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Guangwei Xu, Tianqi Wang, Yongtao Li, Zhi Huang, Xin Wang, Jianyu Zheng, Shengyong Yang, Yan Fan, Rong Xiang
Indoleamine 2,3-dioxygenase 1 (IDO1) activity links to immune escape of cancers. Inhibition of IDO1 provides a new approach for cancer treatment. Most clinical IDO1 drugs show marginal efficacy as single agents. On basis of molecular docking and pharmacophore modelling, a novel inhibitor Roxyl-WL was discovered with a half maximal inhibitory concentration (IC50) value of 1 nM against IDO1 and 10-100-fold increased potent activity compared with IDO1 drugs in clinical trials. Roxyl-WL displayed excellent kinase spectrum selectivity with no activity out of the 337 protein kinases...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Nana H Overgaard, Daniel R Principe, Kyle M Schachtschneider, Jeanne Toft Jakobsen, Laurie A Rund, Paul J Grippo, Lawrence B Schook, Gregers Jungersen
In recent years, immunotherapy has shown considerable promise in the management of several malignancies. However, the majority of preclinical studies have been conducted in rodents, the results of which often translate poorly to patients given the substantial differences between murine and human immunology. As the porcine immune system is far more analogous to that of humans, pigs may serve as a supplementary preclinical model for future testing of such therapies. We have generated the genetically modified Oncopig with inducible tumor formation resulting from concomitant KRASG12D and TP53R167H mutations under control of an adenoviral vector Cre-recombinase (AdCre)...
2018: Frontiers in Immunology
Kimberley Kolijn, Esther I Verhoef, Marcel Smid, René Böttcher, Guido W Jenster, Reno Debets, Geert Jlh van Leenders
Cancer invasion and metastasis are driven by epithelial-to-mesenchymal transition (EMT), yet the exact mechanisms that account for EMT in clinical prostate cancer are not fully understood. Expression of N-cadherin is considered a hallmark of EMT in clinical prostate cancer. In this study, we determined the molecular mechanisms associated with N-cadherin expression in prostate cancer patients. We performed laser capture micro-dissection of matched N-cadherin-positive and -negative prostate cancer areas from patient samples (n=8) followed by RNA sequencing...
June 19, 2018: Cancer Research
Asha Nayak-Kapoor, Zhonglin Hao, Ramses Sadek, Robin Dobbins, Lisa Marshall, Nicholas N Vahanian, W Jay Ramsey, Eugene Kennedy, Mario R Mautino, Charles J Link, Ray S Lin, Stephanie Royer-Joo, Xiaorong Liang, Laurent Salphati, Kari M Morrissey, Sami Mahrus, Bruce McCall, Andrea Pirzkall, David H Munn, John E Janik, Samir N Khleif
BACKGROUND: Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models. METHODS: This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule...
June 20, 2018: Journal for Immunotherapy of Cancer
Robert W Wilkinson, Andrew J Leishman
Significant advances have been made to identify effective therapies that either restore or generate de novo a patient's immune response to cancer, so-called immunotherapy or immuno-oncology (IO) therapies. Some tumors overcome immune surveillance by promoting mechanisms to evade or suppress the immune system. This conference report highlights the clinical promise and current challenges of IO therapy, including the use of immune-checkpoint antagonist monoclonal antibodies. Furthermore, this report investigates advances in preclinical modeling of cancer immunobiology and how this is helping our understanding of which patients will receive clinical benefits from current immune-checkpoint treatment...
2018: Frontiers in Immunology
Tian Li, Shuai Jiang, Mengzhen Han, Zhi Yang, Jianjun Lv, Chao Deng, Russel J Reiter, Yang Yang
Melatonin is a physiological indoleamine involved in circadian rhythm regulation and it is currently used for secondary sleep disorders supported by empirical evidence. A small amount of evidence and some controversial results have been obtained in some randomized controlled trials (RCT). The objective of this meta-analysis is to determine the efficacy of exogenous melatonin versus placebo in managing secondary sleep disorders. Literature retrieval of eligible RCT was performed in 5 databases (PubMed, Embase, Cochrane Library, ClinicalTrials...
