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https://www.readbyqxmd.com/read/28731684/the-binding-mode-of-n-hydroxyamidines-to-indoleamine-2-3-dioxygenase-1-ido1
#1
Ute Friederike Röhrig, Vincent Zoete, Olivier Michielin
Indoleamine 2,3-dioxygenase 1 (IDO1) is an important target in cancer immunotherapy. The most advanced clinical compound, epacadostat (INCB024360), binds to the heme cofactor of IDO1 through a N-hydroxyamidine function. Conflicting binding modes have recently been proposed, reporting iron binding either through the hydroxyamidine oxygen or nitrogen atoms. Here, we use quantum chemical calculations, docking, and QM/MM calculations based on available X-ray data to resolve this issue and to propose a physically meaningful binding mode...
July 21, 2017: Biochemistry
https://www.readbyqxmd.com/read/28724796/host-interleukin-6-production-regulates-inflammation-but-not-tryptophan-metabolism-in-the-brain-during-murine-gvhd
#2
Ludovic Belle, Vivian Zhou, Kara L Stuhr, Margaret Beatka, Emily M Siebers, Jennifer M Knight, Michael W Lawlor, Casey Weaver, Misato Hashizume, Cecilia J Hillard, William R Drobyski
Graft-versus-host disease (GVHD) induces pathological damage in peripheral target organs leading to well-characterized, organ-specific clinical manifestations. Patients with GVHD, however, can also have behavioral alterations that affect overall cognitive function, but the extent to which GVHD alters inflammatory and biochemical pathways in the brain remain poorly understood. In the current study, we employed complementary murine GVHD models to demonstrate that alloreactive donor T cells accumulate in the brain and affect a proinflammatory cytokine milieu that is associated with specific behavioral abnormalities...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28713871/immune-dysfunctionality-of-replicative-senescent-mesenchymal-stromal-cells-is-corrected-by-ifn%C3%AE-priming
#3
Raghavan Chinnadurai, Devi Rajan, Spencer Ng, Kenneth McCullough, Dalia Arafat, Edmund K Waller, Larry J Anderson, Greg Gibson, Jacques Galipeau
Industrial-scale expansion of mesenchymal stromal cells (MSCs) is often used in clinical trials, and the effect of replicative senescence on MSC functionality is of mechanistic interest. Senescent MSCs exhibit cell-cycle arrest, cellular hypertrophy, and express the senescent marker β-galactosidase. Although both fit and senescent MSCs display intact lung-homing properties in vivo, senescent MSCs acquire a significant defect in inhibiting T-cell proliferation and cytokine secretion in vitro. IFNγ does not upregulate HLA-DR on senescent MSCs, whereas its silencing did not reverse fit MSCs' immunosuppressive properties...
April 25, 2017: Blood Advances
https://www.readbyqxmd.com/read/28704075/arecoline-cannot-alter-testicular-dysfunction-and-pineal-activation-caused-by-noise-in-wistar-rat
#4
Indraneel Saha, Aniruddha Chatterjee, Urmi Chatterji, B R Maiti
Millions of people consume betel nut for increased capacity to work and for stress reduction. The nut contains arecoline, which has multiple side effects on endocrine functions. Objective of the work is to investigate pineal-testicular responses to noise and after arecoline treatment in noise in rats. Noise exposure (100 dB, 6 h daily, 10 days) caused pineal stimulation ultrastructurally and at indoleamines level. Leydig cell dysfunction with fall of testosterone level and suppression of sex accessories were noticed...
July 13, 2017: Archives of Physiology and Biochemistry
https://www.readbyqxmd.com/read/28701757/oncolytic-measles-virus-enhances-antitumour-responses-of-adoptive-cd8-nkg2d-cells-in-hepatocellular-carcinoma-treatment
#5
Aiping Chen, Yonghui Zhang, Gang Meng, Dengxu Jiang, Hailin Zhang, Meihong Zheng, Mao Xia, Aiqin Jiang, Junhua Wu, Christian Beltinger, Jiwu Wei
There is an urgent need for novel effective treatment for hepatocellular carcinoma (HCC). Oncolytic viruses (OVs) not only directly lyse malignant cells, but also induce potent antitumour immune responses. The potency and precise mechanisms of antitumour immune activation by attenuated measles virus remain unclear. In this study, we investigated the potency of the measles virus vaccine strain Edmonston (MV-Edm) in improving adoptive CD8(+)NKG2D(+) cells for HCC treatment. We show that MV-Edm-infected HCC enhanced the antitumour activity of CD8(+)NKG2D(+) cells, mediated by at least three distinct mechanisms...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28698009/a-randomised-open-label-phase-2-study-of-the-ido1-inhibitor-epacadostat-incb024360-versus-tamoxifen-as-therapy-for-biochemically-recurrent-ca-125-relapse-only-epithelial-ovarian-cancer-primary-peritoneal-carcinoma-or-fallopian-tube-cancer
#6
Rebecca Kristeleit, Irina Davidenko, Vadim Shirinkin, Fatima El-Khouly, Igor Bondarenko, Michael J Goodheart, Vera Gorbunova, Carol A Penning, Jack G Shi, Xiangdong Liu, Robert C Newton, Yufan Zhao, Janet Maleski, Lance Leopold, Russell J Schilder
OBJECTIVE: Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months)...
