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https://www.readbyqxmd.com/read/29342871/interferons-reprogramming-the-metabolic-network-against-viral-infection
#1
REVIEW
Kavita Raniga, Chen Liang
Viruses exploit the host and induce drastic metabolic changes to ensure an optimal environment for replication and the production of viral progenies. In response, the host has developed diverse countermeasures to sense and limit these alterations to combat viral infection. One such host mechanism is through interferon signaling. Interferons are cytokines that enhances the transcription of hundreds of interferon-stimulated genes (ISGs) whose products are key players in the innate immune response to viral infection...
January 13, 2018: Viruses
https://www.readbyqxmd.com/read/29329953/canine-macrophages-can-like-human-macrophages-be-in-vitro-activated-toward-the-m2a-subtype-relevant-in-allergy
#2
Ina Herrmann, Jelena Gotovina, Judit Fazekas-Singer, Michael B Fischer, Karin Hufnagl, Rodolfo Bianchini, Erika Jensen-Jarolim
The M2a subtype of macrophages plays an important role in human immunoglobulin E (IgE-mediated allergies) and other Th2 type immune reactions. In contrast, very little is known about these cells in the dog. Here we describe an in-vitro method to activate canine histiocytic DH82 cells and primary canine monocyte-derived macrophages (MDMs) toward the M2a macrophages using human cytokines. For a side-by-side comparison, we compared the canine cells to human MDMs, and the human monocytic cell line U937 activated towards M1-and M2a cells on the cellular and molecular level...
January 9, 2018: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/29320557/high-ahr-expression-in-breast-tumors-correlates-with-expression-of-genes-from-several-signaling-pathways-namely-inflammation-and-endogenous-tryptophan-metabolism
#3
Sophie Vacher, Patrice Castagnet, Walid Chemlali, François Lallemand, Didier Meseure, Marc Pocard, Ivan Bieche, Martine Perrot-Applanat
Increasing epidemiological and animal experimental data provide substantial support for the role of aryl hydrocarbon receptor (AhR) in mammary tumorigenesis. The effects of AhR have been clearly demonstrated in rodent models of breast carcinogenesis and in several established human breast cancer cell lines following exposure to AhR ligands or AhR overexpression. However, relatively little is known about the role of AhR in human breast cancers. AhR has always been considered to be a regulator of toxic and carcinogenic responses to environmental contaminants such as TCDD (dioxin) and benzo[a]pyrene (BaP)...
2018: PloS One
https://www.readbyqxmd.com/read/29302770/modulating-tumor-immunology-by-inhibiting-indoleamine-2-3-dioxygenase-ido-recent-developments-and-first-clinical-experiences
#4
Diwakar Davar, Nathan Bahary
Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) catalyze the first rate-limiting step in the oxidative metabolism of compounds containing indole rings, including the transformation of the essential amino acid L-tryptophan to N-formyl-L-kynurenine. Through direct and indirect means, IDO exerts both tolerogenic and pro-inflammatory effects and has a profound immunoregulatory role in the tumor microenvironment. Although the role of IDO in mediating peripheral acquired immunologic tolerance has been known for some time, its role in tumorigenesis and the subversion of anti-tumor immunity have only recently been appreciated...
January 4, 2018: Targeted Oncology
https://www.readbyqxmd.com/read/29275469/tryptophan-catabolism-and-cancer-immunotherapy-targeting-ido-mediated-immune-suppression
#5
Adaobi Amobi, Feng Qian, Amit A Lugade, Kunle Odunsi
Over the last decade, tryptophan catabolism has been firmly established as a powerful mechanism of innate and adaptive immune tolerance. The catabolism of tryptophan is a central pathway maintaining homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses. This is driven by the key and rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase 2 (TDO), resulting in local depletion of tryptophan, while tryptophan catabolites accumulate, including kynurenine and its derivatives, depending on the presence of downstream enzymes in the kynurenine pathway...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29247038/discovery-of-ido1-inhibitors-from-bench-to-bedside
#6
REVIEW
George C Prendergast, William P Malachowski, James B DuHadaway, Alexander J Muller
Small-molecule inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) are emerging at the vanguard of experimental agents in oncology. Here, pioneers of this new drug class provide a bench-to-bedside review on preclinical validation of IDO1 as a cancer therapeutic target and on the discovery and development of a set of mechanistically distinct compounds, indoximod, epacadostat, and navoximod, that were first to be evaluated as IDO inhibitors in clinical trials. As immunometabolic adjuvants to widen therapeutic windows, IDO inhibitors may leverage not only immuno-oncology modalities but also chemotherapy and radiotherapy as standards of care in the oncology clinic...
