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Alice Coletti, Francesca Camponeschi, Elisa Albini, Francesco Antonio Greco, Vincenzo Maione, Chiara Custodi, Federica Ianni, Ursula Grohmann, Ciriana Orabona, Francesca Cantini, Antonio Macchiarulo
Indoleamine 2,3-dioxygenase 1 (IDO1) is attracting a great deal of interest as drug target in immune-oncology being highly expressed in cancer cells and participating to the tumor immune-editing process. Although several classes of IDO1 inhibitors have been reported in literature and patent applications, only few compounds have proved optimal pharmacological profile in preclinical studies to be advanced in clinical trials. Accordingly, the quest for novel structural classes of IDO1 inhibitors is still open...
October 3, 2017: European Journal of Medicinal Chemistry
Gislaine Z Réus, Indianara R T Becker, Giselli Scaini, Fabricia Petronilho, Jean P Oses, Rima Kaddurah-Daouk, Luciane B Ceretta, Alexandra I Zugno, Felipe Dal-Pizzol, João Quevedo, Tatiana Barichello
Evidence has shown that the kynurenine pathway (KP) plays a role in the onset of oxidative stress and also in the pathophysiology of schizophrenia. The aim of this study was to use a pharmacological animal model of schizophrenia induced by ketamine to investigate if KP inhibitors could protect the brains of Wistar rats against oxidative stress and behavioral changes. Ketamine, injected at the dose of 25mg/kg, increased spontaneous locomotor activity. However, the inhibitors of tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and kynurenine-3-monooxygenase (KMO) were able to reverse these changes...
October 10, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
Keywan Mortezaee, Neda Khanlarkhani
It is believed that oxidative stress is a key causing factor of liver damage induced by a variety of agents, and it is a major contributing factor in almost all conditions compromising liver function, including ischemia-reperfusion injury (IRI), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, liver cirrhosis and hepatocellular carcinoma (HCC). Liver is the organ that high concentration of melatonin (N-acetyl-5-methoxytryptamine) accumulates, and it is the sole organ where circulating melatonin is metabolized...
October 12, 2017: Journal of Cellular Physiology
Clement G Adu-Gyamfi, Tracy Snyman, Christopher J Hoffmann, Neil A Martinson, Richard E Chaisson, Jaya A George, Melinda S Suchard
Background: There is no biomarker for diagnosing active tuberculosis in patients with human immunodeficiency virus (HIV) infection. Indoleamine 2, 3-dioxygenase (IDO) is an immunoregulatory enzyme that breaks down tryptophan (Trp) to metabolites known as kynurenines (Kyns). We investigated whether IDO activity, as measured by the ratio of Kyn to Trp, could be used to diagnose or predict active tuberculosis disease in HIV-infected adults. Methods: Kyn and Trp concentrations were measured using ultraperformance liquid chromatography mass spectrometry in plasma samples from 32 HIV-infected patients in whom active tuberculosis developed and who were followed up prospectively...
October 15, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Seon-A Jeon, Eunju Lee, Inhwa Hwang, Boyoung Han, Sangjun Park, Seunghwan Son, Jungmin Yang, Sujeong Hong, Chul Hoon Kim, Junghyun Son, Je-Wook Yu
Background: Inflammation may play a significant role in the pathogenesis of depression, although the molecular target for the treatment of inflammation-mediated depressive symptoms remains to be elucidated. Recent studies have implicated the NLRP3 inflammasome in various psychiatric disorders, including depression. However, the underlying mechanism by which NLRP3 inflammasome activation mediates the progression of depressive-like behaviors remains poorly understood. Methods: We examined whether NLRP3 deficiency influenced depressive-like behaviors and cerebral inflammation following systemic administration of lipopolysaccharide in mice...
July 31, 2017: International Journal of Neuropsychopharmacology
Oleh Andrukhov, Johanna Sang-A Hong, Olena Andrukhova, Alice Blufstein, Andreas Moritz, Xiaohui Rausch-Fan
Periodontal ligament stem cells similarly to the mesenchymal stem cells of other tissues possess immunomodulatory properties, which are regulated by different cytokines, particularly by interferon-γ (IFN-γ). In contrast, less information is provided about the effect of toll-like receptors ligand on immunomodulatory properties of these cells. In the present study we investigated the response of human periodontal ligament stem cells (hPDLSCs) in response to simultaneous stimulation with IFN-γ and toll-like receptor (TLR) agonists...
October 9, 2017: Scientific Reports
Samantha Burugu, Amanda R Dancsok, Torsten O Nielsen
The first generation of immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1) targeted natural immune homeostasis pathways, co-opted by cancers, to drive anti-tumor immune responses. These agents led to unprecedented results in patients with previously incurable metastatic disease and may become first-line therapies for some advanced cancers. However, these agents are efficacious in only a minority of patients. Newer strategies are becoming available that target additional immunomodulatory mechanisms to activate patients' own anti-tumor immune responses...
