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https://www.readbyqxmd.com/read/29241670/glia-and-tissue-specific-changes-in-the-kynurenine-pathway-after-treatment-of-mice-with-lipopolysaccharide-and-dexamethasone
#1
Carlos R Dostal, Nicolaus S Gamsby, Marcus A Lawson, Robert H McCusker
Behavioral symptoms associated with mood disorders have been intimately linked with immunological and psychological stress. Induction of immune and stress pathways is accompanied by increased tryptophan entry into the Kynurenine (Kyn) Pathway as governed by the rate-limiting enzymes indoleamine/tryptophan 2,3-dioxygenases (DO's: Ido1, Ido2, Tdo2). Indeed, elevated DO expression is associated with inflammation- and stress-related depression symptoms. Here we examined central (brain, astrocyte and microglia) and peripheral (lung, liver and spleen) DO expression in mice treated intraperitoneally with lipopolysaccharide (LPS) and dexamethasone (DEX) to model the response of the Kyn Pathway to inflammation and glucocorticoids...
December 11, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29240291/novel-4-amino-1-2-3-triazole-inhibitors-of-indoleamine-2-3-dioxygenase-form-a-long-lived-complex-with-the-enzyme-and-display-exquisite-cellular-potency
#2
Julie Alexandre, Michael Swan, Mike Latchem, Dean Boyall, John Pollard, Stuart Hughes, James Westcott
Indoleamine-2,3 dioxygenase (IDO) has emerged as a central regulator of immune responses in both normal and disease biology. Due to its established role in promoting tumour immune escape, IDO has become an attractive target for cancer treatment. We have identified a novel series of highly cell potent IDO inhibitors based on a 4-amino-1,2,3-triazole core. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a non-competitive kinetic mechanism-of-action with respect to the tryptophan substrate...
December 14, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29238069/kynurenic-acid-an-ido-metabolite-controls-tsg-6-mediated-immunosuppression-of-human-mesenchymal-stem-cells
#3
Guan Wang, Kai Cao, Keli Liu, Yueqing Xue, Arthur I Roberts, Fengying Li, Yanyan Han, Arnold B Rabson, Ying Wang, Yufang Shi
Mesenchymal stem cells (MSCs) have been demonstrated to be anti-inflammatory against various immune disorders through several factors, including indoleamine 2,3-dioxygenase (IDO) and TNF-stimulated gene 6 (TSG-6). However, little is known about the necessity for both of these key immunosuppressive factors. Here we employed the mouse lipopolysaccharide (LPS)-induced acute lung injury (ALI) model, and found that IDO is necessary to achieve the effect of human umbilical cord-derived MSC (hUC-MSC)-based treatment on ALI...
December 13, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29226383/bifidobacterium-alleviated-experimentally-induced-colitis-by-upregulating-in-doleamine-2-3-dioxygenase-expression
#4
Li Zhao, Yangzhen Suolang, Dandan Zhou, Yu Tang, Yan Zhang
The goal of this study was explore the role of indoleamine 2, 3-dioxygenase (IDO) in the therapeutic effect of probiotics on inflammatory bowel disease (IBD). Trinitro-benzene sulfonic acid (TNBS) was used to induce colitis in mice, and 1-methyltryptophan (1-MT) was used to block the expression of IDO. Clinical manifes-tations, macroscopic and microscopic colonic alterations were assessed using the dis-ease activity index (DAI), Wallace-Keenan, and Curtner scoring systems, respectively. The expression of colonic IDO was detected by western blot...
December 11, 2017: Microbiology and Immunology
https://www.readbyqxmd.com/read/29222021/identification-and-validation-of-salivary-proteomic-signatures-for-non-invasive-detection-of-ovarian-cancer
#5
Md Tajmul, Farhat Parween, Lata Singh, Sandeep R Mathur, J B Sharma, Sunesh Kumar, D N Sharma, Savita Yadav
Ovarian cancer (OC) is one of the most lethal cancers among all gynecological malignancies. An effective and non-invasive screening approach is needed urgently to reduce high mortality rate. The purpose of this study was to identify the salivary protein signatures (SPS) for non-invasive detection of ovarian cancer. Differentially expressed SPS were identified by fluorescence-based 2D-DIGE coupled with MALDI/TOF-MS. The expression levels of three differential proteins (Lipocalin-2, indoleamine-2, 3-dioxygenase1 (IDO1) and S100A8) were validated using western blotting and ELISA...