July 8, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28697066/viral-induced-modulation-of-multiple-checkpoint-proteins-in-cancers
#7
Gerard J Nuovo, Virginia A Folcik, Cynthia Magro
Therapy with checkpoint inhibitors represents a major advance in cancer treatment. The purpose of this study was to examine the expression patterns of the checkpoint proteins programmed death ligand 1 (PD L1), PD L2, indoleamine 2,3-dioxygenase 1 (IDO1), and cytotoxic T-lymphocyte antigen 4 (CTLA4) in cancers including those associated with viral infections. Normal, noninflamed tissues rarely express checkpoint proteins with exceptions including the placenta and stomach. Expression of PD L1 was noted in 30%, PD L2 in 18%, IDO1 in 13%, and CTLA4 in 14% of 333 nonviral malignancies including endometrial, ovarian, lung, and breast cancers...
July 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/28689792/functional-role-of-kynurenine-and-aryl-hydrocarbon-receptor-axis-in-chronic-rhinosinusitis-with-nasal-polyps
#8
Heng Wang, Danh C Do, Jinxin Liu, Baofeng Wang, Jingjing Qu, Xia Ke, Xiaoyan Luo, Ho Man Tang, Ho Lam Tang, Chengping Hu, Mark E Anderson, Zheng Liu, Peisong Gao
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with mast cell-mediated inflammation and heightened oxidant stress. Kynurenine (KYN), an endogenous tryptophan metabolite, can promote allergen-induced mast cell activation through the aryl hydrocarbon receptor (AhR). OBJECTIVES: Determine the role of the KYN/AhR axis and oxidant stress in mast cell activation and the development of CRSwNP. METHODS: We measured expression of indoleamine 2, 3-dioxygenase 1 (IDO1), tryptophan 2, 3-dioxygenase (TDO2), KYN, and oxidized calmodulin-dependent protein kinase II (ox-CaMKII) in nasal polyps and controls...
July 6, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28688912/inhibition-of-the-kynurenine-pathway-protects-against-reactive-microglial-associated-reductions-in-the-complexity-of-primary-cortical-neurons
#9
Katherine O'Farrell, Eimear Fagan, Thomas J Connor, Andrew Harkin
Brain glia possess the rate limiting enzyme indoleamine 2, 3-dioxygenase (IDO) which catalyses the conversion of tryptophan to kynurenine. Microglia also express kynurenine monooxygenase (KMO) and kynureninase (KYNU) which lead to the production of the free radical producing metabolites, 3-hydroxykynurenine and 3-hydroxyanthranillic acid respectively and subsequently production of the NMDA receptor agonist quinolinic acid. The aim of this study was to examine the effect of IFNγ-stimulated kynurenine pathway (KP) induction in microglia on neurite outgrowth and complexity, and to determine whether alterations could be abrogated using pharmacological inhibitors of the KP...
