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https://www.readbyqxmd.com/read/29667229/uc-1v150-a-potent-tlr7-agonist-capable-of-activating-macrophages-and-potentiating-mab-mediated-target-cell-deletion
#1
Lekh N Dahal, Adam Gadd, Alexander D Edwards, Mark S Cragg, Stephen A Beers
Toll like receptors (TLR) are critical mediators of the immune system with their activation linked to infection, inflammation and the pathogenesis of immune diseases including autoimmunity and cancer. For this reason, over the last two decades, TLR and their associated signalling pathways have been targeted therapeutically to enhance innate and adaptive immunity. Several TLR ligands, both endogenous and synthetic are at various phases of clinical testing, and new ligands are continually emerging. Agonists of TLR7 are known immune response modifiers, simultaneously stimulating several cell types, resulting in immune cell activation and cytokine and chemokine release...
April 18, 2018: Scandinavian Journal of Immunology
https://www.readbyqxmd.com/read/29667121/backbone-1-h-13-c-and-15-n-resonance-assignments-of-the-ligand-binding-domain-of-the-human-wildtype-glucocorticoid-receptor-and-the-f602s-mutant-variant
#2
Christian Köhler, Göran Carlström, Stefan Tångefjord, Tineke Papavoine, Matti Lepistö, Karl Edman, Mikael Akke
The glucocorticoid receptor (GR) is a nuclear hormone receptor that regulates key genes controlling development, metabolism, and the immune response. GR agonists are efficacious for treatment of inflammatory, allergic, and immunological disorders. Steroid hormone binding to the ligand-binding domain (LBD) of GR is known to change the structural and dynamical properties of the receptor, which in turn control its interactions with DNA and various co-regulators and drive the pharmacological response. Previous biophysical studies of the GR LBD have required the use of mutant forms to overcome issues with limited protein stability and high aggregation propensity...
April 17, 2018: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/29665497/the-effects-of-resiquimod-in-an-ovalbumin-induced-allergic-rhinitis-model
#3
Shenhong Qu, Taijie Qin, Min Li, Shaojie Zhang, Linsong Ye, Jiazhang Wei, Hua Fan, Baiwen Chen
Growing evidence indicates that the Toll-like receptor7/8(TLR7/8) agonist resiquimod (R848) is a potential inhibitor of type-2 immunity. However, the mechanisms mediating its therapeutic effects are not fully understood. This study investigated the effects of R848 on OVA-induced allergic rhinitis(AR) mice and the expression of IL-25, IL-33, TSLP, T-cell immunoglobulin mucin1 (TIM1) and T-cell immunoglobulin mucin3 (TIM3). BALB/c mice were intranasally sensitized and challenged with ovalbumin (OVA), and R848 was intraperitoneally injected into AR mice...
April 14, 2018: International Immunopharmacology
https://www.readbyqxmd.com/read/29662819/variable-localization-of-toll-like-receptors-in-human-fallopian-tube-epithelial-cells
#4
Fatemehsadat Amjadi, Zahra Zandieh, Ensieh Salehi, Reza Jafari, Nasrin Ghasemi, Abbas Aflatoonian, Alireza Fazeli, Reza Aflatoonian
Objective: To determine the localization, expression, and function of Toll-like receptors (TLRs) in fallopian tube epithelial cells. Methods: The localization of TLRs in fallopian tube epithelial cells was investigated by immunostaining. Surprisingly, the intensity of staining was not equal in the secretory and ciliated cells. After primary cell culture of fallopian tube epithelial cells, ring cloning was used to isolate colonies of ciliated epithelial cells, distinct from non-ciliated epithelial cells...
March 2018: Clinical and Experimental Reproductive Medicine
https://www.readbyqxmd.com/read/29662071/lrh-1-agonism-favours-an-immune-islet-dialogue-which-protects-against-diabetes-mellitus
#5
Nadia Cobo-Vuilleumier, Petra I Lorenzo, Noelia García Rodríguez, Irene de Gracia Herrera Gómez, Esther Fuente-Martin, Livia López-Noriega, José Manuel Mellado-Gil, Silvana-Yanina Romero-Zerbo, Mathurin Baquié, Christian Claude Lachaud, Katja Stifter, German Perdomo, Marco Bugliani, Vincenzo De Tata, Domenico Bosco, Geraldine Parnaud, David Pozo, Abdelkrim Hmadcha, Javier P Florido, Miguel G Toscano, Peter de Haan, Kristina Schoonjans, Luis Sánchez Palazón, Piero Marchetti, Reinhold Schirmbeck, Alejandro Martín-Montalvo, Paolo Meda, Bernat Soria, Francisco-Javier Bermúdez-Silva, Luc St-Onge, Benoit R Gauthier
Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis...