October 5, 2017: Seminars in Cancer Biology
David D Chism
With the advent of platinum-based chemotherapy, survival rates for metastatic urothelial carcinoma have plateaued, giving way to the modern immunotherapy paradigm. Although immunotherapy as an effective treatment dates back to the live, attenuated bacillus Calmette-Guérin vaccine, the recent impact of immune checkpoint inhibitors targeting programmed death/programmed death-ligand 1 (PD-1/PD-L1) coupled with the promise of both anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies and indoleamine-2, 3-dioxygenase-1 (IDO-1) inhibitors have provided a resurgence...
October 2017: Journal of the National Comprehensive Cancer Network: JNCCN
Xi Jiang, Qizhi Yan, Fuhe Liu, Changfeng Jing, Lianshu Ding, Lijin Zhang, Cong Pang
Patients suffering from chronic neuropathic pain are at high risk of co-morbid depression, which burdens healthcare. Trans-astaxanthin has been shown in our previous studies to exert antidepressant-like effect. This work aimed to investigate the effects of trans-astaxanthin on pain-related depressive-like behaviors in mice and explored the mechanism(s). Chronic constriction injury (CCI) model was used in this research. Chronic pain was evaluated by thermal hyperalgesia in Hargreaves test and mechanical allodynia in von Frey test, depressive-like behaviors were evaluated by immobility time in forced swim test and tail suspension test...
October 2, 2017: Neuroscience Letters
Ping Hu, Nicholas H Hunt, Frank Arfuso, Lynn C Shaw, Mohammad Nasir Uddin, Meidong Zhu, Raj Devasahayam, Samuel J Adamson, Vicky L Benson, Tailoi Chan-Ling, Maria B Grant
Purpose: We investigated the relationship between inflammation, neuronal loss, and expression of indoleamine 2, 3-dioxygenase (IDO) and quinolinic acid (QUIN) in the retina of subjects with type 1 diabetes (T1D) and type 2 diabetes (T2D) and in the retina of rats with T1D. Methods: Retinas from T1D (n = 7), T2D (n = 13), and 20 age-matched nondiabetic human donors and from T1D (n = 3) and control rats (n = 3) were examined using immunohistochemistry for IDO, QUIN, cluster of differentiation 39 (CD39), ionized calcium-binding adaptor molecule (Iba-1, for macrophages and microglia), Vimentin (VIM; for Müller cells), neuronal nuclei (NeuN; for neurons), and UEA1 lectin (for blood vessels)...
October 1, 2017: Investigative Ophthalmology & Visual Science
Qiongxin Wang, Ye Ding, Ping Song, Huaiping Zhu, Imoh S Okon, Nan-Yang Ding, Houzao Chen, Depei Liu, Ming-Hui Zou
Background -Abnormal amino acid metabolism is associated with vascular disease. However, the causative link between dysregulated tryptophan metabolism and abdominal aortic aneurysm (AAA) is unknown. Methods -Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. Mice with deficiencies in both apolipoprotein e (Apoe) and IDO (Apoe(-/-)/IDO(-/-)) were generated by cross-breeding IDO(-/-) mice with Apoe(-/-) mice. Results -The acute infusion of angiotensin II (AngII) markedly increased the incidence of AAA in Apoe(-/-) mice, but not in Apoe(-/-)/IDO(-/-) mice, which presented decreased elastic lamina degradation and aortic expansion...
October 4, 2017: Circulation
Sarra G Bahna, Lennard P Niles
Melatonin, the primary indoleamine hormone of the mammalian pineal gland, is known to have a plethora of neuroregulatory, neuroprotective and other properties. Melatonergic signaling is mediated by its two G protein-coupled receptors, MT1 and MT2 , which are widely expressed in the mammalian CNS. Melatonin levels and receptor expression often show a decrease during normal aging, and this reduction may be accelerated in some disease states. Depleted melatonergic signaling has been associated with neuropsychiatric dysfunction and impairments in cognition, memory, neurogenesis and neurorestorative processes...
October 2, 2017: British Journal of Pharmacology
Nishel Mohan Shah, Anna A Herasimtschuk, Adriano Boasso, Adel Benlahrech, Dietmar Fuchs, Nesrina Imami, Mark R Johnson
During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner. We analyzed changes in surface markers of peripheral blood T cells, ex vivo antigen-specific T cell responses, indoleamine 2,3-dioxygenase (IDO) activity (kynurenine/tryptophan ratio, KTR), plasma neopterin concentration, and the in vitro expression of progesterone-induced blocking factor (PIBF) in response to peripheral blood mononuclear cell culture with progesterone...