December 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/29241670/glia-and-tissue-specific-changes-in-the-kynurenine-pathway-after-treatment-of-mice-with-lipopolysaccharide-and-dexamethasone
#7
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/29222021/identification-and-validation-of-salivary-proteomic-signatures-for-non-invasive-detection-of-ovarian-cancer
#8
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
#9
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/29212506/chromosome-9p-copy-number-gains-involving-pd-l1-are-associated-with-a-specific-proliferation-and-immune-modulating-gene-expression-program-active-across-major-cancer-types
#10
Jan Budczies, Carsten Denkert, Balázs Győrffy, Peter Schirmacher, Albrecht Stenzinger
BACKGROUND: Inhibition of the PD-L1/PD-1 immune checkpoint axis represents one of the most promising approaches of immunotherapy for various cancer types. However, immune checkpoint inhibition is successful only in subpopulations of patients emphasizing the need for powerful biomarkers that adequately reflect the complex interaction between the tumor and the immune system. Recently, recurrent copy number gains (CNG) in chromosome 9p involving PD-L1 were detected in many cancer types including lung cancer, melanoma, bladder cancer, head and neck cancer, cervical cancer, soft tissue sarcoma, prostate cancer, gastric cancer, ovarian cancer, and triple-negative breast cancer...
December 6, 2017: BMC Medical Genomics
https://www.readbyqxmd.com/read/29205945/improving-the-potency-of-cancer-immunotherapy-by-dual-targeting-of-ido1-and-dna
#11
Kun Fang, Guoqiang Dong, Hongyu Wang, Shipeng He, Shanchao Wu, Wei Wang, Chunquan Sheng
Herein we report the first exploration of a dual-targeting drug design strategy to improve the efficacy of small-molecule cancer immunotherapy. New hybrids of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and DNA alkylating nitrogen mustards that respectively target IDO1 and DNA were rationally designed. As the first-in-class examples of such molecules, they were found to exhibit significantly enhanced anticancer activity in vitro and in vivo with low toxicity. This proof-of-concept study has established a critical step toward the development of a novel and effective immunotherapy for the treatment of cancers...
December 4, 2017: ChemMedChem
https://www.readbyqxmd.com/read/29180488/rhesus-macaque-myeloid-derived-suppressor-cells-demonstrate-t-cell-inhibitory-functions-and-are-transiently-increased-after-vaccination
#12
Ang Lin, Frank Liang, Elizabeth A Thompson, Maria Vono, Sebastian Ols, Gustaf Lindgren, Kimberly Hassett, Hugh Salter, Giuseppe Ciaramella, Karin Loré
Myeloid-derived suppressor cells (MDSCs) are major regulators of T cell responses in several pathological conditions. Whether MDSCs increase and influence T cell responses in temporary inflammation, such as after vaccine administration, is unknown. Using the rhesus macaque model, which is critical for late-stage vaccine testing, we demonstrate that monocytic (M)-MDSCs and polymorphonuclear (PMN)-MDSCs can be detected using several of the markers used in humans. However, whereas rhesus M-MDSCs lacked expression of CD33, PMN-MDSCs were identified as CD33+ low-density neutrophils...