April 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29656235/effective-cancer-immunotherapy-in-mice-by-polyic-imiquimod-complexes-and-engineered-magnetic-nanoparticles
#6
Ana Isabel Bocanegra Gondan, Ane Ruiz-de-Angulo, Aintzane Zabaleta, Nina Gómez Blanco, Beatriz Macarena Cobaleda-Siles, María Jesús García-Granda, Daniel Padro, Jordi Llop, Blanca Arnaiz, María Gato, David Escors, Juan C Mareque-Rivas
Encouraging results are emerging from systems that exploit Toll like receptor (TLR) signaling, nanotechnology, checkpoint inhibition and molecular imaging for cancer immunotherapy. A major remaining challenge is developing effective, durable and tumour-specific immune responses without systemic toxicity. Here, we report a simple and versatile system based on synergistic activation of immune responses and direct cancer cell killing by combined TLR ligation using polyIC as TLR3 and imiquimod (R837) as TLR7 agonist, in combination with the model antigen ovalbumin (OVA) and phospholipid micelles loaded with zinc-doped iron oxide magnetic nanoparticles (MNPs)...
April 3, 2018: Biomaterials
https://www.readbyqxmd.com/read/29649593/gold-nanoparticles-conjugating-recombinant-influenza-hemagglutinin-trimers-and-flagellin-enhanced-mucosal-cellular-immunity
#7
Chao Wang, Wandi Zhu, Yuan Luo, Bao-Zhong Wang
The immunogenicity of subunit vaccines can be augmented by formulating them into nanoparticles. We conjugated recombinant trimetric influenza A/Aichi/2/68(H3N2) hemagglutinin (HA) onto functionalized gold nanoparticles (AuNPs) surfaces in a repetitive, oriented configuration. To further improve the immunogenicity, we generated Toll-like receptor 5 (TLR5) agonist flagellin (FliC)-coupled AuNPs as particulate adjuvants. Intranasal immunizations with an AuNP-HA and AuNP-FliC particle mixture elicited strong mucosal and systemic immune responses that protected hosts against lethal influenza challenges...
April 9, 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/29648839/a-novel-immunoliposome-technology-for-enhancing-the-activity-of-agonistic-antibody-against-tumor-necrosis-factor-receptor-superfamily
#8
Takako Niwa, Yuji Kasuya, Yukie Suzuki, Kimihisa Ichikawa, Hiroko Yoshida, Akiko Kurimoto, Kento Tanaka, Koji Morita
We have developed a technology for efficiently enhancing the anti-cancer apoptosis-inducing activity of agonistic antibodies against the tumor necrosis factor receptor (TNFR) superfamily by the formation of immunoliposomes. To induce apoptosis in cancer cells, agonistic antibodies to the TNFR superfamily normally need cross-linking by internal immune effector cells via the Fc region after binding to receptors on the cell membrane. To develop apoptosis-inducing antibodies that do not require the support of cross-linking by immune cells, we prepared immunoliposomes conjugated with TRA-8, an agonistic antibody against death receptor 5 (DR5), with various densities of antibody on the liposome surface, and evaluated their activities...
April 12, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29643854/the-role-of-quinine-responsive-taste-receptor-family-2-in-airway-immune-defense-and-chronic-rhinosinusitis
#9
Alan D Workman, Ivy W Maina, Steven G Brooks, Michael A Kohanski, Beverly J Cowart, Corrine Mansfield, David W Kennedy, James N Palmer, Nithin D Adappa, Danielle R Reed, Robert J Lee, Noam A Cohen
Background: Bitter (T2R) and sweet (T1R) taste receptors in the airway are important in innate immune defense, and variations in taste receptor functionality in one T2R (T2R38) correlate with disease status and disease severity in chronic rhinosinusitis (CRS). Quinine is a bitter compound that is an agonist for several T2Rs also expressed on sinonasal cells, but not for T2R38. Because of this property, quinine may stimulate innate immune defense mechanisms in the airway, and functional differences in quinine perception may be reflective of disease status in CRS...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29643189/elevated-hepatic-cd1d-levels-coincide-with-invariant-nkt-cell-defects-in-chronic-hepatitis-b-virus-infection
#10
Xiaosheng Tan, Yajie Ding, Peng Zhu, Rui Dou, Zhihui Liang, Daofeng Yang, Zhiyong Huang, Wei Wang, Xiongwen Wu, Xiufang Weng
Activation of invariant NKT (iNKT) cells manifests antiviral immune responses in vivo. However, clinical trials have failed to show consistent hepatitis B virus (HBV) DNA reduction postadministration of iNKT cell-specific agonist α-galactosylceramide (α-GalCer). In this study, we aimed to investigate HBV infection-related iNKT cell defects and explore iNKT cell-based therapeutic potential for chronic hepatitis B (CHB). Liver specimens from 30 HBV-infected hepatocellular carcinoma patients were collected for CD1d/hepatitis B surface Ag (HBsAg) staining and/or intrahepatic iNKT cell assay...
