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ido 1 inhibitor

Devarati Mitra, Nora K Horick, Diane G Brackett, Kent W Mouw, Jason L Hornick, Soldano Ferrone, Theodore S Hong, Harvey Mamon, Jeffrey W Clark, Aparna R Parikh, Jill N Allen, David P Ryan, David T Ting, Vikram Deshpande, Jennifer Y Wo
BACKGROUND: This study characterizes the tumor-immune microenvironment in pretreatment, localized anal squamous cell carcinoma (ASCC), including two markers that have not previously been studied in ASCC: indoleamine 2,3 dioxygenase 1 (IDO1) and human leukocyte antigen (HLA) class I. MATERIALS AND METHODS: Retrospective review identified 63 patients with ASCC receiving definitive chemoradiation between 2005 and 2016 with pretreatment tissue available. Immunohistochemistry was used to quantify cluster of differentiation 8 (CD8), programmed cell death protein 1, programmed death-ligand 1, HLA class I, and IDO1...
February 12, 2019: Oncologist
L B Jesus, A B Santos, E E V Jesus, R G D Santos, M S Grangeiro, A Bispo-da-Silva, M R Arruda, D S Argolo, A M Pinheiro, R S El-Bachá, S L Costa, M F D Costa
Central nervous system (CNS) is the main site for encystment of Neospora caninum in different animal species. In this tissue, glial cells (astrocytes and microglia) modulate responses to aggression in order to preserve homeostasis and neuronal function. Previous data showed that when primary cultures of glial cells are infected with N. caninum, they develop gliosis and the immune response is characterized by the release of TNF and IL-10, followed by the control of parasite proliferation. In order to elucidate this control, three enzymatic systems involved in parasite-versus-host interactions were observed on a model of neuron/glia co/cultures obtained from rat brains...
February 2019: Veterinary Parasitology
Magdalena Massalska, Ewa Kuca-Warnawin, Iwona Janicka, Magdalena Plebanczyk, Dariusz Pawlak, Tomas Dallos, Anna Olwert, Anna Radzikowska, Pawel Maldyk, Ewa Kontny, Wlodzimierz Maslinski
OBJECTIVE: Rheumatoid arthritis (RA) is characterized by expansion of fibroblast-like synoviocytes (FLS) in inflamed joints and activation of lymphocytes. Tryptophan (trp) is an essential amino acid indispensable for the biosynthesis of proteins and critical for survival of lymphocytes. Indoleamine 2,3-dioxygenase (IDO) that initiates the degradation of trp and tryptophanyl-tRNA synthetase (TTS) essential for tryptophan synthesis, regulate trp bioavailability. Here, we tested the hypothesis that triggered by cytokines, enhanced IDO activity modulate regulatory function of otherwise non-tolerogenic FLS isolated from RA patients...
February 4, 2019: Immunopharmacology and Immunotoxicology
Rami S Komrokji, Sheng Wei, Adam W Mailloux, Ling Zhang, Eric Padron, David Sallman, Jeffrey E Lancet, Sara Tinsley, Lisa A Nardelli, Javier Pinilla-Ibarz, Pearlie K Epling-Burnette, Alan F List
BACKGROUND: INCB024360 is an oral inhibitor of the enzyme indoleamine 2,3-dioxygenase (IDO), which catalyzes the degradation of tryptophan to kynurenine. Preclinical data suggest that IDO1 inhibition by INCB024360 will increase T cell proliferation, and decrease T regulatory cells and myeloid derived suppressor cells suppressive activity. We conducted a phase II study to explore activity and pharmacodynamics of INCB024360 in patients with myelodysplastic syndromes. PATIENTS AND METHODS: All patients were treated with INCB024360 600 mg orally twice a day for at least 16 weeks...