November 27, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29178397/review-the-transcripts-associated-with-organ-allograft-rejection
#13
Philip F Halloran, Jeffery M Venner, Katelynn Madill-Thomsen, Gunilla Einecke, Michael Parkes, Luis G Hidalgo, Konrad S Famulski
The molecular mechanisms operating in human organ transplant rejection are best inferred from the mRNAs expressed in biopsies because the corresponding proteins often have low expression and short half-lives, while small non-coding RNAs lack specificity. Associations should be characterized in a population that rigorously identifies T cell-mediated (TCMR) and antibody-mediated rejection (ABMR). This is best achieved in kidney transplant biopsies, but the results are generalizable to heart, lung, or liver transplants...
November 25, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/29177308/discovery-of-ido1-and-dna-dual-targeting-antitumor-agents
#14
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/29167110/blocking-ido1-helps-shrink-bladder-cervical-tumors
#15
(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/29156701/association-of-breast-carcinoma-growth-with-a-non-canonical-axis-of-ifn%C3%AE-ido1-tsp1
#16
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...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29153034/advances-in-maldi-mass-spectrometry-within-drug-discovery
#17
Dale S Cornett, Michael D Scholle
Inhibition of NK and effector T-cell functions and activation of regulatory cell populations are the main immunosuppressive effects of indoleamine-2,3-dioxygenase1 (IDO1). By converting tryptophan (Trp) into kynurenine (Kyn), IDO1 is involved in the immune response homeostasis, and its dysregulated expression is described in immune-related pathologies, as tumors that hijack it to evade immune destruction. Thereby, IDO1 inhibitors are being developed to stimulate antitumor immune responses. Existing and standard quantitation methods of IDO1 substrate and metabolite(s) are based on the total level of Trp and its metabolites determined by liquid chromatography tandem mass spectrometry analysis in human plasma, cerebrospinal fluid, and brain...
December 2017: SLAS Discovery
https://www.readbyqxmd.com/read/29133053/synthesis-and-biological-evaluation-of-new-berberine-derivatives-as-cancer-immunotherapy-agents-through-targeting-ido1
#18
Yan-Xiang Wang, Wei-Qiang Pang, Qing-Xuan Zeng, Zhe-Song Deng, Tian-Yun Fan, Jian-Dong Jiang, Hong-Bin Deng, Dan-Qing Song
To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty-five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure-activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71-90% compared with BBR...
November 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29128855/selective-inhibition-of-ido1-d-1-methyl-tryptophan-d-1mt-effectively-increased-epcam-cd3-bispecific-bite-antibody-mt110-efficacy-against-ido1-hi-breast-cancer-via-enhancing-immune-cells-activity
#19
Ri Hong, Yuhai Zhou, Xiujuan Tian, Lijuan Wang, Xiaoyun Wu
MuS110 and MT110 are BiTE antibodies bispecific for CD3 and EpCAM, which is the most frequently and highly expressed tumor-associated antigen on breast cancer. And pronounced expression of IDO1 has also been reported in breast cancer. Our study aimed to investigate whether IDO1 inhibitor D-1MT combing with MuS110/MT110 had synergistic antitumor effects on IDO expressing EpCAM-positive breast cancer cells in vitro and in vivo. Data suggested that the expression of IDO1 on Epcam-positive breast cancer 4T1 and MCF-7 decreased MuS110/MT110 antitumor efficacy by the suppression of T cells activation in vitro...
November 9, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29120388/synthesis-and-molecular-modeling-studies-of-n-hydroxyindazolecarboximidamides-as-novel-indoleamine-2-3-dioxygenase-1-ido1-inhibitors
#20
Dong-Ho Lee, Joo-Youn Lee, Jieun Jeong, Miok Kim, Kyung Won Lee, Eunseo Jang, Sunjoo Ahn, Chang Hoon Lee, Jong Yeon Hwang
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that is highly overexpressed in various cancer cells and antigen-presenting cells. It has emerged as an attractive therapeutic target for cancer immunotherapy, which has prompted high interest in the development of small-molecule inhibitors. To discover novel IDO1 inhibitors, we designed and synthesized a series of N'-hydroxyindazolecarboximidamides. Among the compounds synthesized, compound 8a inhibited both tryptophan depletion and kynurenine production through the IDO1 enzyme...
November 9, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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