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Michael G Brant, Jake Goodwin-Tindall, Kurt R Stover, Paul M Stafford, Fan Wu, Autumn R Meek, Paolo Schiavini, Stephanie Wohnig, Donald F Weaver
Inhibition of indoleamine 2,3-dioxygenase (IDO1) is an attractive immunotherapeutic approach for the treatment of a variety of cancers. Dysregulation of this enzyme has also been implicated in other disorders including Alzheimer's disease and arthritis. Herein, we report the structure-based design of two related series of molecules: N 1-substituted 5-indoleimidazoles and N 1-substituted 5-phenylimidazoles. The latter (and more potent) series was accessed through an unexpected rearrangement of an imine intermediate during a Van Leusen imidazole synthesis reaction...
February 8, 2018: ACS Medicinal Chemistry Letters
Zhenlong Yu, Xiangge Tian, Yuling Peng, Zheng Sun, Chao Wang, Ning Tang, Bin Li, Yuqing Jian, Wei Wang, Xiaokui Huo, Xiaochi Ma
Melatonin is an endogenous indoleamine with a wide range of biological functions in the various organisms from bacteria to mammals. Evidence indicates that melatonin facilitates apoptosis in cancer cells and enhances the anti-tumor activity of chemotherapy in animals and clinical studies. However, the melatonin metabolism and the key metabolic targets in cancer cells still remain unknown. In this study, U118 and SH-SY5Y tumor cell lines were used to investigate the metabolic pathways of melatonin in cancer cells...
February 17, 2018: Journal of Pineal Research
Qian Ye, Chenglong Wang, Jie Xian, Ming Zhang, Yijia Cao, Youde Cao
Programmed cell death protein 1 (PD-1) and Indoleamine 2,3-dioxygenase (IDO) are both immunosuppressive proteins. Here, we investigated the relationship between PD-1 and IDO in the tumor microenvironment (TME) and in tumor-draining lymph nodes (TDLNs) in breast cancer patients. First, the protein and mRNA expression levels of PD-1 and IDO in 20 frozen tissues were examined using Western blotting and RT-PCR. Second, 151 paraffin-embedded breast samples and 52 lymph node samples were analyzed by immunohistochemistry...
February 12, 2018: Human Pathology
Lilla Hornyák, Nikoletta Dobos, Gábor Koncz, Zsolt Karányi, Dénes Páll, Zoltán Szabó, Gábor Halmos, Lóránt Székvölgyi
Tumors are composed of abnormally transformed cell types and tissues that differ from normal tissues in their genetic and epigenetic makeup, metabolism, and immunology. Molecular compounds that modulate the immune response against neoplasms offer promising new strategies to combat cancer. Inhibitors targeting the indoleamine-2,3-dioxygenase 1 enzyme (IDO1) represent one of the most potent therapeutic opportunities to inhibit tumor growth. Herein, we assess the biochemical role of IDO1 in tumor metabolism and immune surveillance, and review current diagnostic and therapeutic approaches that are intended to increase the effectiveness of immunotherapies against highly aggressive and difficult-to-treat IDO-expressing cancers...
2018: Frontiers in Immunology
Biswojit Debnath, Mubasher Hussain, Muhammad Irshad, Sangeeta Mitra, Min Li, Shuang Liu, Dongliang Qiu
Acid rain (AR) is a serious global environmental issue causing physio-morphological changes in plants. Melatonin, as an indoleamine molecule, has been known to mediate many physiological processes in plants under different kinds of environmental stress. However, the role of melatonin in acid rain stress tolerance remains inexpressible. This study investigated the possible role of melatonin on different physiological responses involving reactive oxygen species (ROS) metabolism in tomato plants under simulated acid rain (SAR) stress...
February 11, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Joo-Hung Park, Jeong-Min Lee, Eun-Jin Lee, Da-Jeong Kim, Won-Bhin Hwang
Various amino acids regulate cell growth and differentiation. In the present study, we examined the ability of HT-29 cells to differentiate into goblet cells in RPMI and DMEM which are largely different in the amounts of numerous amino acids. Most of the HT-29 cells differentiated into goblet cells downregulating the stem cell marker Lgr5 when cultured in DMEM, but remained undifferentiated in RPMI. The goblet cell differentiation in DMEM was inhibited by 1-methyl-tryptophan (1-MT), an inhibitor of indoleamine 2,3 dioxygenase-1 which is the initial enzyme in tryptophan metabolism along the kynurenine (KN) pathway, whereas tryptophan and KN induced goblet cell differentiation in RPMI...
