxp3+ regulatory T cells. METHODS: Purified monocytes from healthy donors were cultured with HCV core protein (HCVc) or cell culture-derived HCV virions (HCVcc), and characterized the phenotype and function of these monocytes by flow cytometry, quantitative PCR, ELISA and western blot assays...
2017: PloS One
https://www.readbyqxmd.com/read/28053021/first-in-human-phase-1-study-of-the-oral-inhibitor-of-indoleamine-2-3-dioxygenase-1-epacadostat-incb024360-in-patients-with-advanced-solid-malignancies
#14
Gregory L Beatty, Peter J O'Dwyer, Jason Clark, Jack G Shi, Kevin J Bowman, Peggy Scherle, Robert C Newton, Richard Schaub, Janet Maleski, Lance Leopold, Thomas F Gajewski
PURPOSE: Indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the degradation of tryptophan to N-formyl-kynurenine. Overexpressed in many solid malignancies, IDO1 can promote tumor escape from host immunosurveillance. This first-in-human phase 1 study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and selective inhibitor of IDO1. PATIENTS AND METHODS: Fifty-two patients with advanced solid malignancies were treated with epacadostat (50 mg once daily or 50, 100, 300, 400, 500, 600, or 700 mg twice daily [BID]) in a dose-escalation 3 + 3 design and evaluated in 28-day cycles...
January 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28027300/gene-expression-differences-in-prostate-cancers-between-young-and-old-men
#15
Yuanchun Ding, Huiqing Wu, Charles Warden, Linda Steele, Xueli Liu, M van Iterson, Xiwei Wu, Rebecca Nelson, Zheng Liu, Yate-Ching Yuan, Susan L Neuhausen
Prostate cancer incidence is increasing in younger men. We investigated whether men diagnosed with Gleason 7 (3+4) T2 prostate cancer at younger ages (≤ 45 years, young cohort) had different mRNA and miRNA expression profiles than men diagnosed at older ages (71-74 years, older cohort). We identified differentially expressed genes (DEGs) related to tumor-normal differences between the cohorts. Subsequent pathway analysis of DEGs revealed that the young cohort had significantly more pronounced inflammatory and immune responses to tumor development compared to the older cohort...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/28011425/discovery-and-evaluation-of-inhibitors-to-the-immunosuppressive-enzyme-indoleamine-2-3-dioxygenase-1-ido1-probing-the-active-site-inhibitor-interactions
#16
Petr Tomek, Brian D Palmer, Jack U Flanagan, Chuanwen Sun, Emma L Raven, Lai-Ming Ching
High expression of the immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1) for a broad range of malignancies is associated with poor patient prognosis, and the enzyme is a validated target for cancer intervention. To identify novel IDO1 inhibitors suitable for drug development, 1597 compounds in the National Cancer Institute Diversity Set III library were tested for inhibitory activity against recombinant human IDO1. We retrieved 35 hits that inhibited IDO1 activity >50% at 20 μM. Five structural filters and the PubChem Bioassay database were used to guide the selection of five inhibitors with IC50 between 3 and 12 μM for subsequent experimental evaluation...
January 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28004656/co-delivery-of-indoleamine-2-3-dioxygenase-prevents-loss-of-expression-of-an-antigenic-transgene-in-dystrophic-mouse-muscles
#17
D Sharma, R Al-Khalidi, S Edgar, Q An, Y Wang, C Young, D Nowis, D C Gorecki
A significant problem affecting gene therapy approaches aiming at achieving long-term transgene expression is the immune response against the protein product of the therapeutic gene, which can reduce or eliminate the therapeutic effect. The problem is further exacerbated when therapy involves targeting an immunogenic tissue and/or one with a pre-existing inflammatory phenotype, such as dystrophic muscles. In this proof-of-principle study, we co-expressed a model antigen, bacterial β-galactosidase, with an immunosuppressive factor, indoleamine 2,3-dioxygenase 1 (IDO1), in muscles of the mdx mouse model of Duchenne muscular dystrophy...
December 22, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27994758/fused-heterocyclic-compounds-as-potent-indoleamine-2-3-dioxygenase-1-inhibitors
#18
Subhankar Panda, Ashalata Roy, Suman Jyoti Deka, Vishal Trivedi, Debasis Manna
Uncontrolled metabolism of l-tryptophan (l-Trp) in the immune system has been recognized as a critical cellular process in immune tolerance. Indoleamine 2,3-dioxygenase 1 (IDO1) enzyme plays an important role in the metabolism of a local l-Trp through the kynurenine pathway in the immune systems. In this regard, IDO1 has emerged as a therapeutic target for the treatment of diseases that are associated with immune suppression like chronic infections, cancer, and others. In this study, we synthesized a series of pyridopyrimidine, pyrazolopyranopyrimidine, and dipyrazolopyran derivatives...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27994058/signal-transducer-and-activator-of-transcription-1-plays-a-pivotal-role-in-ret-ptc3-oncogene-induced-expression-of-indoleamine-2-3-dioxygenase-1
#19
Sonia Moretti, Elisa Menicali, Nicole Nucci, Pasquale Voce, Renato Colella, Rosa Marina Melillo, Federica Liotti, Silvia Morelli, Francesca Fallarino, Antonio Macchiarulo, Massimo Santoro, Nicola Avenia, Efisio Puxeddu
Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it exerts an immunosuppressive function as part of an acquired mechanism of immune escape. Recently, we demonstrated that IDO1 expression is significantly higher in all thyroid cancer histotypes compared with normal thyroid and that its expression levels correlate with T regulatory (Treg) lymphocyte densities in the tumor microenvironment. BRAF(V600E)- and RET/PTC3-expressing PcCL3 cells were used as cellular models for the evaluation of IDO1 expression in thyroid carcinoma cells and for the study of involved signal transduction pathways...
February 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27990653/population-pharmacokinetic-and-pharmacodynamic-modeling-of-epacadostat-in-patients-with-advanced-solid-malignancies
#20
Jack G Shi, Kevin J Bowman, Xuejun Chen, Janet Maleski, Lance Leopold, Swamy Yeleswaram
Epacadostat (EPA, INCB024360) is a selective inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an orally active immunotherapy to treat advanced malignancies. In the first clinical study investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of EPA in oncology patients, increasing doses of EPA ranging from 50 mg once daily to 700 mg twice daily were administered as a monotherapy to 52 subjects with advanced solid tumors. The EPA plasma concentration-time profiles were adequately described by a population PK model comprised of the first-order kinetics of oral absorption with 2-compartment distribution and constant clearance from the central compartment...
December 19, 2016: Journal of Clinical Pharmacology
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