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ido 1 inhibitor

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
Paolo A Ascierto, Keith Flaherty, Stephanie Goff
Recent years have seen major improvements in survival of patients with advanced melanoma with the advent of various novel systemic immunotherapies and targeted therapies. As our understanding of these agents and their various mechanisms of action improves, even more impressive outcomes are being achieved through use of various combination strategies, including the combining of different immunotherapies with one another as well as with other modalities. However, despite the improved outcomes that have been achieved in advanced melanoma, responses to treatment are heterogeneous and may not always be durable...
May 23, 2018: American Society of Clinical Oncology Educational Book
Alexander M M Eggermont, Marka Crittenden, Jennifer Wargo
Melanoma has been the most important cancer to drive immunotherapy development of solid tumors. Since 2010, immunotherapy has been revolutionized by the concept of breaking tolerance. It represents a major paradigm shift and marks the beginning of a new era. The impact of the first immune checkpoint inhibitors, anti-CTLA-4 and anti-PD-1/anti-PD-L1, is unprecedented. In 7 years, it transformed advanced-stage melanoma into a curable disease in over 50% of patients. Another major step has been the development of the combination of BRAF inhibitors plus MEK inhibitors in the treatment of BRAF-mutant melanomas...
May 23, 2018: American Society of Clinical Oncology Educational Book
Yuga Komaki, Shuji Kanmura, Fumisato Sasaki, Hidehito Maeda, Kohei Oda, Shiho Arima, Shiroh Tanoue, Yuichiro Nasu, Shinichi Hashimoto, Seiichi Mawatari, Hirohito Tsubouchi, Akio Ido
BACKGROUND/AIMS: Esophageal mucosal damage often causes scar tissue, leading to refractory stricture. The aim of this study was to clarify the effect of hepatocyte growth factor (HGF) on esophageal mucosal repair and fibrosis leading to stricture in a rat model of esophageal ulcer. METHODS: Esophageal ulcers were induced in rats by topical exposure of the lower esophageal serosa to acetic acid, followed by intraperitoneal administration of HGF (200 µg/day) using an osmotic pump for 7 days...
September 18, 2018: Digestion
Aleksei Kaleda, Lotem Haleva, Guy Sarusi, Tova Pinsky, Marco Mangiagalli, Maya Bar Dolev, Marina Lotti, Marco Nardini, Ido Braslavsky
Ice-binding proteins (IBPs) bind to ice crystals and control their growth, enabling host organisms to adapt to subzero temperatures. By binding to ice, IBPs can affect the shape and recrystallization of ice crystals. The shapes of ice crystals produced by IBPs vary and are partially due to which ice planes the IBPs are bound to. Previously, we have described a bacterial IBP found in the metagenome of the symbionts of Euplotes focardii ( EfcIBP). EfcIBP shows remarkable ice recrystallization inhibition activity...
September 26, 2018: Langmuir: the ACS Journal of Surfaces and Colloids
Ana C R Moreno, Bruna F M M Porchia, Roberta L Pagni, Patrícia da Cruz Souza, Rafael Pegoraro, Karine B Rodrigues, Tácita B Barros, Luana R de Melo Moraes Aps, Eliseu F de Araújo, Vera L G Calich, Luís C de Souza Ferreira
Immunotherapy has become an important ally in the fight against distinct types of cancer. However, the metabolic plasticity of the tumor environment frequently influences the efficacy of therapeutic procedures, including those based on immunological tools. In this scenario, immunometabolic adjuvants arise as an alternative toward the development of more efficient cancer therapies. Here we demonstrated that the combination of melatonin, a neuroimmunomodulator molecule, and an indoleamine 2,3-dioxygenase (IDO) inhibitor (1-methyl-DL-tryptophan, DL-1MT) improves the efficacy of an immunotherapy (gDE7) targeting human papillomavirus (HPV)-associated tumors...
2018: Frontiers in Immunology
Jyoti Chauhan, Moumita Dasgupta, Tania Luthra, Akanksha Awasthi, Sayantan Tripathy, Anindyajit Banerjee, Santanu Paul, Debasish Nag, Saikat Chakrabarti, Gopal Chakrabarti, Subhabrata Sen
A novel library of C2 -substituted tryptamines (based on diverse C2 -aroyl/arylimino indoles and indole-diketopiperazine hybrids) possessing antimitotic properties were designed, synthesized and screened for their inhibitory activity against tubulin polymerization, and against proliferation of A549 lung cancer, HeLa cervical cancer, MCF7 breast cancer and HePG2 liver cancer cell lines. The design of molecules were inspired from known antimitotic compounds and natural products. The molecular docking of the designed compounds indicated that they bind to the colchicin binding site of tubulin...
