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J Klimentova, M Cebova, A Barta, Z Matuskova, S Vrankova, R Rehakova, M Kovacsova, O Pechanova
Melatonin, a multitasking indolamine, seems to be involved in a variety of physiological and metabolic processes via both receptor-mediated and receptor-independent mechanisms. The aim of our study was to find out whether melatonin can affect blood pressure (BP), nitric oxide synthase (NOS) activity, eNOS and nNOS protein expressions in rats with metabolic syndrome (SHR/cp). Rats were divided into four groups: 6-week-old male WKY andSHR/cp and age-matched WKY and SHR/cp treated with melatonin (10 mg/kg/day) for 3 weeks...
October 24, 2016: Physiological Research
Ashton A Connor, Robert E Denroche, Gun Ho Jang, Lee Timms, Sangeetha N Kalimuthu, Iris Selander, Treasa McPherson, Gavin W Wilson, Michelle A Chan-Seng-Yue, Ivan Borozan, Vincent Ferretti, Robert C Grant, Ilinca M Lungu, Eithne Costello, William Greenhalf, Daniel Palmer, Paula Ghaneh, John P Neoptolemos, Markus Buchler, Gloria Petersen, Sarah Thayer, Michael A Hollingsworth, Alana Sherker, Daniel Durocher, Neesha Dhani, David Hedley, Stefano Serra, Aaron Pollett, Michael H A Roehrl, Prashant Bavi, John M S Bartlett, Sean Cleary, Julie M Wilson, Ludmil B Alexandrov, Malcolm Moore, Bradly G Wouters, John D McPherson, Faiyaz Notta, Lincoln D Stein, Steven Gallinger
Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance. Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium...
October 20, 2016: JAMA Oncology
Carolina Scagnolari, Giuseppe Corano Scheri, Carla Selvaggi, Ivan Schietroma, Saeid Najafi Fard, Andrea Mastrangelo, Noemi Giustini, Sara Serafino, Claudia Pinacchio, Paolo Pavone, Gianfranco Fanello, Giancarlo Ceccarelli, Vincenzo Vullo, Gabriella d'Ettorre
Recently the tryptophan pathway has been considered an important determinant of HIV-1 infected patients' quality of life, due to the toxic effects of its metabolites on the central nervous system (CNS). Since the dysbiosis described in HIV-1 patients might be responsible for the microbial translocation, the chronic immune activation, and the altered utilization of tryptophan observed in these individuals, we speculated a correlation between high levels of immune activation markers in the cerebrospinal fluid (CSF) of HIV-1 infected patients and the over-expression of indolamine-2,3-dioxygenase (IDO) at the gut mucosal surface...
2016: International Journal of Molecular Sciences
Josephine F Trott, Jeffrey Kim, Omran Abu Aboud, Hiromi Wettersten, Benjamin Stewart, Grace Berryhill, Francisco Uzal, Russell C Hovey, Ching-Hsien Chen, Katie Anderson, Ashley Graef, Aaron L Sarver, Jaime F Modiano, Robert H Weiss
Renal cell carcinoma (RCC) is increasing in incidence, and a complete cure remains elusive. While immune-checkpoint antibodies are promising, interferon-based immunotherapy has been disappointing. Tryptophan metabolism, which produces immunosuppressive metabolites, is enhanced in RCC. Here we show indolamine-2,3-dioxygenase-1 (IDO1) expression, a kynurenine pathway enzyme, is increased not only in tumor cells but also in the microenvironment of human RCC compared to normal kidney tissues. Neither kynurenine metabolites nor IDO inhibitors affected the survival or proliferation of human RCC or murine renal cell adenocarcinoma (RENCA) cells in vitro...
August 27, 2016: Oncotarget
Sergej Tomić, Vanja Kokol, Dušan Mihajlović, Aleksandar Mirčić, Miodrag Čolić
Cellulose nanofibrills (CNFs) are attractive biocompatible, natural nanomaterials for wide biomedical applications. However, the immunological mechanisms of CNFs have been poorly investigated. Considering that dendritic cells (DCs) are the key immune regulatory cells in response to nanomaterials, our aim was to investigate the immunological mechanisms of CNFs in a model of DC-mediated immune response. We found that non-toxic concentrations of CNFs impaired the differentiation, and subsequent maturation of human monocyte-derived (mo)-DCs...
2016: Scientific Reports
François Couderc, Varravaddheay Ong-Meang, Véréna Poinsot
Native laser induced fluorescence using UV lasers associated to capillary electrophoresis (CE) offers now a large related literature, for now thirty years. The main works have been performed using very expensive Ar-ion lasers emitting at 257 and 275 nm. They are not affordable for routine analyses, but have numerous applications like protein, catecholamine and indolamine analysis. Some other lasers like HeCd 325 nm have been used but only for few applications. Diode lasers, emitting at 266 nm, cheaper, are extensively used for the same topics, even if the obtained sensitivity is lower than the one observed using the costly UV-Ar-ion lasers...
