Pharmacokinetics of S‐epacadostat, an indoleamine 2,3‐dioxygenase 1 inhibitor in dog plasma and identification of its metabolites in vivo and in vitro

2021 ◽  
Author(s):  
Yumu Zhang ◽  
Xin Li ◽  
Yufei Sun ◽  
Xinghua Liu ◽  
Wenyan Wang ◽  
...  
Keyword(s):  
Indoleamine 2,3 Dioxygenase ◽  
Dog Plasma

scholarly journals Nano-encapsulated tryptanthrin derivative for combined anticancer therapy via inhibiting indoleamine 2,3-dioxygenase and inducing immunogenic cell death

Nanomedicine ◽  
2019 ◽  
Vol 14 (18) ◽  
pp. 2423-2440 ◽  
Author(s):  
Canyu Yang ◽  
Bing He ◽  
Qiang Zheng ◽  
Dakuan Wang ◽  
Mengmeng Qin ◽  
...  
Keyword(s):  
Cell Death ◽  
Single Agent ◽  
Tumor Burden ◽  
Antitumor Efficacy ◽  
In Vivo Studies ◽  
Immunogenic Cell Death ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tumor Tissues

Aim: We developed a polycaprolactone-based nanoparticle (NP) to encapsulate tryptanthrin derivative CY-1-4 and evaluated its antitumor efficacy. Materials & methods: CY-1-4 NPs were prepared and evaluated for their cytotoxicity and associated mechanisms, indoleamine 2,3-dioxygenase (IDO)-inhibitory ability, immunogenic cell death (ICD)-inducing ability and antitumor efficacy. Results: CY-1-4 NPs were 123 nm in size. In vitro experiments indicated that they could both induce ICD and inhibit IDO. In vivo studies indicated that a medium dose reduced 58% of the tumor burden in a B16-F10-bearing mouse model, decreased IDO expression in tumor tissues and regulated lymphocytes subsets in spleen and tumors. Conclusion: CY-1-4 is a potential antitumor candidate that could act as a single agent with combined functions of IDO inhibition and ICD induction.

scholarly journals Increased activity of indoleamine 2,3-dioxygenase in serum from acutely infected dengue patients linked to gamma interferon antiviral function

2009 ◽  
Vol 90 (4) ◽  
pp. 810-817 ◽  
Author(s):  
Aniuska Becerra ◽  
Rajas V. Warke ◽  
Kris Xhaja ◽  
Barbara Evans ◽  
James Evans ◽  
...  
Keyword(s):  
Antiviral Effect ◽  
Denv Infection ◽  
Gamma Interferon ◽  
Indoleamine 2,3 Dioxygenase ◽  
Inhibition Of Growth ◽  
Healthy Donors ◽  
Antiviral Function ◽  
Micro Organisms

The depletion of l-tryptophan (L-Trp) has been associated with the inhibition of growth of micro-organisms and also has profound effects on T cell proliferation and immune tolerance. The enzyme indoleamine 2,3-dioxygenase (IDO) catalyses the rate-limiting step in the catabolic pathway of L-Trp. Gene expression analysis has shown upregulation of genes involved in L-Trp catabolism in in vitro models of dengue virus (DENV) infection. To understand the role of IDO during DENV infection, we measured IDO activity in sera from control and DENV-infected patients. We found increased IDO activity, lower levels of L-Trp and higher levels of l-kynurenine in sera from DENV-infected patients during the febrile days of the disease compared with patients with other febrile illnesses and healthy donors. Furthermore, we confirmed upregulation of IDO mRNA expression in response to DENV infection in vitro, using a dendritic cell (DC) model of DENV infection. We found that the antiviral effect of gamma interferon (IFN-γ) in DENV-infected DCs in vitro was partially dependent on IDO activity. Our results demonstrate that IDO plays an important role in the antiviral effect of IFN-γ against DENV infection in vitro and suggest that it has a role in the immune response to DENV infections in vivo.

Neopterin suppresses the activity of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase in human peripheral blood mononuclear cells

Pteridines ◽  
2013 ◽  
Vol 24 (3) ◽  
pp. 237-243
Author(s):  
Sebastian Schroecksnadel ◽  
Elena-Sophia Ledjeff ◽  
Johanna Gostner ◽  
Christiana Winkler ◽  
Katharina Kurz ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Peripheral Blood Mononuclear ◽  
Indoleamine 2,3 Dioxygenase ◽  
Blood Mononuclear Cells ◽  
Ifn Γ