June 14, 2018: Frontiers in Neuroendocrinology
Ashley Volaric, Ryan Gentzler, Richard Hall, James H Mehaffey, Edward B Stelow, Timothy N Bullock, Linda W Martin, Anne M Mills
The immune regulatory enzyme indoleamine-2,3-dioxygenase (IDO-1) suppresses T cell responses and may reduce efficacy of therapies targeting immune checkpoints such as programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1). Early phase clinical trials combining IDO-1 and PD-1/PD-L1 inhibitors have shown some promise in non-small cell lung cancers (NSCLCs). However, the coexpression of IDO-1 and PD-L1 has not been thoroughly investigated, and the potential for IDO-1 immunohistochemical expression as a therapeutic biomarker is unknown...
June 12, 2018: American Journal of Surgical Pathology
Soo Jeong Nam, Sehui Kim, Dohee Kwon, Hannah Kim, Soyeon Kim, Eunyoung Lee, Tae Min Kim, Dae Seog Heo, Sung Hye Park, Megan S Lim, Chul Woo Kim, Yoon Kyung Jeon
Primary diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive disease with a poor prognosis. The status of the tumor immune microenvironment in CNS-DLBCL remains unclear. We investigated the prognostic implications of tumor-associated macrophages (TAMs), regulatory T-cells (Tregs), and indoleamine 2,3-dioxygenase (IDO)+ cells in primary CNS-DLBCL (n = 114) by immunohistochemical analysis. The numbers of tumor-infiltrating immune cells, including CD68+ TAMs, CD163+ or CD204+ M2 macrophages, FOXP3+ Tregs, and IDO+ cells were all significantly lower in CNS-DLBCL versus systemic DLBCL (n = 165; all P < 0...
2018: Oncoimmunology
Ariel Lewis-Ballester, Shay Karkashon, Dipanwita Batabyal, Thomas L Poulos, Syun-Ru Yeh
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) catalyze the same dioxygenation reaction of Trp to generate N-formyl kynurenine (NFK). They share high structural similarity, especially in the active site. However, hIDO1 possesses a unique inhibitory substrate binding site (Si) that is absent in hTDO. In addition, in hIDO1, the indoleamine group of the substrate Trp is H-bonded to S167 through a bridging water, while that in hTDO is directly H-bonded to H76. Here we show that Trp binding to the Si site or the mutation of S167 to histidine in hIDO1 retards its turnover activity, and that the inhibited activity can be rescued by an effector, 3-indole ethanol (IDE)...
June 13, 2018: Journal of the American Chemical Society
Shanshan Jia, Pin Guo, Xiangjin Ge, Huanhuan Wu, Junhua Lu, Xiaofang Fan
Indoleamine 2, 3-dioxygenase (IDO) catalyzes the degradation of trytophan, which serves a key role in immune suppression via regulating the production of several metabolites. The present study aimed to explore the effects and mechanisms of IDO in the repair of human airway epithelium suppressed by dexamethasone (DEX). Cell viability, proliferation and migration were evaluated using a Cell Counting Kit-8 (CCK-8), 5(6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling, and wound-healing assay, respectively...
July 2018: Experimental and Therapeutic Medicine
Irina Banzola, Chantal Mengus, Stephen Wyler, Tvrko Hudolin, Gabriele Manzella, Alberto Chiarugi, Renzo Boldorini, Giovanni Sais, Tobias S Schmidli, Gabriele Chiffi, Alexander Bachmann, Tullio Sulser, Giulio C Spagnoli, Maurizio Provenzano
Inflammation has been suggested to play an important role in onset and progression of prostate cancer (PCa). Histological analysis of prostatectomy specimens has revealed focal inflammation in early stage lesions of this malignancy. We addressed the role of inflammatory stimuli in the release of PCa-specific, tumor-derived soluble factors (PCa-TDSFs) already reported to be mediators of PCa morbidity, such as indoleamine 2,3-dioxygenase (IDO) and interleukin (IL)-6. Inflammation-driven production and functions of PCa-TDFSs were tested " in vitro " by stimulating established cell lines (CA-HPV-10 and PC3) with IFN-γ or TNF-α...
