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Miaomiao Bai, Hongnan Liu, Kang Xu, Abimbola Oladele Oso, Xin Wu, Gang Liu, Myrlene Carine B Tossou, Naif Abdullah Al-Dhabi, Veeramuthu Duraipandiyan, Qianyun Xi, Yinlong Yin
Tryptophan, a nutritionally essential amino acid, is active in the regulation of immune responses in animals. The products of tryptophan metabolism, such as indoleamine 2,3-dioxygenase, kynurenine, quinolinic acid, and melatonin, may improve immunity in an organism and induce anti-inflammatory responses. The immune tolerance processes mediated by tryptophan metabolites are not well understood. Recent studies have reported that the enzymes that break down tryptophan through the kynurenine metabolic pathway are found in numerous cell types, including immunocytes...
October 24, 2016: Amino Acids
Jean-Pierre Routy, Bertrand Routy, Gina M Graziani, Vikram Mehraj
The term "immune privilege" was originally coined to describe the suppression of inflammatory responses within organs protected by anatomic barriers, ie, the eyes, brain, placenta, and testes. However, cellular and metabolic processes, which orchestrate immune responses, also control inflammation within these sites. Our current understanding of tolerogenic mechanisms has extended the definition of immune privilege to include hair follicles, the colon, and cancer. By catabolizing tryptophan, cells expressing the enzyme indoleamine-2,3-dioxygenase produce kynurenine metabolites, which orchestrate local and systemic responses to control inflammation, thus maintaining immune privilege...
2016: International Journal of Tryptophan Research: IJTR
Shan Qian, Tao He, Wei Wang, Yanying He, Man Zhang, Lingling Yang, Guobo Li, Zhouyu Wang
Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50 value of 5...
October 6, 2016: Bioorganic & Medicinal Chemistry
Ramu Guda, Sirassu Narsimha, Ramavath Babu, Srujana Muthadi, Harikiran Lingabathula, Rambabu Palabindela, Narsimha Reddy Yellu, Girijesh Kumar, Mamatha Kasula
A series of novel substituted hydrazono indolo[2,1-b]quinazoline-6,12-dione analogues have been synthesized and screened for their in vitro cytotoxic and antimicrobial activities. Among all the target compounds, 3c exhibited the most potent inhibitory activity against three cancer cell lines MCF-7, A549, HeLa with IC50 values 07.14±1.285μM, 09.18±0.968μM and 10.57±0.581μM respectively, while maintaining low toxicity towards non-cancer originated cell line, HEK-293. The detailed studies about molecular interactions with probable target protein indoleamine 2,3-dioxygenase (IDO1) were done by using docking simulations...
October 5, 2016: Bioorganic & Medicinal Chemistry Letters
Ariel Lewis-Ballester, Farhad Forouhar, Sung-Mi Kim, Scott Lew, YongQiang Wang, Shay Karkashon, Jayaraman Seetharaman, Dipanwita Batabyal, Bing-Yu Chiang, Munif Hussain, Maria Almira Correia, Syun-Ru Yeh, Liang Tong
Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) play a central role in tryptophan metabolism and are involved in many cellular and disease processes. Here we report the crystal structure of human TDO (hTDO) in a ternary complex with the substrates L-Trp and O2 and in a binary complex with the product N-formylkynurenine (NFK), defining for the first time the binding modes of both substrates and the product of this enzyme. The structure indicates that the dioxygenation reaction is initiated by a direct attack of O2 on the C2 atom of the L-Trp indole ring...
October 20, 2016: Scientific Reports
Mario Cezar Saffi Junior, Ivone da Silva Duarte, Rodrigo Barbosa de Oliveira Brito, Giovana Garcia Prado, Sergio Makabe, Humberto Dellê, Cleber P Camacho
Cervical cancer (CC) is one of the most common cancers among women worldwide. The relation of the human papillomavirus (HPV) with CC and its precursor lesions was first suspected for over 40 years. The indoleamine 2,3 dioxygenase (IDO) is an immune modulator enzyme responsible for the immune system tissue protection mechanism, which may be the key to the tumoural persistence. HPV oncoprotein E7 promotes the increase in cyclin-dependent kinase inhibitor p16 (CDKN2A/p16). The isolated and combined analysis of CDKN2A/p16 mRNA to CC diagnosis was done with promising results...
November 2016: Medical Oncology
Kenichi Sakurai, Shigeru Fujisaki, Keita Adachi, Shuhei Suzuki, Yuki Masuo, Saki Nagashima, Yukiko Hara, Katsuhisa Enomoto, Tomohiro Hirano, Ryouichi Tomita, Kenji Gonda
We evaluated the clinical significance of indoleamine 2,3-dioxygenase(IDO)in intra-cystic tumors of the breast. IDO activitycan be measured byusing the tryptophan(Trp)/kynurenine(Kyn)ratio. Trp and Kyn were measured by high performance liquid chromatography(HPLC). We took liquid from 3 intra-cystic papilloma cases and 5 intra-cystic breast cancer cases. Then, we measured the Trp/Kyn ratio in these samples, and we evaluated the difference in the Trp/Kyn ratio between the papilloma group and the breast cancer group...