December 5, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29220788/recent-discovery-of-indoleamine-2-3-dioxygenase-1-inhibitors-targeting-cancer-immunotherapy
#6
Tianwei Weng, Xiaqiu Qiu, Jubo Wang, Zhiyu Li, Jinlei Bian
There has been great attention on indoleamine-2,3-dioxygenase 1 (IDO1) around cancer immunotherapy because of its role in enabling cancers to evade the immune system. The most recent spurt of high potent IDO1 inhibitors has been driven by the solution of the increased crystal structures of inhibitors with IDO1. Though the structural information of the active site of IDO1 obtained from the crystals are quite similar, the structures of reported potent inhibitors are quite different. Besides, while thousands of bioactive small molecule inhibitors of IDO1 exist, to date, only five compounds have entered clinical trials...
December 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29217494/regulation-of-the-kynurenine-metabolism-pathway-by-xiaoyao-san-and-the-underlying-effect-in-the-hippocampus-of-the-depressed-rat
#7
Jiajia Wang, Xiaofang Li, Shugui He, Lijun Hu, Jiewen Guo, Xiangning Huang, Jinqing Hu, Yaoqun Qi, Bin Chen, Dewei Shang, Yuguan Wen
ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyao San (XYS) is a classic Chinese herbal formula for treatment of depression. The present study aimed to investigate the antidepressant effects of XYS in a rat model of chronic unpredictable mild stress (CUMS) and the underlying mechanisms. MATERIALS AND METHODS: A CUMS rat model of depression was established via 4 weeks of unpredictable stimulation. Then the rats were orally administered paroxetine and XYS for 2 weeks with continued stress...
December 4, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/29209565/tumor-targeted-costimulation-with-antibody-fusion-proteins-improves-bispecific-antibody-mediated-immune-response-in-presence-of-immunosuppressive-factors
#8
Sabrina Sapski, Nadine Beha, Roland Kontermann, Dafne Müller
Therapeutic strategies aiming for the induction of an effective immune response at the tumor site can be severely hampered by the encounter of an immunosuppressive microenvironment. We investigated here the potential of concerted costimulation by tumor-directed antibody-fusion proteins with B7.1, 4-1BBL and OX40L to enforce bispecific antibody-induced T cell stimulation in presence of recognized immunosuppressive factors including IL-10, TGF-β, indoleamine 2,3-dioxygenase (IDO), PD-L1 and regulatory T cells...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29206172/melatonin-efficacy-in-obese-leptin-deficient-mice-heart
#9
Alessandra Stacchiotti, Gaia Favero, Lorena Giugno, Igor Golic, Aleksandra Korac, Rita Rezzani
Cardiomyocytes are particularly sensitive to oxidative damage due to the link between mitochondria and sarcoplasmic reticulum necessary for calcium flux and contraction. Melatonin, important indoleamine secreted by the pineal gland during darkness, also has important cardioprotective properties. We designed the present study to define morphological and ultrastructural changes in cardiomyocytes and mainly in mitochondria of an animal model of obesity (ob/ob mice), when treated orally or not with melatonin at 100 mg/kg/day for 8 weeks (from 5 up to 13 week of life)...
December 5, 2017: Nutrients
https://www.readbyqxmd.com/read/29205945/improving-the-potency-of-cancer-immunotherapy-by-dual-targeting-ido1-and-dna
#10
Kun Fang, Guoqiang Dong, Hongyu Wang, Shipeng He, Shanchao Wu, Wei Wang, Chunquan Sheng
Here we report the first effort on exploration of the dual-targeting drug design strategy to improve the efficacy of small molecule cancer immunotherapy. New hybrids of IDO1 (indoleamine 2, 3-dioxygenase 1) inhibitors and DNA alkylating nitrogen mustards targeting respective IDO1 and DNA are rationally designed. As the first-in-class example of such molecules, they exhibited significantly enhanced anticancer activity in vitro and in vivo with low toxicity. The proof-of-concept by the studies has established a critical step toward developing novel and effective immunotherapy for the treatment of cancers...