AbstractIn vitro, large amounts of neopterin are released from human monocyte-derived macrophages and dendritic cells primarily upon stimulation with Th1-type cytokine interferon-γ (IFN-γ). IFN-γ also induces the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan (TRP) to form kynurenine (KYN). IDO-mediated TRP catabolism is very effective in suppressing the proliferation of T lymphocytes as well as of pathogens in vitro and in vivo. In this study, we investigated whether exogenously added neopterin may influence IDO activity in resting and in stimulated peripheral blood mononuclear cells (PBMC). PBMC were isolated from healthy donors, and neopterin was added in a concentration range from 0.01 to 50 μmol/L. After 30 min, PBMC were stimulated or not with 10 μg/mL of mitogen phytohemagglutinin (PHA). After 48 h, culture supernatants were collected, KYN and TRP concentrations were measured by high-performance liquid chromatography, and the ratio of KYN vs. TRP was calculated as an estimate of IDO activity. Spontaneous as well as PHA-induced TRP breakdown was suppressed by exogenously added neopterin in a dose-dependent way; the lowest active concentration of neopterin was <100 nmol/L. As neopterin concentrations in the nanomolar range are commonly observed in patients suffering from infections, sepsis, or uremia, our results suggest that neopterin formation might also serve as a feedback mechanism to slow down TRP degradation in vivo.

Effects of antibiotics on platelet functions in human plasma In Vitro and dog plasma in vivo

1980 ◽  
Vol 69 (11) ◽  
pp. 1282-1284 ◽  
Author(s):  
M.I. Genua ◽  
J. Giraldez ◽  
E. Rocha ◽  
A. Monge
Keyword(s):  
Human Plasma ◽  
Dog Plasma ◽  
Platelet Functions

scholarly journals Studying the immunosuppressive role of indoleamine 2,3-dioxygenase: tryptophan metabolites suppress rat allogeneic T-cell responses in vitro and in vivo

2005 ◽  
Vol 18 (1) ◽  
pp. 95-100 ◽  
Author(s):  
Thomas M. Bauer ◽  
Lucian P. Jiga ◽  
Jing-Jing Chuang ◽  
Marco Randazzo ◽  
Gerhard Opelz ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Cell Responses ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tryptophan Metabolites

scholarly journals Indoleamine 2,3-dioxygenase-1 is protective in atherosclerosis and its metabolites provide new opportunities for drug development

2015 ◽  
Vol 112 (42) ◽  
pp. 13033-13038 ◽  
Author(s):  
Jennifer E. Cole ◽  
Nagore Astola ◽  
Adam P. Cribbs ◽  
Michael E. Goddard ◽  
Inhye Park ◽  
...  
Keyword(s):  
B Cells ◽  
Anthranilic Acid ◽  
Ex Vivo ◽  
Arterial Injury ◽  
Lesion Size ◽  
Chemokine Production ◽  
Indoleamine 2,3 Dioxygenase ◽  
Enhanced Production

Atherosclerosis is the major cause of cardiovascular disease (CVD), the leading cause of death worldwide. Despite much focus on lipid abnormalities in atherosclerosis, it is clear that the immune system also has important pro- and antiatherogenic functions. The enzyme indoleamine-2,3-dioxygenase (IDO) catalyses degradation of the essential amino acid tryptophan into immunomodulatory metabolites. How IDO deficiency affects immune responses during atherogenesis is unknown and we explored potential mechanisms in models of murine and human atherosclerosis. IDO deficiency in hypercholesterolemic ApoE−/− mice caused a significant increase in lesion size and surrogate markers of plaque vulnerability. No significant changes in cholesterol levels were observed but decreases in IL-10 production were found in the peripheral blood, spleen and lymph node B cells of IDO-deficient compared with IDO-competent ApoE−/− mice. 3,4,-Dimethoxycinnamoyl anthranilic acid (3,4-DAA), an orally active synthetic derivative of the tryptophan metabolite anthranilic acid, but not l-kynurenine, enhanced production of IL-10 in cultured splenic B cells. Finally, 3,4-DAA treatment reduced lesion formation and inflammation after collar-induced arterial injury in ApoE−/− mice, and reduced cytokine and chemokine production in ex vivo human atheroma cell cultures. Our data demonstrate that endogenous production of tryptophan metabolites via IDO is an essential feedback loop that controls atherogenesis and athero-inflammation. We show that the IDO pathway induces production of IL-10 in B cells in vivo and in vitro, suggesting that IDO may induce immunoregulatory functions of B cells in atherosclerosis. The favorable effects of anthranilic acid derivatives in atherosclerosis indicate a novel approach toward therapy of CVD.

scholarly journals THE BINDING OF MYOGLOBIN BY PLASMA PROTEIN

1960 ◽  
Vol 111 (1) ◽  
pp. 65-75 ◽  
Author(s):  
Willoughby Lathem
Keyword(s):  
Plasma Protein ◽  
Binding Sites ◽  
Binding Capacity ◽  
Plasma Hemoglobin ◽  
Renal Threshold ◽  
Dog Plasma ◽  
Beta Globulin ◽  
Maximal Binding