2018: Frontiers in Immunology
Abdulla A-B Badawy
Tumoral immune escape is an obstacle to successful cancer therapy. Tryptophan (Trp) metabolites along the kynurenine pathway induce immunosuppression involving apoptosis of effector immune cells, which tumors use to escape an immune response. Production of these metabolites is initiated by indoleamine 2,3-dioxygenase (IDO1). IDO1 inhibitors, however, do not always overcome the immune escape and another enzyme expressed in tumors, Trp 2,3-dioxygenase (TDO2), has been suggested as the reason. However, without Trp, tumors cannot achieve an immune escape through either enzyme...
June 10, 2018: Immunology and Cell Biology
Rita Romani, Giorgia Manni, Chiara Donati, Irene Pirisinu, Caterina Bernacchioni, Marco Gargaro, Matteo Pirro, Mario Calvitti, Giorgia Manni, Francesco Bagaglia, Amirhossein Sahebkar, Graziano Clerici, Davide Matino, Giovanni Pomili, Gian Carlo Di Renzo, Vincenzo Nicola Talesa, Paolo Puccetti, Francesca Fallarino
Stem cells have high potential for cell therapy in regenerative medicine. We previously isolated stem cell types from human amniotic fluid, derived from prenatal amniocentesis. One type, characterized by a fast doubling time, was designated as fast human amniotic stem cells (fHASCs). These cells exhibited high differentiation potential and immunoregulatory properties. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that influences stem-cell pluripotency, differentiation, mobility, and regulates immune functions...
June 7, 2018: European Journal of Pharmacology
Kensuke Shima, Nadja Kaeding, Iretiolu Mayokun Ogunsulire, Inga Kaufhold, Matthias Klinger, Jan Rupp
Interferon-γ (IFN-γ) is a central mediator of host immune responses including T-cell differentiation and activation of macrophages for the control of bacterial pathogens. Anti-bacterial mechanisms of IFN-γ against the obligate intracellular bacteria Chlamydiatrachomatis in epithelial cells have been intensively investigated in the past, focusing on cellular tryptophan depletion by an IFN-γ induced expression of the indoleamine 2, 3-deoxygenase (IDO). In this study, we could show that IFN-γ treatment caused a significant reduction of the host cell glycolysis that was accompanied by a reduction of glucose transporter-1 (GLUT1) and hypoxia inducible factor-1α (HIF-1α) expression...
June 6, 2018: Cytokine
Xi Feng, Xiaqiu Qiu, Huidan Huang, Jubo Wang, Xi Xu, Pengfei Xu, Ruijia Ge, Xiaojin Liu, Zhiyu Li, Jinlei Bian
An efficient reaction utilizing propargyl carbonates through Claisen rearrangement to synthesize furanonaphthoquinones is described. The remarkable transformation exhibits excellent functional group tolerance, affording the target furanonaphthoquinones in moderate to good yields (41-85%) under mild reaction condition. Scaled up preparation of the model product can make this reaction a method of choice for synthesis of furanonaphthoquinone derivatives. The resulting furanonaphthoquinones were evaluated as potential indoleamine 2,3-dioxygenase inhibitors in vitro...