December 20, 2018: Clinical Lymphoma, Myeloma & Leukemia
Mayanne M T Zhu, Amanda R Dancsok, Torsten O Nielsen
PURPOSE OF REVIEW: This review focuses on the recent clinical development of indolamine-2,3-dioxygenase-1 (IDO-1) inhibitors. RECENT FINDINGS: IDO-1 alters tryptophan metabolism in a manner enhancing T-regulatory cell activity, but pre-clinical data show that its role in tumorigenesis is context-dependent on host and tumor interaction, highlighting some challenges in understanding the molecular oncology of this enzymatic drug target. Because results from phase I/II trials of IDO-1 inhibitor monotherapy have been disappointing, current clinical trials employ IDO-1 inhibitors in combination strategies with other immunotherapy agents or with chemotherapy ± radiation...
January 18, 2019: Current Oncology Reports
Ning Wang, Jie Zhang, Qiao Li, Hui Xu, Geng Chen, Zhiyong Li, Difa Liu, Xin Yang
Indoleamine 2,3-dioxygenase (IDO) is one of the important targets for cancer immunotherapy through tryptophan pathway. Recently it has being paid great attention to search potent and safe IDO inhibitor from small-molecule compounds. Picrasma quassioides is a kind of medicinal plant abundant with tryptophan-derived indole alkaloids. By virtual screening and kinetic method for enzymatic analysis, lead compounds with potential IDO inhibitory activity were discovered for the first time from PQAs, the natural alkaloids in Picrasma quassioides...
January 14, 2019: Fitoterapia
Tuba N Gide, Benjamin M Allanson, Alexander M Menzies, Peter M Ferguson, Jason Madore, Robyn P M Saw, John F Thompson, Georgina V Long, James S Wilmott, Richard A Scolyer
AIMS: Indoleamine 2,3-dioxygenase (IDO), an immunomodulatory enzyme, facilitates immune escape by tumors and promotes tumor progression. IDO inhibitors with and without additional anti-PD-1 therapy have been evaluated in recent and ongoing melanoma clinical trials, but IDO expression in melanoma tumors and therefore its potential role as a predictive biomarker remains unknown. This study sought to evaluate IDO expression in immunotherapy-naïve metastatic melanoma patients in order to determine patterns of expression in corresponding primary melanomas, locoregional metastases and distant metastases...
December 27, 2018: Histopathology
Yean J Lim, Timothy C Foo, Amanda Yeung, Xiaofan Tu, Yuanqing Ma, Clare L Hawkins, Paul K Witting, Guy N L Jameson, Andrew C Terentis, Shane R Thomas
The heme enzyme indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the first reaction of L-tryptophan oxidation along the kynurenine pathway. IDO1 is a central immunoregulatory enzyme with important implications for inflammation, infectious disease, autoimmune disorders and cancer. Here we demonstrate that IDO1 is a mammalian nitrite reductase capable of chemically reducing nitrite to nitric oxide (NO) under hypoxia. UV-visible absorption and resonance Raman spectroscopy showed that incubation of dithionite-reduced, ferrous IDO1 protein (FeII -IDO) with nitrite under anaerobic conditions resulted in the time-dependent formation of a FeII -nitrosyl IDO1 species, which was inhibited by substrate L-tryptophan, dependent on the concentration of nitrite or IDO1 and independent of the concentration of the reductant, dithionite...
December 26, 2018: Biochemistry
Chang Chen, Cong Guo, Jian Gao, Kaifeng Shi, Jingtang Cheng, Jun Zhang, Sha Chen, Yan Liu, An Liu
BACKGROUND: Both Chuanxiong (Ligusticum chuanxiong Hort) and Tianma (Gastrodia elata Blume) have the effects of vasorelaxation and antihypertension. However, the effects of Tianshu Capsule (TSC, composed of Chuanxiong and Tianma in the mass ratio of 4:1) on antihypertensive activity have not been explored. This study aimed to investigate the eff ;ects of TSC on vascular tension and blood pressure in rats and to explore the underlying mechanisms. METHODS: The vasorelaxant effect of TSC was explored on thoracic aortic rings (both intact endothelium and denuded) preincubated with phenylephrine (Phe) or potassium chloride (KCL)...
