Ji-Min Ju, Giri Nam, Young-Kwan Lee, Minho Jung, Hanna Chang, Woojin Kim, Woo Jeong Shon, Ji Young Lim, Joo Young Kim, Jun Chang, Chang Ki Min, Dong-Sup Lee, Kyungho Choi, Dong-Mi Shin, Eun Young Choi
Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) also has an immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient ( Ido1 -/- ) BMT to understand why myeloid IDO limits the severity of GVHD...
March 9, 2021: Proceedings of the National Academy of Sciences of the United States of America
Jisun H J Lee, Guddadarangavvanahally K Jayaprakasha, Juan Enciso, Carlos A Avila, Kevin M Crosby, Bhimanagouda S Patil
Tomato (Solanum lycopersicum) fruit is a rich source of health-promoting compounds, and epidemiological studies show that tomato consumption may reduce the risk of chronic diseases. This study compared the effect of genotype, production system, and their interaction on eight tomato varieties grown in the open-field (OF) or net-house (NH), a structure completely covered with a 50-mesh screen to reduce pest and wind damage, in South Texas. The NH structure reduced solar radiation up to ~30% and decreased wind speed by 6...
February 2021: Food Research International
Tiffany Cho, Lie Yun Kok, Jack Uetrecht
Idiosyncratic drug reactions are unpredictable adverse reactions. Although most such adverse reactions appear to be immune mediated, their exact mechanism(s) remain elusive. The idiosyncratic drug reaction most associated with serious consequences is idiosyncratic drug-induced liver injury (IDILI). We have developed a mouse model of amodiaquine (AQ)-induced liver injury that reflects the clinical characteristics of IDILI in humans. This was accomplished by impairing immune tolerance by using PD-1-/- mice and an antibody against CTLA-4...
February 23, 2021: ACS Omega
Daojing Yan, Jiakun Xu, Xiangshi Tan
Inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) have received wide attention for their roles in cancer immunotherapy. It highlights the important role of metalloenzymes in performing human physiological functions. Herein, the recombinant human IDO1 was expressed and purified successfully, and the protein molecule was characterized by SDS-PAGE, MALDI-TOF mass spectrometry, and metalloenzymology. A series of niacin derivatives were investigated with regard to their inhibition on metalloenzyme IDO1, and the resulting potential anti-cancer activities in cell lines...
February 26, 2021: Metallomics: Integrated Biometal Science
Li Fan, Ying Peng, Jingwen Wang, Ping Ma, Lijuan Zhao, Xiaobo Li
BACKGROUND: As the most frequently used kidney-yang tonifying herb in traditional Chinese medicine, dried succulent stems of Cistanche tubulosa (Schenk) Wight (CT) have been shown to be effective in the treatment of depression. However, the antidepressant components and their underlying mechanism remain unclear. PURPOSE: To explore the active components of CT against depression, as well as the potential mechanisms. STUDY DESIGN AND METHODS: Behavioral despair tests were used to assess the antidepressant activities of polysaccharides, oligosaccharides and different glycoside-enriched fractions separated from CT, as well as the typical gut microbiota metabolites including 3-hydroxyphenylpropionic acid (3-HPP) and hydroxytyrosol (HT)...
January 22, 2021: Phytomedicine
Dhara Patel, Matthew Potter, Jordan Marcano Anaya, Meghan E McGee-Lawrence, Mark W Hamrick, William D Hill, Carlos M Isales, Sadanand Fulzele
Advanced age is one of the important contributing factors for musculoskeletal deterioration. Although the exact mechanism behind this degeneration is unknown, it has been previously established that nutritional signaling plays a vital role in musculoskeletal pathophysiology. Our group established the vital role of the essential amino acid, tryptophan, in aging musculoskeletal health. With advanced age, inflammatory factors activate indoleamine 2,3-dioxygenase (IDO1) and accumulate excessive intermediate tryptophan metabolites such as Kynurenine (KYN)...
February 22, 2021: Mechanisms of Ageing and Development
Souvik Dey, Arpita Mondal, James B DuHadaway, Erika Sutanto-Ward, Lisa D Laury-Kleintop, Sunil Thomas, George C Prendergast, Laura Mandik-Nayak, Alexander J Muller
In addition to immunosuppression, it is generally accepted that MDSCs (myeloid-derived suppressor cells) also support tumor angiogenesis. The tryptophan catabolizing enzyme IDO1 (indoleamine 2,3-dioxygenase) has been implicated in promoting neovascularization through its positioning as a key regulatory node between the inflammatory cytokines IFNγ and IL6. Here, we report that within the heterogeneous expanse of Gr-1+ MDSCs, both IDO1 expression and the ability to elicit neovascularization in vivo was associated with a minor subset of autofluorescent, CD11blo cells...