July 22, 2016: Electrophoresis
Begoña M Escribano, Macarena Aguilar, Carmen Bahamonde, Cristina Conde, Rafael Lillo, Fernando Sánchez-López, Ana I Giraldo, Antonio H Cruz, Evelio Luque, Félix Gascón, Eduardo Agüera, Isaac Tunez
AIMS: The main aim of this study was to verify the effect of natalizumab on the levels of circulating catecholamines and indolamine and their possible relation with MS. METHODS: For this purpose, 12 healthy individuals (control group) and 12 relapsing-remitting multiple sclerosis patients (RR-MS) were selected. The patients were treated with 300 mg of natalizumab during 56 weeks (1 dose/4 weeks) (MS-56). This selection was based on the McDonalds revision criterion and scheduled to star treatment with natalizumab...
July 7, 2016: Current Pharmaceutical Design
Sevgi Eminel, Na Jin, Martin Rostami, Stefan Dibbert, Ulrich Mrowietz, Ina Suhrkamp
Fumaric acid esters (FAEs) are used as an oral treatment for psoriasis. Dimethylfumarate (DMF) and its metabolite monomethylfumarate (MMF) are regarded as the pharmacologically active moieties. Indoleamine 2,3-dioxygenase (IDO) is the key enzyme for the metabolism of tryptophan. The kynurenine pathway is established as a major regulator of innate and adaptive immunity. Here we investigated the effect of DMF and MMF on IDO activity and expression in human peripheral blood mononuclear cells (PBMCs). IDO activity was determined by measuring the concentration of kynurenine in the culture medium using a HPLC technique...
July 4, 2016: Experimental Dermatology
Roxana Magaña-Maldonado, Elda Georgina Chávez-Cortez, Nora Karen Olascoaga-Arellano, Mariana López-Mejía, Fernando Manuel Maldonado-Leal, Julio Sotelo, Benjamín Pineda
Glioblastoma is the most aggressive tumor in Central Nervous System in adults. Among its features, modulation of immune system stands out. Although immune system is capable of detecting and eliminating tumor cells mainly by cytotoxic T and NK cells, tumor microenvironment suppresses an effective response through recruitment of modulator cells such as regulatory T cells, monocyte-derived suppressor cells, M2 macrophages, and microglia as well as secretion of immunomodulators including IL-6, IL-10, CSF-1, TGF-β, and CCL2...
2016: BioMed Research International
Dénes Zádori, Gábor Veres, Levente Szalárdy, Péter Klivényi, Ferenc Fülöp, József Toldi, László Vécsei
INTRODUCTION: The proven pathological alterations in the kynurenine pathway of tryptophan metabolism, either in preclinical models of neurological and psychiatric disorders or in human samples themselves, elicited numerous attempts to restore the altered balance via pharmaceutical manipulation of the pathway. AREAS COVERED: The aim of the authors was to conduct a review of relevant scientific data on enzyme inhibitors of the kynurenine pathway, with special attention to pipeline drug development strategies based on relevant patent literature, covering the period of 2012-2015...
July 2016: Expert Opinion on Therapeutic Patents
Eduardo Esteban-Zubero, Francisco Agustín García-Gil, Laura López-Pingarrón, Moisés Alejandro Alatorre-Jiménez, José Manuel Ramírez, Dun-Xian Tan, José Joaquín García, Russel J Reiter
Liver steatosis is a prevalent process that is induced due to alcoholic or non-alcoholic intake. During the course of these diseases, the generation of reactive oxygen species, followed by molecular damage to lipids, protein and DMA occurs generating organ cell death. Transplantation is the last-resort treatment for the end stage of both acute and chronic hepatic diseases, but its success depends on ability to control ischemia-reperfusion injury, preservation fluids used, and graft quality. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other because of its efficacy in organs; melatonin has been investigated to improve the outcome of organ transplantation by reducing ischemia-reperfusion injury and due to its synergic effect with organ preservation fluids...
August 2016: Cellular and Molecular Life Sciences: CMLS
Arta M Monjazeb, Michael S Kent, Steven K Grossenbacher, Christine Mall, Anthony E Zamora, Annie Mirsoian, Mingyi Chen, Amir Kol, Stephen L Shiao, Abhinav Reddy, Julian R Perks, William T N Culp, Ellen E Sparger, Robert J Canter, Gail D Sckisel, William J Murphy
PURPOSE: Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy...
September 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ramagonolla Kranthikumar, Rambabu Chegondi, Srivari Chandrasekhar
A novel insertion reaction of N-tosylacetimidates and N-tosylacetimidamides onto arynes via a benzocyclobutene intermediate followed by ring cleavage is developed to afford o-benzylbenzoic acid derivatives in good yields. Interestingly, the use of cyclic 2-sulfonyliminoindolines provided two distinct products such as azepanimines via [2 + 2] cycloaddition and indolamines via protonation based on solvent medium.