July 5, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28687008/association-of-breast-carcinoma-growth-with-a-non-canonical-axis-of-ifn%C3%AE-ido1-tsp1
#10
Bruno Lopes-Bastos, Liang Jin, Fiona Ruge, Sioned Owen, Andrew Sanders, Christopher Cogle, John Chester, Wen G Jiang, Jun Cai
Reciprocal interactions between cancers and the surrounding microenvironment have an important role in tumour evolution. In this study, our data suggested that through thrombospondin 1 (TSP1), tumour-associated microvessel provides a dormant niche to sustain inactive status of breast invasive ductal carcinoma (IDC) cells. TSP1 levels in the tumour stroma were negatively correlated with vascular indoleamine 2,3-dioxygenase 1 (IDO1) in IDC tissues. IDO1 is an intracellular enzyme initiating the first and rate-limited step of tryptophan breakdown...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28684130/indoleamine-2-3-dioxygenase-and-iron-are-required-for-mycobacterium-leprae-survival
#11
Mayara Garcia de Mattos Barbosa, Rhana Berto da Silva Prata, Priscila Ribeiro Andrade, Helen Ferreira, Bruno Jorge de Andrade Silva, Jéssica Araújo da Paixão de Oliveira, Tayná Quintella Assis, Thiago Gomes de Toledo-Pinto, Ohanna Cavalcanti de Lima Bezerra, José Augusto da Costa Nery, Patricia Sammarco Rosa, Marcelo Torres Bozza, Flávio Alves Lara, Milton Ozório Moraes, Veronica Schmitz, Euzenir Nunes Sarno, Roberta Olmo Pinheiro
Our previous study has demonstrated that IL-10 may modulate both indoleamine 2,3-dioxygenase (IDO) and CD163 expression in lepromatous leprosy (LL) cells, favoring Mycobacterium leprae persistence through induction of regulatory pathways and iron storage. Here, we observed that in LL lesion cells there is an increase in the expression of proteins involved in iron metabolism such as hemoglobin (Hb), haptoglobin, heme oxygenase 1 and transferrin receptor 1 (TfR1) when compared to tuberculoid leprosy (BT) cells...
July 3, 2017: Microbes and Infection
https://www.readbyqxmd.com/read/28673995/inhibition-of-acute-lethal-pulmonary-inflammation-by-the-ido-ahr-pathway
#12
Soung-Min Lee, Ha Young Park, Young-Sill Suh, Eun Hye Yoon, Juyang Kim, Won Hee Jang, Won-Sik Lee, Sae-Gwang Park, Il-Whan Choi, Inhak Choi, Sun-Woo Kang, Hwayoung Yun, Takanori Teshima, Byungsuk Kwon, Su-Kil Seo
The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4(+) T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-γ-dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-γ gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS)...
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28673339/human-limbal-fibroblast-like-stem-cells-induce-immune-tolerance-in-autoreactive-t-lymphocytes-from-female-patients-with-hashimoto-s-thyroiditis
#13
Antonina Coppola, Laura Tomasello, Maria Pitrone, Salvatore Cillino, Pierina Richiusa, Giuseppe Pizzolanti, Carla Giordano
BACKGROUND: Due to their "natural immune privilege" and immunoregulatory properties human fibroblast-like limbal stem cells (f-LSCs) have acquired great interest as a potential tool for achieving immunotolerance. Hashimoto's thyroiditis (HT) is the most common thyroid autoimmune disease and cause of hypothyroidism. To date, conventional hormone replacement therapy and unspecific immunosuppressive regimens cannot provide a definitive cure for HT subjects. We explored the immunosuppressant potential of human f-LSCs on circulating lymphomonocytes (PBMCs) collected from healthy donors and female HT patients...
July 3, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28667875/discovery-of-potent-ido1-inhibitors-derived-from-tryptophan-using-scaffold-hopping-and-structure-based-design-approaches
#14
Yi Zou, Yan Wang, Fang Wang, Minghao Luo, Yuezhen Li, Wen Liu, Zhangjian Huang, Yihua Zhang, Wenjie Guo, Qiang Xu, Yisheng Lai
Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently hijacked by tumors to escape the host immune response, and the enzyme is now firmly established as an attractive target for cancer immunotherapy. To identify novel IDO1 inhibitors suitable for drug development, a scaffold-hopping strategy combined with the average electrostatic potentials calculation was ultilized to design novel benzoxazolinone derivatives. Among these, compounds 7e, 7f and 9c exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against HeLa cells...
June 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28666226/comprehensive-analysis-of-the-tryptophan-metabolome-in-urine-of-patients-with-acute-intermittent-porphyria
#15
Alex Gomez-Gomez, Josep Marcos, Paula Aguilera, Jordi To-Figueras, Oscar J Pozo
BACKGROUND: Acute intermittent porphyria (AIP) is a rare metabolic disorder due to a deficiency of porphobilinogen deaminase, the third enzyme of the heme biosynthetic pathway. This low enzymatic activity may predispose to the appearance of acute neurological attacks. Seminal studies suggested that AIP was associated with changes in tryptophan homeostasis with inconclusive results. Therefore, the aim of this study was to analyze the urinary metabolome of AIP patients focusing on tryptophan metabolism using state-of-the-art technology...