February 13, 2018: Oncology Reports
Avinoam Nevler, Alexander J Muller, Joseph A Cozzitorto, Austin Goetz, Jordan M Winter, Theresa P Yeo, Harish Lavu, Charles J Yeo, George C Prendergast, Jonathan R Brody
BACKGROUND: Variation in an individual's genetic status can impact the development of pancreatic ductal adenocarcinoma (PDA), however the majority of familial pancreatic cancers (FPC) cannot yet be attributed to a specific inherited mutation. We present data suggesting a correlation between loss of function single nucleotide polymorphisms (SNPs) in an immune regulator gene, indoleamine-2,3-dioxygenase-2 (IDO2), and an increased risk of FPC. METHODS: Germline DNA from patients who underwent resection for PDA (n=79) was sequenced for the IDO2 SNPs R248W and Y359Stop...
February 6, 2018: Journal of the American College of Surgeons
Aline Bozec, Yubin Luo, Cecilia Engdahl, Camille Figueiredo, Holger Bang, Georg Schett
BACKGROUND: The anti-inflammatory effect of abatacept is most pronounced in patients with high-titer autoantibodies (including anticitrullinated protein antibodies [ACPA] and rheumatoid factor [RF]). Considering that autoantibodies trigger inflammatory cytokine production by monocytes and that abatacept binds to monocytes, influencing their functional state, we hypothesized that abatacept may effectively inhibit the production of several different cytokines by ACPA- or RF-challenged monocytes...
February 7, 2018: Arthritis Research & Therapy
George C Prendergast, William J Malachowski, Arpita Mondal, Peggy Scherle, Alexander J Muller
The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization, and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers...
2018: International Review of Cell and Molecular Biology
George C Prendergast, Arpita Mondal, Souvik Dey, Lisa D Laury-Kleintop, Alexander J Muller
We discuss how small-molecule inhibitors of the tryptophan (Trp) catabolic enzyme indoleamine 2,3-dioxygenase (IDO) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy, or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO inhibitors re-program inflammatory processes to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier...
January 2018: Trends in Cancer
Benjar Issaranggun Na Ayuthaya, Vincent Everts, Prasit Pavasant
Interleukin 12 (IL-12) is an inflammatory cytokine that promotes the response of the immune system. This cytokine has been implicated as a potent stimulator of several diseases characterized by inflammatory-induced bone destruction, such as rheumatoid arthritis and periodontitis. Yet, the exact role of IL-12 in the development and progress of periodontitis has not been clarified. Several studies have demonstrated a positive correlation between the level of IL-12 and the severity of periodontal destruction. Deletion of IL-12 in mice with periodontitis significantly suppressed the level of bone destruction...
February 7, 2018: European Journal of Oral Sciences
Miwa Sasai, Ariel Pradipta, Masahiro Yamamoto
Toxoplasma gondii can infect homoeothermic animals including humans and cause lethal toxoplasmosis in immunocompromised individuals. When hosts are infected with T. gondii, the cells induce immune responses against T. gondii. The pathogen infection is recognized by immune sensors that directly detect T. gondii structural components, leading to production of proinflammatory cytokines and chemokines. Antigen-presenting cells such as macrophages and dendritic cells strongly activate T cells and induce development of Th1 cells and antigen-specific killer CD8 T cells...
February 2, 2018: International Immunology
Neila Hiraishi Mallmann, Emerson Silva Lima, Pritesh Lalwani
OBJECTIVE: Obesity and metabolic syndrome are preventable complex-multifactorial disorders that severely increase risk of cardiovascular disease (CVD). Indoleamine 2,3-dioxygenase (IDO) enzyme converts tryptophan (TRP) to kynurenine (KYN); besides, KYN/TRP ratio has been shown to predict major coronary events and all-cause mortality in patients with coronary artery disease. However, their role in metabolic syndrome is not understood. METHODS: In a cross-sectional study (n = 161, mean population age in years = 32 ± 7...