March 18, 2016: Journal of Organic Chemistry
Elisa Wirthgen, Andreas Hoeflich
The degradation of tryptophan (TRP) along the kynurenine pathway plays a crucial role as a neuro- and immunomodulatory mechanism in response to inflammatory stimuli, such as lipopolysaccharides (LPS). In endotoxemia or sepsis, an enhanced activation of the rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO) is associated with a higher mortality risk. It is assumed that IDO induced immunosuppressive effects provoke the development of a protracted compensatory hypoinflammatory phase up to a complete paralysis of the immune system, which is characterized by an endotoxin tolerance...
2015: Journal of Amino Acids
Andrew Stiff, Prashant Trikha, Robert Wesolowski, Kari Kendra, Vincent Hsu, Sarvani Uppati, Elizabeth McMichael, Megan Duggan, Amanda Campbell, Karen Keller, Ian Landi, Yiming Zhong, Jason Dubovsky, John Harrison Howard, Lianbo Yu, Bonnie Harrington, Matthew Old, Sean Reiff, Thomas Mace, Susheela Tridandapani, Natarajan Muthusamy, Michael A Caligiuri, John C Byrd, William E Carson
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cells that expand in tumor-bearing hosts in response to soluble factors produced by tumor and stromal cells. MDSC expansion has been linked to loss of immune effector cell function and reduced efficacy of immune-based cancer therapies, highlighting the MDSC population as an attractive therapeutic target. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL2-inducible T-cell kinase (ITK), is in clinical use for the treatment of B-cell malignancies...
April 15, 2016: Cancer Research
Karen Wolf, Attila Braun, Elizabeth J Haining, Yu-Lun Tseng, Peter Kraft, Michael K Schuhmann, Sanjeev K Gotru, Wenchun Chen, Heike M Hermanns, Guido Stoll, Klaus-Peter Lesch, Bernhard Nieswandt
BACKGROUND: Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation...
2016: PloS One
Lucas Sagrillo-Fagundes, Eugênia Maria Assunção Salustiano, Philippe Wong Yen, Ahmed Soliman, Cathy Vaillancourt
Melatonin is an important neuroprotective factor and its receptors are expressed in the fetal brain. During normal pregnancy, maternal melatonin level increases progressively until term and is highly transferred to the fetus, with an important role in brain formation and differentiation. Maternal melatonin provides the first circadian signal to the fetus. This indolamine is also produced de novo and plays a protective role in the human placenta. In pregnancy disorders, both maternal and placental melatonin levels are decreased...
2016: Current Pharmaceutical Design
L Marseglia, C Cuppari, S Manti, G D'Angelo, C Salpietro, R J Reiter, E Gitto
Atopic dermatitis (AD) is a chronic relapsing-remitting inflammatory skin disorder, characterized by a skin barrier dysfunction resulting in epidermal damage and altered permeability to allergens and microbes. Traditionally, the immunological mechanism involving the Th1-Th2 paradigm is considered central in the pathogenesis of AD. However, oxidative stress is, currently, recognized as a fundamental predisposing stimulus for AD. Several therapeutic approaches have been proposed as treatment, including the use of melatonin...
April 2015: Journal of Biological Regulators and Homeostatic Agents
Kyoung Woo Kim, Soo Hyun Park, Doo Hwan Oh, Seung Hoon Lee, Kyung Sub Lim, Kwangsic Joo, Yeoun Sook Chun, Soo-Ik Chang, Kyong-Mi Min, Jae Chan Kim
Glaucoma is a vision-threatening disorder characterized by progressive death of retinal ganglion cells (RGCs), although little is known about therapeutic milestones. Due to its complex and multifactorial pathogenesis, multipronged therapeutic approach is needed. Angiogenin (ANG), now called ribonuclease (RNase) 5, has been previously known as angiogenic factor and more recently its biologic activity is extended to promoting cell survival via its ribonucleolytic activity. Here, we revealed the defect of ANG in human glaucomatous trabecular meshwork (TM) cells and identified novel multiple functions of ANG as an anti-glaucomatous strategy...
February 2016: Biochimica et Biophysica Acta
Abdel-Rahman El-Mashad, Heba Elmahdy, Mohamed El-Dib, Manal Elbatch, Hany Aly
BACKGROUND: Melatonin, an indolamine endogenously produced by pineal body, has important role as an anti-oxidant, anti-inflammatory and anti-apoptotic. Whether melatonin concentration changes in neonatal sepsis and whether it can be used as a marker of sepsis is unknown. OBJECTIVE: The objective of this study is to evaluate melatonin concentration in the serum as a marker for neonatal sepsis and compare it to standard markers. STUDY DESIGN: We prospectively studied 40 neonates: 20 diagnosed with late neonatal sepsis and 20 healthy neonates as a control group...
November 23, 2015: Journal of Maternal-fetal & Neonatal Medicine
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