December 4, 2017: ChemMedChem
https://www.readbyqxmd.com/read/29201185/relationship-of-socs3-and-tgf-%C3%AE-with-ido-expression-in-early-pregnancy-chorionic-villi-and-decidua
#11
Wei Liu, Yongli Huang, Guanyou Huang, Congrong Zhou, Xiaoling Zeng, Shuyun Zhao, Lingfei Wu, Hua Zhou, Qingqing Wu, Lujun Dai
We aimed to investigate the expression of suppressors cytokine signaling (SOCS)-3, transforming growth factor (TGF)-β and indoleamine 2,3-dioxygense (IDO) and to analyse the relationship of SOCS3 and TGF-β with IDO expression in early pregnancy chorionic villi and decidua in the maternal-fetal interface. Western blot analysis and immunohistochemical method were used to detect the expression of TGF-β, SOCS3 and IDO in chorionic villi and decidua tissues of normal pregnant women. SOCS3, TGF-β and IDO protein was identified in chorionic villi and decidua tissues of normal pregnant women and there was a negative correlation between the expression of IDO and SOCS3, but TGF-β expression was positively correlated with IDO expression...
November 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29195782/hmgb1-mediates-depressive-behavior-induced-by-chronic-stress-through-activating-the-kynurenine-pathway
#12
Bo Wang, Yong-Jie Lian, Wen-Jun Su, Wei Peng, Xin Dong, Lin-Lin Liu, Hong Gong, Ting Zhang, Chun-Lei Jiang, Yun-Xia Wang
Our previous study has reported that the proactive secretion and role of central high mobility group box 1 (HMGB1) in lipopolysaccharide-induced depressive behavior. Here, the potential mechanism of HMGB1 mediating chronic-stress-induced depression through the kynurenine pathway (KP) was further explored both in vivo and in vitro. Depression model was established with the 4-week chronic unpredictable mild stress (CUMS). Sucrose preference and Barnes maze test were performed to reflect depressive behaviors. The ratio of kynurenine (KYN)/tryptophan (Trp) represented the enzyme activity of indoleamine-2,3-dioxygenase (IDO)...
November 28, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29190885/the-ido-inhibitor-1-methyl-tryptophan-activates-the-aryl-hydrocarbon-receptor-response-in-mesenchymal-stromal-cells
#13
Holly C Lewis, Raghavan Chinnadurai, Steven E Bosinger, Jacques Galipeau
The catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is a key step in tolerance effected by a variety of cell types, including mesenchymal stromal cells (MSCs). Trp catabolism generates molecules known as kynurenines, whose tolerance mechanisms involve activation of the Aryl Hydrocarbon Receptor (AHR). A synthetic analog of Trp, 1-methyl tryptophan (1MT), is a selective inhibitor of IDO enzymatic activity being utilized in cancer immunotherapy trials. We hypothesized 1MT might activate AHR independently of its effects on IDO...
November 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29184765/the-novel-targets-of-dl-3-n-butylphthalide-predicted-by-similarity-ensemble-approach-in-combination-with-molecular-docking-study
#14
Yan Wang, Wei Qi, Li Zhang, Zhenguang Ying, Ou Sha, Chunman Li, Lanhai Lü, Xiangyan Chen, Zhenzhong Li, Feng Niu, Fang Xue, Dong Wang, Tzi-Bun Ng, Lihong Zhang
Background: DL-3-n-butylphthalide (NBP) is a drug for treating acute ischemic stroke, and may play a neuroprotective role by acting on multiple active targets. The aim of this study was to predict the target proteins of NBP in mammalian cells. Methods: The similarity ensemble approach search tool (SEArch), one of the commonly used public bioinformatics tools for target prediction, was employed in the experiment. The molecular docking of NBP to target proteins was performed by using the three-dimensional (3-D) crystal structure, substrate free...