February 6, 2018: Metabolic Syndrome and related Disorders
Na Wang, Zhigang Wang, Zoufeng Xu, Xianfeng Chen, Guangyu Zhu
The efficacy of conventional chemotherapy is hindered by cancer cells' escape from the immune system. Herein, we report a multifunctional nanohybrid system for effective immuno-chemotherapy against cervical cancer. This nanohybrid contains both immune checkpoint inhibitor and cisplatin anticancer prodrug, showing improved cellular accumulation and increased binding of Pt to DNA and resulting in elevated apoptosis than using cisplatin alone when tested in cervical cancer cells. Intriguingly, the use of immune checkpoint inhibitors enables the inhibition of indoleamine-2,3-dioxygenase and reverses immunosuppressive T cells to recognize cancer cells, leading to T cell proliferation and activation, cancer cell cycle arrest, and ultimately increased cancer cell death...
February 5, 2018: Angewandte Chemie
Noa Ziklo, Miranda E Vidgen, Kuong Taing, Wilhelmina M Huston, Peter Timms
The natural course of Chlamydia trachomatis urogenital tract infections varies between individuals. While protective immunity can occur, some women can become reinfected, contributing to the development of severe pathology. While the reasons for these differences are unknown, an individual's response to induced interferon-γ (IFN-γ) is suggested to be critical. IFN-γ induction of the enzyme indoleamine 2,3-dioxygenase, which depletes tryptophan, may be the key. One hypothesis suggests that indole-producing bacteria in the vaginal microbiota can provide a substrate for the Chlamydia to synthesize tryptophan, rescuing the Chlamydia from host IFN-γ attack...
2018: Frontiers in Cellular and Infection Microbiology
Barbara Dillinger, Sarah Ahmadi-Erber, Manuel Lau, Markus A Hoelzl, Friedrich Erhart, Birgit Juergens, Dietmar Fuchs, Andreas Heitger, Stephan Ladisch, Alexander M Dohnal
Gangliosides shed by tumors into their microenvironment (TME) are immunoinhibitory. Interferon-γ (IFN-γ) may boost antitumor immune responses. Thus we wondered whether IFN-γ would counteract tumor ganglioside-mediated immune suppression. To test this hypothesis, we exposed human monocyte-derived LPS-activated dendritic cells (DC) to IFN-γ and to a highly purified ganglioside, GD1a. DC ganglioside exposure decreased TLR-dependent p38 signaling, explaining the previously observed ganglioside-induced down-modulation of pro-inflammatory surface markers and cytokines...
February 2, 2018: Cellular Immunology
Alessia Griglio, Enza Torre, Marta Serafini, Alice Bianchi, Roberta Schmid, Giulia Coda Zabetta, Alberto Massarotti, Giovanni Sorba, Tracey Pirali, Silvia Fallarini
Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub-micromolar IC50 values in the enzyme-based assay...
February 2, 2018: Bioorganic & Medicinal Chemistry Letters
David K Williams, Jay A Markwalder, Aaron J Balog, Bin Chen, Libing Chen, Jennifer Donnell, Lauren Haque, Amy C Hart, Sunil K Mandal, Andrew Nation, Weifang Shan, Gregory D Vite, Kelly Covello, John T Hunt, Maria N Jure-Kunkel, Steven P Seitz
A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay...
January 11, 2018: Bioorganic & Medicinal Chemistry Letters
Hao Wu, Jianping Gong, Yong Liu
Indoleamine 2, 3-dioxygenase (IDO) catalyzes the initial and rate‑limiting step in the degradation pathway of the essential amino acid tryptophan and is expressed by professional antigen presenting cells (APCs), epithelial cells, vascular endothelium and tumor cells. IDO‑mediated catabolic products, which are additionally termed 'kynurenines', exerts important immunosuppressive functions primarily via regulating T effector cell anergy and inducing the proliferation of T regulatory cells. This endogenous tolerogenic pathway has a critical effect on mediating the magnitude of immune responses under various stress conditions, including tumor, infection and transplantation...
February 1, 2018: Molecular Medicine Reports
Yanling Liu, Huan Liu, Yingqing Xiang, Xiaoyan Chen, Ping Xu, Weiping Min
Objective To study the role of indoleamine 2, 3-dioxygenase 2 (IDO2) in anti-tumor therapy and its effect on the immune response when using IDO2 as therapeutic target. Methods B16-BL6 cells were used to construct mouse xenografted melanoma model. IDO2-shRNA that contained IDO2-siRNA or control shRNA (scrambled-shRNA) was injected hydrodynamically via the tail vein to treat melanoma. The tumor size was measured by vernier caliper. Flow cytometry was performed to analyze the percentage of regulatory T cells (Tregs), T cell apoptosis rate in draining lymph nodes and the expressions of co-stimulatory molecules on splenic dendritic cells (DCs) from different treatment groups...
December 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
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