April 11, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29628795/the-revival-of-cpg-oligonucleotide-based-cancer-immunotherapies
#11
REVIEW
Tomasz Adamus, Marcin Kortylewski
The promising results of clinical trials using immune checkpoint inhibitors revived interests in cancer immunotherapy. However, it also became apparent that efficacy of immune checkpoint blockade can benefit from combining it with immunostimulatory strategies. Here, we review prior and re-emerging approaches using Toll-like Receptor 9 (TLR9) agonists, CpG oligodeoxynucleotides (ODNs), focused on the generation of antitumor immune responses in cancer patients. While numerous early clinical trials using TLR9 ligands in monotherapies provided evidence of CpG ODNs tolerability and safety, they failed to demonstrate sufficient antitumor efficacy...
March 2018: Contemporary Oncology Współczesna Onkologia
https://www.readbyqxmd.com/read/29628151/safety-of-a-two-dose-investigational-hepatitis-b-vaccine-hbsag-1018-using-a-toll-like-receptor-9-agonist-adjuvant-in-adults
#12
Randall Hyer, Darren K McGuire, Biao Xing, Sam Jackson, Robert Janssen
BACKGROUND: Hepatitis B virus infection remains an important global public health problem. Approved alum-adjuvanted vaccines are well tolerated but require three doses and have reduced immunogenicity in adults. A two-dose vaccine containing hepatitis B surface antigen combined with a novel, Toll-like receptor 9 agonist adjuvant (HBsAg-1018 [HEPLISAV-B®]) has demonstrated significantly higher seroprotection rates than a three dose vaccine. METHODS: A post hoc analysis compared the safety of HBsAg-1018 with HBsAg-Eng (Engerix-B®), in three randomized, observer-blinded, active-controlled, multi-center phase 3 trials in adults...
April 5, 2018: Vaccine
https://www.readbyqxmd.com/read/29626056/methylindoles-and-methoxyindoles-are-agonists-and-antagonists-of-human-aryl-hydrocarbon-receptor-ahr
#13
Martina Stepankova, Iveta Bartonkova, Eva Jiskrova, Radim Vrzal, Sridhar Mani, Sandhya Kortagere, Zdenek Dvorak
Novel methyl-indoles were identified as endobiotic and xenobiotic ligands of human aryl hydrocarbon receptor (AhR). We examined the effects of 22 methylated and methoxylated indoles on the transcriptional activity of AhR. Employing reporter gene assays in AZ-AHR transgenic cells, we determined full agonist, partial agonist or antagonist activities of tested compounds, having substantially variable EC50 , IC50 and relative efficacies. The most effective agonists (EMAX relative to 5 nM dioxin) of AhR were 4-Me-indole (134%), 6-Me-indole (91%) and 7-MeO-indole (80%), respectively...
April 6, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29611471/peroxisome-proliferated-activated-receptors-ppars-opportunities-and-challenges-for-ocular-therapy
#14
Prachi Khatol, Shivani Saraf, Ankit Jain
Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors. They exist in three isoforms (PPAR-α, PPAR-β/δ, and PPAR-Υ) in humans, but mainly PPAR-Υ, and they are expressed in retinal epithelial pigment. PPARs are involved in mediating numerous pathological implications in eye such as diabetic retinopathy (DR), choroidal neovascularization (CNV), glaucoma, diabetic macular edema, and other retinal diseases. Peroxisome proliferator-activated receptors are key players in various biological pathways like lipid degeneration, immune regulation, and reactive oxygen species regulation, regulation of vascular endothelial growth factor, matrixmetalloproteinase-9, and docosahexaenoic acid pathway...
2018: Critical Reviews in Therapeutic Drug Carrier Systems
https://www.readbyqxmd.com/read/29610140/-mycobacterium-tuberculosis-transfer-rna-induces-il-12p70-via-synergistic-activation-of-pattern-recognition-receptors-within-a-cell-network
#15
Caroline Keegan, Stephan Krutzik, Mirjam Schenk, Philip O Scumpia, Jing Lu, Yan Ling Joy Pang, Brandon S Russell, Kok Seong Lim, Scarlet Shell, Erin Prestwich, Dan Su, David Elashoff, Robert M Hershberg, Barry R Bloom, John T Belisle, Sarah Fortune, Peter C Dedon, Matteo Pellegrini, Robert L Modlin
Upon recognition of a microbial pathogen, the innate and adaptive immune systems are linked to generate a cell-mediated immune response against the foreign invader. The culture filtrate of Mycobacterium tuberculosis contains ligands, such as M. tuberculosis tRNA, that activate the innate immune response and secreted Ags recognized by T cells to drive adaptive immune responses. In this study, bioinformatics analysis of gene-expression profiles derived from human PBMCs treated with distinct microbial ligands identified a mycobacterial tRNA-induced innate immune network resulting in the robust production of IL-12p70, a cytokine required to instruct an adaptive Th1 response for host defense against intracellular bacteria...