October 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Kenichi Sakurai, Shigeru Fujisaki, Keita Adachi, Shuhei Suzuki, Yuki Masuo, Saki Nagashima, Yukiko Hara, Tomohiro Hirano, Katsuhisa Enomoto, Ryouichi Tomita, Kenji Gonda
We evaluated the clinical significance of indoleamine 2,3-dioxygenase(IDO)during fulvestrant therapyfor multiple metastatic breast cancer patients. IDO activitycan be measured using the tryptophan(Trp)/kynurenine(Kyn)ratio. Trp and Kyn were measured using high-performance liquid chromatography(HPLC). The serum Trp/Kyn level in patients with multiple metastatic breast cancer was lower than in patients without metastases. IDO activityincreased after breast cancer metastases developed. IDO activitywas correlated with the number of metastatic lesions during toremifene and fulvestrant therapy...
October 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Xuhao Zhang, Shan Zhu, Tete Li, Yong-Jun Liu, Wei Chen, Jingtao Chen
Malignant glioma is the most common and a highly aggressive cancer in the central nervous system (CNS). Cancer immunotherapy, strategies to boost the body's anti-cancer immune responses instead of directly targeting tumor cells, recently achieved great success in treating several human solid tumors. Although once considered "immune privileged" and devoid of normal immunological functions, CNS is now considered a promising target for cancer immunotherapy, featuring the recent progresses in neurobiology and neuroimmunology and a highly immunosuppressive state in malignant glioma...
October 16, 2016: Oncotarget
J M Parrott, L Redus, D Santana-Coelho, J Morales, X Gao, J C O'Connor
The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression...
October 18, 2016: Translational Psychiatry
Lauren A E Erland, Christina E Turi, Praveen K Saxena
Serotonin is an ancient indoleamine that was presumably part of the life cycle of the first prokaryotic life forms on Earth millions of years ago where it functioned as a powerful antioxidant to combat the increasingly oxygen rich atmosphere. First identified as a neurotransmitter signaling molecule in mammals, it is ubiquitous across all forms of life. Serotonin was discovered in plants many years after its discovery in mammals; however, it has now been confirmed in almost all plant families, where it plays important roles in plant growth and development, including functions in energy acquisition, seasonal cycles, modulation of reproductive development, control of root and shoot organogenesis, maintenance of plant tissues, delay of senescence, and responses to biotic and abiotic stresses...
October 11, 2016: Biotechnology Advances
Laura Arroyo, Ricard Carreras, Daniel Valent, Raquel Peña, Eva Mainau, Antonio Velarde, Josefa Sabrià, Anna Bassols
Chemical neurotransmitters (NT) are principal actors in all neuronal networks of animals. The central nervous system plays an important role in stress susceptibility and organizes the response to a stressful situation through the interaction of the dopaminergic and the serotonergic pathways, leading to the activation of the hypothalamus-pituitary-adrenal axis (HPA). This study was designed to investigate: a) the effects of stressful handling of pigs at the slaughterhouse on the neurotransmitter profile in four brain areas: amygdala, prefrontal cortex (PFC), hippocampus and hypothalamus, and b) whether the alterations in the brain NT profile after stressful handling were associated with fear, determined by the tonic immobility (TI) test...
October 11, 2016: Physiology & Behavior
Sally A Abuelezz, Nevien Hendawy, Yosra Magdy
Depression is a major health problem in which oxidative stress and inflammation are inextricably connected in its pathophysiology. Coenzyme Q10 (CoQ10) is an important anti-oxidant compound with anti-inflammatory and neuro-protective properties. This study was designed to investigate the hypothesis that CoQ10 by its anti-oxidant and anti-inflammatory potentials can alleviate depressive- like behavior by restoring the balance of the tryptophan catabolites kynurenine/serotonin toward the serotonin pathway by down-regulation of hippocampal indoleamine 2,3-dioxygenase 1 (IDO-1)...
October 11, 2016: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
Makedonka Gulcev, Cavan Reilly, Timothy J Griffin, Corey D Broeckling, Brian J Sandri, Bruce A Witthuhn, Shane W Hodgson, Prescott G Woodruff, Chris H Wendt
INTRODUCTION: Exacerbations are a leading cause of morbidity in COPD. The objective of this study was to identify metabolomic biomarkers of acute exacerbations of COPD (AECOPD). METHODS: We measured metabolites via mass spectrometry (MS) in plasma drawn within 24 hours of admission to the hospital for 33 patients with an AECOPD (day 0) and 30 days later and for 65 matched controls. Individual metabolites were measured via selective reaction monitoring with mass spectrometry...