February 23, 2021: Cancer Immunology Research
Heng Du, Xianrui Zheng, Qiqi Zhao, Zhengzheng Hu, Haifei Wang, Lei Zhou, Jian-Feng Liu
Structural variants (SVs) represent essential forms of genetic variation, and they are associated with various phenotypic traits in a wide range of important livestock species. However, the distribution of SVs in the pig genome has not been fully characterized, and the function of SVs in the economic traits of pig has rarely been studied, especially for most domestic pig breeds. Meishan pig is one of the most famous Chinese domestic pig breeds, with excellent reproductive performance. Here, to explore the genome characters of Meishan pig, we construct an SV map of porcine using whole-genome sequencing data and report 33,698 SVs in 305 individuals of 55 globally distributed pig breeds...
2021: Frontiers in Genetics
Maryanne C Herzig, Barbara A Christy, Robbie K Montgomery, Christopher P Delavan, Katherine J Jensen, Sarah E Lovelace, Carolina Cantu, Christi L Salgado, Andrew P Cap, James A Bynum
BACKGROUND: Immunomodulation by mesenchymal stromal cells (MSCs) is a potentially important therapeutic modality. MSCs suppress peripheral blood mononuclear cell (PBMC) proliferation in vitro, suggesting a mechanism for suppressing inflammatory responses in vivo. This study details the interactions of PBMCs and MSCs. METHODS: Pooled human PBMCs and MSCs were co-cultured at different MSC:PBMC ratios and harvested from 0 to 120 h, with and without phytohaemagglutin A (PHA) stimulation...
February 17, 2021: Journal of Immunological Methods
Christian Bogdan
Leishmania are protozoan parasites that predominantly reside in myeloid cells within their mammalian hosts. Monocytes and macrophages play a central role in the pathogenesis of all forms of leishmaniasis, including cutaneous and visceral leishmaniasis. The present review will highlight the diverse roles of macrophages in leishmaniasis as initial replicative niche, antimicrobial effectors, immunoregulators and as safe hideaway for parasites persisting after clinical cure. These multiplex activities are either ascribed to defined subpopulations of macrophages (e...
December 2020: Cytokine: X
Emily C Cherney, Liping Zhang, Susheel Nara, Xiao Zhu, Johnni Gullo-Brown, Derrick Maley, Tai-An Lin, John T Hunt, Christine Huang, Zheng Yang, Celia Darienzo, Lorell Discenza, Asoka Ranasinghe, Mary Grubb, Theresa Ziemba, Sarah C Traeger, Xin Li, Kathy Johnston, Lisa Kopcho, Mark Fereshteh, Kimberly Foster, Kevin Stefanski, Joseph Fargnoli, Jesse Swanson, Jennifer Brown, Diane Delpy, Steven P Seitz, Robert Borzilleri, Gregory Vite, Aaron Balog
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase enzyme implicated in cancer immune response. This account details the discovery of BMS-986242, a novel IDO1 inhibitor designed for the treatment of a variety of cancers including metastatic melanoma and renal cell carcinoma. Given the substantial interest around this target for cancer immunotherapy, we sought to identify a structurally differentiated clinical candidate that performs comparably to linrodostat (BMS-986205) in terms of both in vitro potency and in vivo pharmacodynamic effect in a mouse xenograft model...
February 11, 2021: ACS Medicinal Chemistry Letters
Miyuki Kumazawa, Manabu Tejima, Miwa Fukuda, Shota Takeda, Kenji Suzuki, Yukiko Mizumoto, Kakeru Sato, Minoru Waki, Hiroyuki Miyachi, Akira Asai, Osamu Takikawa, Tomoko Hashimoto, Osamu Ohno, Kenji Matsuno
A structure-activity relationship study unexpectedly showed that carbonothioates 4a and 4b , obtained by a unique alkaline hydrolysis of 2-alkylthio-oxazolines 3a and 3b , respectively, are a novel scaffold for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. Derivatization of the carbonothioates enhanced inhibitory activity against IDO1 and cellular kynurenine production without cytotoxicity and led to the discovery of the related scaffolds carbonodithioates 5 and cyanocarbonimidodithioates 6 as IDO1 inhibitors...
February 11, 2021: ACS Medicinal Chemistry Letters
Fangfang Jin, Qiyue Hu, Hongbo Fei, Hejun Lv, Shenglan Wang, Bin Gui, Junzhen Zhang, Wangyang Tu, Yun Zhang, Lei Zhang, Hong Wan, Limin Zhang, Bin Hu, Fanglong Yang, Chang Bai, Feng He, Lianshan Zhang, Weikang Tao
In this study, a series of novel hydroxyamidine derivatives were identified as potent and selective IDO1 inhibitors by structure-based drug design. Among them, compounds 13 - 15 and 18 exhibited favorable enzymatic and cellular activities. Compound 18 showed improved bioavailability in mouse, rat, and dog (F% = 44%, 58.8%, 102.1%, respectively). With reasonable in vivo pharmacokinetic properties, compound 18 was further evaluated in a transgenic MC38 xenograft mouse model. The combination of compound 18 with PD-1 monoclonal antibody showed a synergistic antitumor effect...