June 8, 2018: Journal of Organic Chemistry
Jinrong Peng, Yao Xiao, Wenting Li, Qian Yang, Liwei Tan, Yanpeng Jia, Ying Qu, Zhiyong Qian
The therapeutic outcome of photothermal therapy (PTT) remains impeded by the transparent depth of light. Combining PTT with immunotherapy provides strategies to solve this problem. Regulating metabolism-related enzymes is a promising strategy to stimulate immune response. Here, a nanosystem (NLG919/IR780 micelles) with the properties of photothermal conversion and regulation of the tryptophan metabolic pathway is used to suppress the growth of the tumor margin beyond effective PTT and promote tumor PTT and immunotherapy...
May 2018: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
Gislaine Z Réus, Ritele H Silva, Airam B de Moura, Jaqueline F Presa, Helena M Abelaira, Mariane Abatti, Andriele Vieira, Bruna Pescador, Monique Michels, Zuleide M Ignácio, Felipe Dal-Pizzol, João Quevedo
Maternal deprivation (MD) induces behavioral changes and impacts brain circuits that could be associated with the pathophysiology of depression. This study investigated the markers of microglia and astrocyte activation as well as indoleamine 2,3-dioxygenase (IDO) expression in developmental programming after early life MD (on postnatal days (PNDs) 20, 30, 40, and 60). On PND 60, the rats that were subjected to MD displayed depressive-like behavior. On PND 10, it was found that there was a decrease in the level of glial fibrillary acidic protein (GFAP) immunopositive cells, a decrease in the level of IDO expression, and an increase in the level of Iba-1 (microglial marker) in the hippocampus of rats that were subjected to MD...
June 5, 2018: Molecular Neurobiology
Reza B Jalili, Ruhangiz T Kilani, Yunyuan Li, Mohsen Khosravi-Maharlooie, Layla Nabai, Eddy Hsi Chun Wang, Kevin J McElwee, Aziz Ghahary
Alopecia areata (AA) is an autoimmune hair loss disease with infiltration of proinflammatory cells into hair follicles. Current therapeutic regimens are unsatisfactory mainly because of the potential for side effects and/or limited efficacy. Here we report that cultured, transduced fibroblasts, which express the immunomodulatory molecule indoleamine 2,3-dioxygenase (IDO), can be applied to prevent hair loss in an experimental AA model. A single intraperitoneal (IP) injection of IDO-expressing primary dermal fibroblasts was given to C3H/HeJ mice at the time of AA induction...
January 1, 2018: Cell Transplantation
Marcelo Gomes de Gomes, Leandro Cattelan Souza, André Rossito Goes, Lucian Del Fabbro, Carlos Borges Filho, Franciele Donato, Marina Prigol, Cristiane Luchese, Silvane Souza Roman, Robson Luiz Puntel, Silvana Peterini Boeira, Cristiano Ricardo Jesse
Sickness behavior is an expression of a central motivational state triggered by activation of the immune system, being considered a strategy of the organism to fight infection. Sickness behavior is induced by peripheral administration of lipopolysaccharide (LPS). LPS can increase the levels of proinflammatory cytokines, which induce the activation of the kynurenine pathway (KP) and behavioral alterations. Previous studies have shown that omega-3 (n-3) polyunsaturated fatty acid (PUFA) has anti-inflammatory properties...
May 16, 2018: Journal of Nutritional Biochemistry
Karolina Åkesson, Susanne Pettersson, Sara Ståhl, Izabella Surowiec, Mattias Hedenström, Susanna Eketjäll, Johan Trygg, Per-Johan Jakobsson, Iva Gunnarsson, Elisabet Svenungsson, Helena Idborg
Objective: Fatigue has been reported as the most disturbing symptom in a majority of patients with SLE. Depression is common and often severe. Together these symptoms cause significant morbidity and affect patients with otherwise relatively mild disease. Tryptophan and its metabolites in the kynurenine pathway are known to be important in several psychiatric conditions, for example, depression, which are often also associated with fatigue. We therefore investigated the kynurenine pathway in patients with SLE and controls...
2018: Lupus Science & Medicine
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