December 21, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Mengmeng Yan, Yijia Liu, Xianghui Zhu, Xiaoli Wang, Lanxia Liu, Hongfan Sun, Chun Wang, Deling Kong, Guilei Ma
Despite the potential efficacy of immune checkpoint blockade for effective treatment of cancer, this therapeutic modality is not generally curative and only a fraction of patients respond. Combination approaches provide strategies to target multiple antitumor immune pathways to induce synergistic antitumor immunity. Here, a multi-combination immunotherapy including photothermal therapy (PTT), indoleamine-2,3-dioxygenase (IDO) inhibition and programmed cell death-ligand 1 (PD-L1) blockade is introduced for inducing synergistic antitumor immunity...
December 24, 2018: ACS Applied Materials & Interfaces
Laurence Booth, Jane L Roberts, Cindy Sander, Alshad S Lalani, John M Kirkwood, John F Hancock, Andrew Poklepovic, Paul Dent
There is no efficacious standard of care therapy for uveal melanoma. Unlike cutaneous disease, uveal melanoma does not exhibit RAS mutations but instead contains mutations with ~90% penetrance in either Gαq or Gα11 . Previously we demonstrated that neratinib caused ERBB1/2/4 and RAS internalization into autolysosomes which resulted in their proteolytic degradation. In PDX isolates of uveal melanoma, neratinib caused the internalization and degradation of Gαq and Gα11 in parallel with ERBB1 breakdown. These effects were enhanced by the HDAC inhibitor entinostat...
December 20, 2018: Cancer Biology & Therapy
Wenyan Wang, Xuhui Zhuang, Heyuan Sun, Lina Dong, Zongliang Liu, Guangying Du, Liang Ye, Jingwei Tian
1.S-EPA is a sulfur-substitution analogue of epacadostat (EPA), an effective small molecule indoleamine 2,3-dioxgenase1 (IDO) inhibitor. By in vitro and in vivo experiments, pharmacokinetic differences of two closely related analogs, S-EPA and EPA was investigated in this study. 2.Liver microsomes clearance experiments showed S-EPA had comparable metabolic stability with EPA in rat and human liver microsomes. The whole blood distribution experiments showed the distribution ratio of S-EPA in blood cells to plasma in mice, rats, dogs and monkey was 1...
December 3, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Jianqin Lu, Xiangsheng Liu, Yu-Pei Liao, Xiang Wang, Ayman Ahmed, Wen Jiang, Ying Ji, Huan Meng, Andre E Nel
Immunotherapy provides the best approach to reduce the high mortality of metastatic breast cancer (BC). We demonstrate a chemo-immunotherapy approach, which utilizes a liposomal carrier to simultaneously trigger immunogenic cell death (ICD) as well as interfere in the regionally overexpressed immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO-1) at the BC tumor site. The liposome was constructed by self-assembly of a phospholipid-conjugated prodrug, indoximod (IND), which inhibits the IDO-1 pathway, followed by the remote loading of the ICD-inducing chemo drug, doxorubicin (DOX)...
November 27, 2018: ACS Nano
Massimo Romani, Maria Pia Pistillo, Roberta Carosio, Anna Morabito, Barbara Banelli
Targeting the Immune Checkpoint molecules (ICs; CTLA-4, PD-1, PD-L1/2, and others) which provide inhibitory signals to T cells, dramatically improves survival in hard-to-treat tumors. The establishment of an immunosuppressive environment prevents endogenous immune response in glioblastoma; therefore, manipulating the host immune system seems a reasonable strategy also for this tumor. In glioma patients the accumulation of CD4+ /CD8+ T cells and Treg expressing high levels of CTLA-4 and PD-1, or the high expression of PD-L1 in glioma cells correlates with WHO high grade and short survival...
2018: Frontiers in Oncology
Tiziana Larussa, Serena Gervasi, Rita Liparoti, Evelina Suraci, Raffaella Marasco, Maria Imeneo, Francesco Luzza
The anti-inflammatory and antimicrobial properties of curcumin suggest its use as an anti- Helicobacter pylori ( H. pylori ) agent, but mechanisms underlying its helpful activity are still not clear. Indoleamine 2,3-dioxygenase (IDO) promotes the effector T cell apoptosis by catalyzing the rate-limiting first step in tryptophan catabolism, and its high expression in H. pylori -infected human gastric mucosa attenuates Th1 and Th17 immune response. The aim of this study was to investigate the role of curcumin in modulating the expression of IL-17 and IDO in H...