2017: Frontiers in Immunology
Yi Zou, Fang Wang, Yan Wang, Qirui Sun, Yue Hu, Yuezhen Li, Wen Liu, Wenjie Guo, Zhangjian Huang, Yihua Zhang, Qiang Xu, Yisheng Lai
Indoleamine-2,3-dioxygenase-1 (IDO1) is an attractive target for cancer immunotherapy. Herein, a series of novel imidazoleisoindole derivatives were prepared and evaluated for their ability to inhibit IDO1. Among these, derivative 11r was the most active compound with nanomolar potency in the Hela cell-based assay, while showed negligible cellular toxicity. UV-visible spectra study demonstrated that compounds 11p and 11r bound to IDO1 and coordinated with the heme iron. Furthermore, they could significantly promote T cell proliferation, increase IFN-γ production, and reduce the numbers of Foxp3(+) regulatory T cells...
September 18, 2017: European Journal of Medicinal Chemistry
Devi Rajan, Raghavan Chinnadurai, Evan O Keefe, Seyhan Boyoglu-Barnum, Sean O Todd, Tina V Hartert, Jacques Galipeau, Larry J Anderson
RSV is a major cause of severe lower respiratory infection in infants and young children. With no vaccine yet available, it is important to clarify mechanisms of disease pathogenesis. Since indoleamine-2,3-dioxygenase (IDO) is an immunomodulatory enzyme and is upregulated with RSV infection, we studied it in vivo during infection of BALB/c mice and in vitro in A549 cells. RSV infection upregulated IDO transcripts in vivo and in vitro. IDO siRNA decreased IDO transcripts ~2 fold compared to control siRNA after RSV infection but this decrease did not affect RSV replication...
September 27, 2017: Virology
Jiro Ogura, Seiji Miyauchi, Kazumi Shimono, Shengping Yang, Sathisha Gonchigar, Vadivel Ganapathy, Yangzom D Bhutia
Carbidopa is used with l-DOPA (l-3,4-dihydroxyphenylalanine) to treat Parkinson's disease (PD). PD patients exhibit lower incidence of most cancers including pancreatic cancer, but with the notable exception of melanoma. The decreased cancer incidence is not due to l-DOPA; however, the relevance of Carbidopa to this phenomenon has not been investigated. Here, we tested the hypothesis that Carbidopa, independent of l-DOPA, might elicit an anticancer effect. Carbidopa inhibited pancreatic cancer cell proliferation both in vitro and in vivo Based on structural similarity with phenylhydrazine, an inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1), we predicted that Carbidopa might also inhibit IDO1, thus providing a molecular basis for its anticancer effect...
September 28, 2017: Biochemical Journal
Qi-Xiang Ye, Lv-Hong Xu, Pei-Jie Shi, Ting Xia, Jian-Pei Fang
Cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4Ig) and anti-cluster of differentiation 154 (anti-CD154) are able to block B7/CD28 and CD40/CD154 co-stimulatory signals in T cells. Additionally, they promote hematopoietic stem cell transplantation (HSCT) in sensitized recipients and are able to induce immune tolerance and complete hematopoietic reconstitution. Indoleamine 2, 3-dioxygenase (IDO) and nitric oxide (NO) have been implicated in T cell immune tolerance. The aim of the present report was to study the in vivo tolerogenic mechanisms by which CTLA4Ig and anti-CD154 induce transplantation survival in mice receiving HSCT...
September 2017: Experimental and Therapeutic Medicine
Agnieszka Kobylińska, Russel J Reiter, Malgorzata M Posmyk
Melatonin was discovered in plants more than two decades ago and, especially in the last decade, it has captured the interests of plant biologists. Beyond its possible participation in photoperiod processes and its role as a direct free radical scavenger as well as an indirect antioxidant, melatonin is also involved in plant defense strategies/reactions. However, the mechanisms that this indoleamine activates to improve plant stress tolerance still require identification and clarification. In the present report, the ability of exogenous melatonin to protect Nicotiana tabacum L...
2017: Frontiers in Plant Science
Ladda Meesuk, Chairat Tantrawatpan, Pakpoom Kheolamai, Sirikul Manochantr
Mesenchymal stromal cells derived from amnion (AM-MSCs) can be easily obtained in large quantity by less invasive method in comparison to bone marrow-derived MSCs (BM-MSCs). However, the biological and immunosuppressive properties of AM-MSCs are still poorly characterized. Previous studies demonstrated that BM-MSCs expressed indoleamine 2,3-dioxygenase (IDO) to suppress T-cell responses. This study was designed to address whether IDO contributes to the immunosuppressive function of AM-MSCs. MSCs isolated from amnion were cultured in complete medium similar to BM-MSCs...
December 2016: Biochemistry and Biophysics Reports
Oluyomi Stephen Adeyemi, Yuho Murata, Tatsuki Sugi, Yongmei Han, Kentaro Kato
BACKGROUND: Toxoplasmosis constitutes a large global burden that is further exacerbated by the shortcomings of available therapeutic options, thus underscoring the urgent need for better anti-Toxoplasma gondii therapy or strategies. Recently, we showed that the anti-parasitic action of inorganic nanoparticles (NPs) could, in part, be due to changes in redox status as well as in the parasite mitochondrial membrane potential. METHODS: In the present study, we explored the in vitro mode of action of the anti-T...
September 2017: Biochemistry and Biophysics Reports
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