When added to dog plasma in vitro and in vivo, myoglobin was bound to plasma protein in a concentration which, maximally, averaged 21 ± 6 mg. per cent. Electrophoretically, bound myoglobin was separated from free myoglobin and migrated between alpha-2 and beta globulin. The electrophoretic characteristics of protein-bound myoglobin were similar to, although not identical with, those of protein-bound hemoglobin. The maximal binding capacity of plasma for myoglobin was less than for hemoglobin, which averaged 123 mg. per cent. At concentrations below the maximal binding capacity, from 15 to 50 per cent of the myoglobin was in the free, unbound state, differing from hemoglobin which was completely bound at all concentrations below the binding capacity. When myoglobin and hemoglobin were added together to plasma, hemoglobin appeared to interfere with the binding of myoglobin or to replace it at the binding sites. Myoglobin, however, did not appear to interfere with the binding of hemoglobin. These observations suggested that myoglobin and hemoglobin were bound at least in part by the same protein. When myoglobin was given intravenously, free myoglobin was excreted in the urine, whereas protein-bound myoglobin was not excreted. This suggests that protein-binding contributes to or determines the apparent renal threshold to myoglobin.

scholarly journals Enhancement of Innate Immunity againstMycobacterium avium Infection by Immunostimulatory DNA Is Mediated by Indoleamine 2,3-Dioxygenase

2001 ◽  
Vol 69 (10) ◽  
pp. 6156-6164 ◽  
Author(s):  
Tomoko Hayashi ◽  
Savita P. Rao ◽  
Kenji Takabayashi ◽  
John H. Van Uden ◽  
Richard S. Kornbluth ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Indoleamine 2,3 Dioxygenase ◽  
Mouse Macrophages ◽  
Avium Infection ◽  
Human And Mouse

ABSTRACT Bacterial DNA and its synthetic immunostimulatory oligodeoxynucleotide analogs (ISS-ODN) activate innate immunity and promote Th1 and cytotoxic T-lymphocyte immune responses. Based on these activities, we investigated whether ISS-ODN could modify the course ofMycobacterium avium infection. M. aviumgrowth in vitro was significantly inhibited by ISS-ODN treatment of human and mouse macrophages, and M. avium growth in vivo was similarly inhibited in C57BL/6 mice treated with ISS-ODN. This protective effect of ISS-ODN was largely independent of tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12), nitric oxide, NADPH oxidase, alpha/beta interferon (IFN-α/β), and IFN-γ. In contrast, we found that the induction of indoleamine 2,3-dioxygenase (IDO) was required for the antimycobacterial effect of ISS-ODN. To evaluate the potential for synergism between ISS-ODN and other antimycobacterial agents, treatment with a combination of ISS-ODN and clarithromycin (CLA) was tested in vitro and in vivo. ISS-ODN significantly enhanced the therapeutic effect of CLA in both human and mouse macrophages and in C57BL/6 mice. This study newly identifies IDO as being involved in the antimicrobial activity of ISS-ODN and suggests the usefulness of ISS-ODN when used in combination with conventional chemotherapy for microbial infections.

Quantitative evaluation of fibrinolytic enzymes in a simulated human system

1964 ◽  
Vol 19 (3) ◽  
pp. 536-539 ◽  
Author(s):  
Albert E. Munson ◽  
Nathan Back ◽  
Clara M. Ambrus ◽  
Howard Lassman ◽  
Eugene Lippschutz ◽  
...  
Keyword(s):  
Human Plasma ◽  
Vascular System ◽  
In Vitro System ◽  
Fibrinolytic Enzymes ◽  
Human System ◽  
Dog Plasma ◽  
In Vitro Systems ◽  
Pathologic Processes

A simple in vitro system for the assay of fibrinolytic enzymes intended for therapeutic use has been described. The system employs small quantities of human plasma from outdated bank blood as perfusing medium and purified human fibrin clots labeled with radioactive iodine. Thus, it is possible to follow the dissolution of a human clot without the intervention of reactions of the vascular system (e.g., release of activators). It was shown that the simulated system compares favorably with the in vivo assay. In the assay of a urokinase-activated human plasmin preparation, substitution of human plasma with dog plasma as a perfusing medium resulted in a decrease of the fibrinolytic response. In the case of two preparations, data from the simulated human system correlated well with results of preliminary clinical testing. In using this system as an initial screen for fibrinolytic agents, one must be aware of the fact that in vitro systems represent only part of the mechanisms involved in physiologic or pathologic processes. fibrinolysin system; plasmin; urokinase; thrombolysis; plasma Submitted on December 6, 1963

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