2018: Journal of Immunology Research
Michael D Rugen, Mathieu M J L Vernet, Laila Hantouti, Amalia Soenens, Vasilios M E Andriotis, Martin Rejzek, Paul Brett, Richard J B H N van den Berg, Johannes M F G Aerts, Hermen S Overkleeft, Robert A Field
Iminosugars are carbohydrate mimics that are useful as molecular probes to dissect metabolism in plants. To analyse the effects of iminosugar derivatives on germination and seedling growth, we screened a library of 390 N-substituted iminosugar analogues against Arabidopsis and the small cereal Eragrostis tef (Tef). The most potent compound identified in both systems, N-5-(adamantane-1-yl-ethoxy)pentyl- L-ido-deoxynojirimycin (L-ido-AEP-DNJ), inhibited root growth in agar plate assays by 92% and 96% in Arabidopsis and Tef respectively, at 10 µM concentration...
November 6, 2018: Scientific Reports
Marta Artola, Chi-Lin Kuo, Stephen A McMahon, Verena Oehler, Thomas Hansen, Martijn van der Lienden, Xu He, Hans van den Elst, Bogdan I Florea, Allison R Kermode, Tracey M Gloster, Gijsbert A van der Marel, Jeroen D C Codée, Hermen S Overkleeft, Johannes M F G Aerts
Cyclophellitol aziridines are potent irreversible inhibitors of retaining glycosidases and versatile intermediates in the synthesis of activity-based glycosidase probes (ABPs). Direct 3-amino-2-(trifluoromethyl)quinazolin-4(3H)-one-mediated aziridination on L-ido-configured cyclohexene has enabled the synthesis of new covalent inhibitors and ABPs of α-L-iduronidase, deficiency of which underlies the lysosomal storage disorder mucopolysaccharidosis type I (MPS I). The iduronidase ABPs react covalently and irreversibly in an activity-based manner with human recombinant α-L-iduronidase (rIDUA, Aldurazyme®)...
October 11, 2018: Chemistry: a European Journal
Yana Wang, Shiyu Lv, Qiang Wang, Chan Wang, Mingxing Zhu, Zhanbing Ma, Wei Zhao
Mice immunized with recombinant Echinococcus granulosus antigens Eg10 and Eg mMDH do not show elevated resistance to E. granulosus infection but show aggravated infection instead. To gain a deeper insight in the immune tolerance mechanisms in mice immunized with Eg10 and Eg mMDH, this study simulated the immune tolerance process in vitro by culturing bone marrow-derived dendritic cells (BMDCs) in the presence of Eg10 or Eg mMDH. Scanning electron microscopy revealed that Eg10- and Eg mMDH-treated DCs exhibited immature cell morphology, while addition of LPS to the cells induced changes in cell morphology and an increase in the number of cell-surface protrusions...
2018: PloS One
Eric Fox, Thomas Oliver, Melissa Rowe, Sunil Thomas, Yousef Zakharia, Paul B Gilman, Alexander J Muller, George C Prendergast
Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects...
2018: Frontiers in Oncology
Xiao-Jun Zhang, Zhong-Wen Yuan, Chang Qu, Xiu-Ting Yu, Tao Huang, Ping Vicky Chen, Zi-Ren Su, Yao-Xing Dou, Jia-Zhen Wu, Hui-Fang Zeng, Ying Xie, Jian-Nan Chen
Inflammatory bowel disease (IBD), majorly include Crohn's disease (CD) and ulcerative colitis (UC), is chronic and relapsing inflammatory disorders of the gastrointestinal tract, which treatment options remain limited. Here we examined the therapeutic effects of an isoquinoline alkaloid, Palmatine (Pal), on mice experimental colitis induced by dextran sulfate sodium (DSS) and explored underlying mechanisms. Colitis was induced in BALB/c mice by administering 3% DSS in drinking water for 7 days. Pal (50 and 100 mg kg-1 ) and the positive drug Sulfasalazine (SASP, 200 mg kg-1 ) were orally administered for 7 days...
September 19, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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