October 2017: Quantitative Imaging in Medicine and Surgery
https://www.readbyqxmd.com/read/29181001/disease-tolerance-mediated-by-phosphorylated-indoleamine-2-3-dioxygenase-confers-resistance-to-a-primary-fungal-pathogen
#15
Eliseu Frank de Araújo, Flávio Vieira Loures, Cláudia Feriotti, Tania Costa, Carmine Vacca, Paolo Puccetti, Luigina Romani, Vera Lúcia Garcia Calich
Resistance to primary fungal pathogens is usually attributed to the proinflammatory mechanisms of immunity conferred by interferon-γ activation of phagocytes that control microbial growth, whereas susceptibility is attributed to anti-inflammatory responses that deactivate immunity. This study challenges this paradigm by demonstrating that resistance to a primary fungal pathogen such as Paracoccidiodes brasiliensis can be mediated by disease tolerance, a mechanism that preserves host fitness instead of pathogen clearance...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29180759/nano-enabled-pancreas-cancer-immunotherapy-using-immunogenic-cell-death-and-reversing-immunosuppression
#16
Jianqin Lu, Xiangsheng Liu, Yu-Pei Liao, Felix Salazar, Bingbing Sun, Wen Jiang, Chong Hyun Chang, Jinhong Jiang, Xiang Wang, Anna M Wu, Huan Meng, Andre E Nel
While chemotherapy delivery by nanocarriers has modestly improved the survival prospects of pancreatic ductal adenocarcinoma (PDAC), additional engagement of the immune response could be game changing. We demonstrate a nano-enabled approach for accomplishing robust anti-PDAC immunity in syngeneic mice through the induction of immunogenic cell death (ICD) as well as interfering in the immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway. This is accomplished by conjugating the IDO inhibitor, indoximod (IND), to a phospholipid that allows prodrug self-assembly into nanovesicles or incorporation into a lipid bilayer that encapsulates mesoporous silica nanoparticles (MSNP)...
November 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/29177308/discovery-of-ido1-and-dna-dual-targeting-antitumor-agents
#17
Kun Fang, Shanchao Wu, Guoqiang Dong, Ying Wu, Shuqiang Chen, Jianhe Liu, Wei Wang, Chunquan Sheng
The development of small molecules for cancer immunotherapy is highly challenging and indoleamine 2,3-dioxygenase 1 (IDO1) represents a promising target. Inspired by the synergistic effects between IDO1 inhibitors and traditional antitumor chemotherapeutics, the first orally active dual IDO1 and DNA targeting agents were designed by the pharmacophore fusion strategy. The bifunctional hybrids exhibited enhanced IDO1 enzyme inhibitory activity and in vitro cytotoxicity as compared to IDO1 inhibitor 1-methyl-tryptophan and DNA alkylating agent melphalan...
November 27, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29167421/structural-insights-into-substrate-and-inhibitor-binding-sites-in-human-indoleamine-2-3-dioxygenase-1
#18
Ariel Lewis-Ballester, Khoa N Pham, Dipanwita Batabyal, Shay Karkashon, Jeffrey B Bonanno, Thomas L Poulos, Syun-Ru Yeh
Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si)...
November 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/29167110/blocking-ido1-helps-shrink-bladder-cervical-tumors
#19
(no author information available yet)
Findings from a phase I/IIa study indicate that combining the investigational indoleamine 2,3-dioxygenase 1 inhibitor BMS-986205 with nivolumab is safe and boosts response rates among patients with bladder and cervical cancers.
November 22, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29163540/local-high-dose-radiotherapy-induces-systemic-immunomodulating-effects-of-potential-therapeutic-relevance-in-oligometastatic-breast-cancer
#20
Elena Muraro, Carlo Furlan, Michele Avanzo, Debora Martorelli, Elisa Comaro, Aurora Rizzo, Damiana A Fae', Massimiliano Berretta, Loredana Militello, Alessandro Del Conte, Simon Spazzapan, Riccardo Dolcetti, Marco Trovo'
Local irradiation of cancer through radiotherapy can induce spontaneous regression of non-directly irradiated lesions, suggesting the involvement of systemic antitumor immune responses. In oligometastatic breast cancer (BC) patients, the use of stereotactic body radiotherapy (SBRT) favors the local control of treated lesions and may contribute to break local tolerance and release tumor-associated antigens (TAAs), improving host antitumor immunity. We performed a detailed immunomonitoring of BC patients undergoing SBRT to verify its ability to "switch on" the anti-tumor immunity both systemically, in peripheral blood, and locally, employing in vitro BC models...
2017: Frontiers in Immunology
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