February 11, 2021: ACS Medicinal Chemistry Letters
Lei Gao, Tingting Gao, Ting Zeng, Peng Huang, Nai-Kei Wong, Zhaoyang Dong, Yunjia Li, Guanghui Deng, Zhiyong Wu, Zhiping Lv
Indoleamine 2, 3-dioxygenase 1 (IDO1) has been implicated in the pathogenesis of depression, though its molecular mechanism is still poorly understood. We investigated the molecular mechanism of IDO1 in depression by using the chronic unpredictable mild stress (CUMS) model in Ido1-/- mice and WT mice. The brain blood oxygen level dependent (BOLD) signals in mice were collected by functional magnetic resonance imaging (fMRI) technology. IDO1 inhibitor INCB024360 was intervened in dorsal raphe nucleus (DRN) through stereotactic injection...
February 11, 2021: Aging
F Hosseinkhani, A Heinken, I Thiele, P W Lindenburg, A C Harms, T Hankemeier
The interaction disorder between gut microbiota and its host has been documented in different non-communicable diseases (NCDs) such as metabolic syndrome, neurodegenerative disease, and autoimmune disease. The majority of these altered interactions arise through metabolic cross-talk between gut microbiota and host immune system, inducing a low-grade chronic inflammation that characterizes all NCDs. In this review, we discuss the contribution of bacterial metabolites to immune signaling pathways involved in NCDs...
January 2021: Gut Microbes
Kuipeng Yu, Dengren Li, Fuping Xu, Hao Guo, Feng Feng, Yu Ding, Xiang Wan, Nan Sun, Yang Zhang, Jiahui Fan, Lei Liu, Huimin Yang, Xiangdong Yang
INTRODUCTION: Indoleamine 2,3-dioxygenase 1(IDO1) has complicated roles in immune-inflammatory response regulation, but its correlation with immune cell infiltration in diabetic nephropathy (DN) remains unknown. METHODS: Gene expression data were extracted from the GEO database. Differentially expressed genes (DEGs) were identified and functional correlation analysis was performed. The immune hub gene was screened using Maximal Clique Centrality, and verified in DN model mice via western blotting, immunohistochemistry, and immunofluorescence analysis...
February 10, 2021: International Immunopharmacology
Maysaa Abdulla, Andrei Alexsson, Christer Sundström, Claes Ladenvall, Larry Mansouri, Cecilia Lindskog, Mattias Berglund, Lucia Cavelier, Gunilla Enblad, Peter Hollander, Rose-Marie Amini
BACKGROUND: Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2, as well as Indoleamine 2,3-deoxygenase (IDO1) can be expressed both by tumor and microenvironmental cells and are crucial for tumor immune escape. We aimed to evaluate the role of PD-1, its ligands and IDO1 in a cohort of patients with primary diffuse large B-cell lymphoma of the CNS (PCNSL). MATERIAL AND METHODS: Tissue microarrays (TMAs) were constructed in 45 PCNSL cases. RNA extraction from whole tissue sections and RNA sequencing were successfully performed in 33 cases...
February 12, 2021: Acta Oncologica
Wenlong Sheng, Shijun Weng, Fei Li, Yun Zhang, Qiuxia He, Wenxiang Sheng, Ying Fu, Haiyue Yan, Kechun Liu
Background: Melatonin (N-acetyl-5-methoxytryptamine), a significant indoleamine neuromodulator implicated in circadian rhythms and sleep patterns, regulates diverse rhythmic functions via activating its high-affinity G-protein-coupled receptors. However, the detailed cellular expression of the Mel1a receptor in the retina is still a research gap. Methods: The expression of the Mel1a receptor in pigeon retina was assessed using Western blot analysis and immunofluorescent staining...
2021: Nature and Science of Sleep
Shamsunnahar Khushi, Angela A Salim, Ahmed H Elbanna, Laizuman Nahar, Robert J Capon
Thorectandra choanoides (CMB-01889) was prioritized as a source of promising new chemistry from a library of 960 southern Australian marine sponge extracts, using a global natural products social (GNPS) molecular networking approach. The sponge was collected at a depth of 45 m. Chemical fractionation followed by detailed spectroscopic analysis led to the discovery of a new tryptophan-derived alkaloid, thorectandrin A ( 1 ), with the GNPS cluster revealing a halo of related alkaloids 1a - 1n . In considering biosynthetic origins, we propose that Thorectandra choanoides (CMB-01889) produces four well-known alkaloids, 6-bromo-1',8-dihydroaplysinopsin ( 2 ), 6-bromoaplysinopsin ( 3 ), aplysinopsin ( 4 ), and 1',8-dihydroaplysinopsin ( 10 ), all of which are susceptible to processing by a putative indoleamine 2,3-dioxygenase- like (IDO) enzyme to 1a - 1n ...
February 9, 2021: Marine Drugs
Qihui Zhou, Yu Shi, Chao Chen, Fengtian Wu, Zhi Chen
Indoleamine 2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are induced by several immune factors, such as interferon-γ, and act as intracellular enzymes that catabolize essential amino acid tryptophan into kynurenine and other downstream metabolites, including kynurenic acid (KYNA), xanthurenic acid (XA) and so on. IDO and TDO work as a double-edge sword. On one hand, they exert the immunomodulatory effects, especially immunosuppressive effects on the microenvironment including infections, pregnancy, tumor cells escape and transplantation...
January 2021: Annals of Translational Medicine
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