2016: International Journal of Chronic Obstructive Pulmonary Disease
Helena Gaspar, Adele Cutignano, Laura Grauso, Nuno Neng, Vasco Cachatra, Angelo Fontana, Joana Xavier, Marta Cerejo, Helena Vieira, Susana Santos
Among marine organisms, sponges are the richest sources of pharmacologically-active compounds. Stemming from a previous lead discovery program that gathered a comprehensive library of organic extracts of marine sponges from the off-shore region of Portugal, crude extracts of Erylus cf. deficiens collected in the Gorringe Bank (Atlantic Ocean) were tested in the innovative high throughput screening (HTS) assay for inhibitors of indoleamine 2,3-dioxygenase (IDO) and showed activity. Bioassay guided fractionation of the dichloromethane extract led to the isolation of four new glycolipids, named erylusamide A-D...
October 11, 2016: Marine Drugs
Iwona Adamska, Bogdan Lewczuk, Magdalena Markowska, Pawel M Majewski
The aim of the present study was to characterize the daily profiles of melatonin synthesis-related indoles in the pineal glands of male Hy-Line chickens hatched in the winter and reared under controlled light (L:D 12:12) conditions. The pineal glands were isolated from 16-day-old birds immediately after decapitation every 2h over a 24-h period. The indole contents were measured using HPLC with fluorescence detection. According to the obtained data, in chicken pineal glands tryptophan occurred at the highest level among the investigated compounds, showing rhythmical, daily changes with decreased levels during the scotophase...
October 5, 2016: Journal of Photochemistry and Photobiology. B, Biology
Cara C Schafer, Yong Wang, Kenneth P Hough, Anandi Sawant, Stefan C Grant, Victor J Thannickal, Jaroslaw Zmijewski, Selvarangan Ponnazhagan, Jessy S Deshane
Indoleamine 2,3-dioxygenase (IDO) has been implicated in immune evasion by tumors. Upregulation of this tryptophan (Trp)-catabolizing enzyme, in tumor cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME), leads to Trp depletion that impairs cytotoxic T cell responses and survival; however, exact mechanisms remain incompletely understood. We previously reported that a combination therapy of gemcitabine and a superoxide dismutase mimetic promotes anti-tumor immunity in a mouse model of lung cancer by inhibiting MDSCs, enhancing polyfunctional response of CD8+ memory T cells, and extending survival...
September 26, 2016: Oncotarget
Tatiane da Silva Araújo, Adriano Jose Maia Chaves Filho, Aline Santos Monte, Ana Isabelle de Góis Queiroz, Rafaela Carneiro Cordeiro, Michel de Jesus Souza Machado, Ricardo de Freitas Lima, David Freitas de Lucena, Michael Maes, Danielle Macêdo
Immune dysregulation observed in schizophrenia alters tryptophan metabolism. Tryptophan metabolism is triggered by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Tryptophan is converted to quinolinic acid, a potent neurotoxin, and to kynurenic acid, an NMDA antagonist. 1-Methyl-D-tryptophan (MDT) inhibits IDO. Melatonin is metabolized by IDO while inhibiting TDO. We evaluated the reversal of ketamine-induced schizophrenia-like behavioral and neurochemical alterations in mice by the administration of MDT (20 or 40 mg/kg, i...
September 21, 2016: Journal of Psychiatric Research
Elisa Albini, Verdiana Rosini, Marco Gargaro, Giada Mondanelli, Maria L Belladonna, Maria Teresa Pallotta, Claudia Volpi, Francesca Fallarino, Antonio Macchiarulo, Cinzia Antognelli, Roberta Bianchi, Carmine Vacca, Paolo Puccetti, Ursula Grohmann, Ciriana Orabona
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the initial, rate-limiting step in tryptophan (Trp) degradation, resulting in tryptophan starvation and the production of immunoregulatory kynurenines. IDO1's catalytic function has long been considered as the one mechanism responsible for IDO1-dependent immune suppression by dendritic cells (DCs), which are master regulators of the balance between immunity and tolerance. However, IDO1 also harbours immunoreceptor tyrosine-based inhibitory motifs, (ITIM1 and ITIM2), that, once phosphorylated, bind protein tyrosine phosphatases, (SHP-1 and SHP-2), and thus trigger an immunoregulatory signalling in DCs...
September 30, 2016: Journal of Cellular and Molecular Medicine
Shardulendra Sherchand, Joyce A Ibana, Alison J Quayle, Ashok Aiyar
Chlamydia trachomatis is an obligate intracellular bacterial pathogen that cannot synthesize several amino acids, including tryptophan. Rather, C. trachomatis acquires these essential metabolites from its human host cell. Chlamydial dependence on host-provided tryptophan underlies a major host defense mechanism against the bacterium; namely, the induction of the host tryptophan-catabolizing enzyme, indoleamine 2,3- dioxygenase (IDO1) by interferon gamma (IFNγ), which leads to eradication of C. trachomatis by tryptophan starvation...
August 2016: Journal of Bacteriology & Parasitology
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