November 1, 2018: European Journal of Pharmaceutical Sciences
Aleksandar Acovic, Bojana Simovic Markovic, Marina Gazdic, Aleksandar Arsenijevic, Nemanja Jovicic, Nevena Gajovic, Marina Jovanovic, Natasa Zdravkovic, Tatjana Kanjevac, C Randall Harrell, Crissy Fellabaum, Zana Dolicanin, Valentin Djonov, Nebojsa Arsenijevic, Miodrag L Lukic, Vladislav Volarevic
Background: Dendritic cell (DC)-derived indolamine 2,3-dioxygenase (IDO) degrades tryptophan to kynurenine, which promotes conversion of inflammatory T cells in immunosuppressive regulatory T cells (Tregs). We analyzed the significance of the IDO:Treg axis for inducing and maintaining mucosal healing in ulcerative colitis (UC). Methods: Dextran sodium sulphate (DSS)-induced colitis in BALB/c mice (model for mucosal healing) and C57BL/6 mice (model for persistent disease) was used...
2018: Therapeutic Advances in Gastroenterology
Hongao Zhang, Wei Liu, Zhihong Liu, Yingchen Ju, Mengyang Xu, Yue Zhang, Xinyu Wu, Qiong Gu, Zhong Wang, Jun Xu
Indoleamine 2,3-dioxygenase (IDO), an immune checkpoint, is a promising target for cancer immunotherapy. However, current IDO inhibitors are not approved for clinical use yet; therefore, new IDO inhibitors are still demanded. To identify new IDO inhibitors, we have built naive Bayesian (NB) and recursive partitioning (RP) models from a library of known IDO inhibitors derived from recent publications. Thirteen molecular fingerprints were used as descriptors for the models to predict IDO inhibitors. An in-house compound library was virtually screened using the best machine learning model, which resulted in 50 hits for further enzyme-based IDO inhibitory assays...
June 1, 2018: MedChemComm
Xuan-Tong Liu, Hui-Ting Sun, Zhong-Fang Zhang, Ru-Xia Shi, Li-Bing Liu, Jia-Jun Yu, Wen-Jie Zhou, Chun-Jie Gu, Shao-Liang Yang, Yu-Kai Liu, Hui-Li Yang, Feng-Xuan Xu, Ming-Qing Li
It has been reported that the impaired cytotoxicity of natural killer (NK) cells and abnormal cytokines that are changed by the interaction between ectopic endometrial cells and immune cells is indispensable for the initiation and development of endometriosis (EMS). However, the mechanism of NK cells dysfunction in EMS remains largely unclear. Here, we found that NK cells in peritoneal fluid from women with EMS highly expressed indoleamine 2,3-dioxygenase (IDO). Furthermore, IDO+NK cells possessed lower NKp46 and NKG2D but higher IL-10 than that of IDO-NK...
August 7, 2018: Reproduction: the Official Journal of the Society for the Study of Fertility
Andrea Botticelli, Bruna Cerbelli, Luana Lionetto, Ilaria Zizzari, Massimiliano Salati, Annalinda Pisano, Mazzuca Federica, Maurizio Simmaco, Marianna Nuti, Paolo Marchetti
BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment paradigm of highly lethal malignancies like advanced non-small cell lung cancer (NSCLC), demonstrating long-term tumour control and extended patient survival. Unfortunately, only 25-30% of patients experience a durable benefit, while the vast majority demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) activity has been proposed as a possible mechanism of resistance to anti-PD-1 treatment leading to an immunosuppressive microenvironment...
August 6, 2018: Journal of Translational Medicine
Miwa Fukuda, Tomomi Sasaki, Tomoko Hashimoto, Hiroyuki Miyachi, Minoru Waki, Akira Asai, Osamu Takikawa, Osamu Ohno, Kenji Matsuno
Kynurenine is biosynthesised from tryptophan catalysed by indoleamine 2,3-dioxygenase (IDO). The abrogation of kynurenine production is considered a promising therapeutic target for immunological cancer treatment. In the course of our IDO inhibitor programme, formal cyclisation of the isothiourea moiety of the IDO inhibitor 1 afforded the 5-Cl-benzimidazole derivative 2b-6, which inhibited both recombinant human IDO (rhIDO) activity and cellular kynurenine production. Further derivatisation of 2b-6 provided the potent inhibitor of cellular kynurenine production 2i (IC50  = 0...
July 20, 2018: Bioorganic & Medicinal Chemistry Letters
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