June 19, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28662235/use-of-pd-1-targeting-macrophage-infiltration-and-ido-pathway-activation-in-sarcomas-a-phase-2-clinical-trial
#16
Maud Toulmonde, Nicolas Penel, Julien Adam, Christine Chevreau, Jean-Yves Blay, Axel Le Cesne, Emmanuelle Bompas, Sophie Piperno-Neumann, Sophie Cousin, Thomas Grellety, Thomas Ryckewaert, Alban Bessede, François Ghiringhelli, Marina Pulido, Antoine Italiano
Importance: There is a strong rationale for treating sarcomas with immunotherapy. Objective: To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas. Design, Setting, and Participants: This was an open-label, multicenter, phase 2 study of 4 cohorts of patients with advanced soft-tissue sarcoma (STS), including leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (others), and gastrointestinal stromal tumor (GIST)...
June 29, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28659913/lactobacillus-johnsonii-n6-2-modulates-the-host-immune-responses-a-double-blind-randomized-trial-in-healthy-adults
#17
Guillermo E Marcial, Amanda L Ford, Michael J Haller, Salvador A Gezan, Natalie A Harrison, Dan Cai, Julie L Meyer, Daniel J Perry, Mark A Atkinson, Clive H Wasserfall, Timothy Garrett, Claudio F Gonzalez, Todd M Brusko, Wendy J Dahl, Graciela L Lorca
Lactobacillus johnsonii N6.2 mitigates the onset of type 1 diabetes (T1D) in biobreeding diabetes-prone rats, in part, through changes in kynurenine:tryptophan (K:T) ratios. The goal of this pilot study was to determine the safety, tolerance, and general immunological response of L. johnsonii N6.2 in healthy subjects. A double-blind, randomized clinical trial in 42 healthy individuals with no known risk factors for T1D was undertaken to evaluate subject responses to the consumption of L. johnsonii N6.2. Participants received 1 capsule/day containing 10(8) colony-forming units of L...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28659861/the-effect-of-systemic-nitroglycerin-administration-on-the-kynurenine-pathway-in-the-rat
#18
Gábor Nagy-Grócz, Klaudia F Laborc, Gábor Veres, Attila Bajtai, Zsuzsanna Bohár, Dénes Zádori, Annamária Fejes-Szabó, Eleonóra Spekker, László Vécsei, Árpád Párdutz
The primary headache disorders include migraine, which is one of the most frequent neurological disorders, which influences more than 14% of the whole population. Despite the research efforts, its exact pathomechanism is not fully revealed, but evidence points to the role of glutamate and its receptors. Kynurenic acid is an endogenous glutamate receptor antagonist produced by the kynurenine pathway (KP). Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) convert l-tryptophan to N-formyl-l-kynurenine, to be further transformed to l-kynurenine...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28656203/1-methyl-l-tryptophan-promotes-the-apoptosis-of-hepatic-stellate-cells-arrested-by-interferon-%C3%AE-by-increasing-the-expression-of-ifn-%C3%AE-r%C3%AE-irf-1-and-fas
#19
Ji Eun Oh, Kwang Yong Shim, Jong In Lee, Soo In Choi, Soon Koo Baik, Young Woo Eom
Liver fibrosis, a precursor to cirrhosis, is the result of the deposition of extracellular matrix (ECM) proteins and is mediated primarily by activated hepatic stellate cells (HSCs). In this study, we investigated the anti-fibrotic effects of interferon (IFN)-γ in activated HSCs in vitro and whether cell viability would be decreased by the inhibition of indoleamine 2,3-dioxygemase (IDO), which is responsible for cell cycle arrest. Following treatment with IFN-γ, cell signaling pathways and DNA content were analyzed to assess the inactivation of HSCs or the decrease in HSC proliferation...
June 26, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28653857/anti-inflammatory-treatment-for-major-depressive-disorder-implications-for-patients-with-an-elevated-immune-profile-and-non-responders-to-standard-antidepressant-therapy
#20
Paula Kopschina Feltes, Janine Doorduin, Hans C Klein, Luis Eduardo Juárez-Orozco, Rudi Ajo Dierckx, Cristina M Moriguchi-Jeckel, Erik Fj de Vries
Major depressive disorder (MDD) is a prevalent and disabling psychiatric disease with rates of non-responsiveness to antidepressants ranging from 30-50%. Historically, the monoamine depletion hypothesis has dominated the view on the pathophysiology of depression. However, the lack of responsiveness to antidepressants and treatment resistance suggests that additional mechanisms might play a role. Evidence has shown that a subgroup of depressive patients may have an underlying immune deregulation that could explain the lack of therapeutic benefit from antidepressants...
June 1, 2017: Journal of Psychopharmacology
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