April 2, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29609683/are-gnrh-and-fsh-potentially-damaging-factors-in-the-cardiovascular-system
#16
Z Poljak, I Hulin, L Maruscakova, B Mladosievicova
In the physiological view the human cardiomyocytes express receptors of gonadotropin-releasing hormone and follicle-stimulating hormone. The local effects of these hormones in the heart are related also to some interstitial cells, such as endothelial cells with follicle-stimulating hormone receptors and immune cells with gonadotropin-releasing hormone receptors. The administration of androgen deprivation therapy in patients with prostate cancer is associated with increased incidence of cardiovascular complications...
April 2, 2018: Die Pharmazie
https://www.readbyqxmd.com/read/29608601/sting-agonists-enable-antiviral-cross-talk-between-human-cells-and-confer-protection-against-genital-herpes-in-mice
#17
Morten K Skouboe, Alice Knudsen, Line S Reinert, Cedric Boularan, Thierry Lioux, Eric Perouzel, Martin K Thomsen, Søren R Paludan
In recent years, there has been an increasing interest in immunomodulatory therapy as a means to treat various conditions, including infectious diseases. For instance, Toll-like receptor (TLR) agonists have been evaluated for treatment of genital herpes. However, although the TLR7 agonist imiquimod was shown to have antiviral activity in individual patients, no significant effects were observed in clinical trials, and the compound also exhibited significant side effects, including local inflammation. Cytosolic DNA is detected by the enzyme cyclic GMP-AMP (2'3'-cGAMP) synthase (cGAS) to stimulate antiviral pathways, mainly through induction of type I interferon (IFN)s...
April 2, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29603875/toll-like-receptor-2-and-3-enhance-melanogenesis-and-melanosome-transport-in-human-melanocytes
#18
AutSaaya Koike, Kenshi Yamasaki, Takeshi Yamauchi, Mai Inoue, Ryoko Shimada-Ohmori, Kenichiro Tsuchiyama, Setsuya Aiba
Because little is known about how the innate immune response influences skin pigmentation, we examined whether Toll-like receptor (TLR) agonists participate in melanogenesis and melanosome transportation. We observed that TLR2/2 agonist HKLM and TLR3 agonist Poly(I:C) increased the amount of extracellular melanin from primary human epidermal melanocytes. HKLM, but not Poly(I:C), increased the melanogenic genes such as tyrosinase and dopachrome tautomerase. Poly(I:C) increased the expression of Rab27A, a molecule that facilitates melanosome transport to perimembranous actin filament...
March 30, 2018: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29602776/mitocryptides-from-human-mitochondrial-dna-encoded-proteins-activate-neutrophil-formyl-peptide-receptors-receptor-preference-and-signaling-properties
#19
Michael Gabl, Martina Sundqvist, Andre Holdfeldt, Simon Lind, Jonas Mårtensson, Karin Christenson, Takayuki Marutani, Claes Dahlgren, Hidehito Mukai, Huamei Forsman
Phagocytic neutrophils express formyl peptide receptors (FPRs; FPR1 and FPR2) that distinctly recognize peptides starting with an N-formylated methionine (fMet). This is a hallmark of bacterial metabolism; similar to prokaryotes, the starting amino acid in synthesis of mitochondrial DNA-encoded proteins is an fMet. Mitochondrial cryptic peptides (mitocryptides; MCTs) with an N-terminal fMet could be identified by our innate immune system; however, in contrast to our knowledge about bacterial metabolites, very little is known about the recognition profiles of MCTs...
March 30, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29600327/the-histamine-h4-receptor-modulates-the-differentiation-process-of-human-monocyte-derived-m1-macrophages-and-the-release-of-ccl4-mip-1%C3%AE-from-fully-differentiated-m1-macrophages
#20
Susanne Mommert, Lisanne Ratz, Holger Stark, Ralf Gutzmer, Thomas Werfel
OBJECTIVE: Histamine is an important mediator of biological functions and present in high amounts in inflammatory skin lesions which are characterised by a marked infiltration of myeloid derived cell populations. The aim of the study was to investigate the expression and function of histamine receptors, with a focus on the histamine H4 receptor (H4R) in detail during the differentiation process from monocytes to macrophages and on fully differentiated M1 macrophages. METHODS: Quantitative PCR, ELISA technique, and flow cytometry were applied to analyze expression levels of histamine receptors, of CXCL10, CCL4, CCL3, or IL-23 and of the macrophage differentiation marker CD68, respectively...
March 29, 2018: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
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