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Agonist triggering

Lawrence J Billing, Christopher A Smith, Pierre Larraufie, Deborah A Goldspink, Sam Galvin, Richard G Kay, Jonathan D Howe, Ryan Walker, Mihai Pruna, Leslie Glass, Ramona Pais, Fiona M Gribble, Frank Reimann
OBJECTIVE: Insulin-like peptide-5 (INSL5) is an orexigenic gut hormone found in a subset of colonic and rectal enteroendocrine L-cells together with the anorexigenic hormones glucagon-like peptide-1 (GLP-1) and peptideYY (PYY). Unlike GLP-1 and PYY, INSL5 levels are elevated by calorie restriction, raising questions about how these hormones respond to different stimuli when they arise from the same cell type. The aim of the current study was to identify whether and how INSL5, GLP-1 and PYY are co-secreted or differentially secreted from colonic L-cells...
July 30, 2018: Molecular Metabolism
Juan A Giménez-Bastida, William E Boeglin, Olivier Boutaud, Michael G Malkowski, Claus Schneider
Aspirin (acetylsalicylic acid) inhibits prostaglandin (PG) synthesis by transfer of its acetyl group to a serine residue in the cyclooxygenase (COX) active site. Acetylation of Ser530 inhibits catalysis by preventing access of arachidonic acid substrate in the COX-1 isoenzyme. Acetylated COX-2, in contrast, gains a new catalytic activity and forms 15 R hydroxy-eicosatetraenoic acid (15 R-HETE) as alternate product. Here we show that acetylated COX-2 also retains COX activity, forming predominantly 15 R-configuration PGs (70 or 62% 15 R, respectively, determined using radiolabeled substrate or LC-MS analysis)...
August 10, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Julie Simons, Lisa Fauci
The acrosome reaction is a complex, calcium-dependent reaction that results in an exocytotic event required for successful fertilization of the egg. It has long been thought that the acrosome reaction occurs upon sperm binding to the zona pellucida, a viscoelastic layer surrounding the oocyte. Recent studies have suggested that the reaction may even occur before the sperm encounters the zona, perhaps mediated by progesterone or some other agonist. It has been particularly difficult to understand differences between progesterone-induced and zona-induced reactions experimentally and whether one substance is the more biologically relevant trigger...
August 9, 2018: Bulletin of Mathematical Biology
Shailender Bhatia, Natalie J Miller, Hailing Lu, Natalie Vandeven Vandeven, Dafina Ibrani, Michi Shinohara, David Byrd, Upendra Parvathaneni, Rima M Kulikauskas, Jan Ter Meulen, Frank J Hsu, David M Koelle, Paul Nghiem
PURPOSE: G100 is a toll-like receptor 4 (TLR4) agonist that triggers innate and adaptive anti-tumor immune responses in preclinical models. This pilot study assessed the safety, efficacy, and immunologic activity of intratumoral (IT) administration of G100 in patients with Merkel cell carcinoma (MCC). EXPERIMENTAL DESIGN: Patients with loco-regional MCC (n=3; Cohort A) received neoadjuvant IT G100 (2 weekly doses at 5 μg/dose) followed by surgery and radiotherapy; patients with metastatic MCC (n=7; Cohort B) received 3 doses in a 6-week cycle and could receive additional cycles with/without radiotherapy...
August 9, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Lili Zhou, Shan Zhou, Peng Yang, Yuan Tian, Zhiwei Feng, Xiang-Qun Xie, Youhua Liu
The cannabinoid receptor type 2 (CB2) is a G protein-coupled seven transmembrane receptor that transmits endogenous cannabinoid signaling. The role of CB2 in the pathogenesis of kidney injury and fibrosis remains poorly understood. Here we demonstrate that CB2 was induced, predominantly in kidney tubular epithelium, in various models of kidney disease induced by unilateral ureteral obstruction, adriamycin or ischemia/reperfusion injury. In vitro, forced expression of CB2 or treatment with a CB2 agonist was sufficient to trigger matrix gene expression, whereas knockdown of CB2 by siRNA abolished transforming growth factor-β1-induced signaling and fibrogenic responses in kidney tubular cells...
August 6, 2018: Kidney International
Muhammad Tahir Khan, Juan Liu, Jana Nerlich, Yong Tang, Heike Franke, Peter Illes
P2X7 receptors (Rs) mediate apoptosis/necrosis in neuronal and non-neuronal systems. Patch-clamp recordings from dentate gyrus (DG) granule cells in acutely prepared hippocampal slices of mice showed that incubation with 4-aminopyridine (4-AP) causes an excitability increase. This led to an enhanced sensitivity of P2X7Rs of the underlying subgranular zone neural progenitor cells (NPCs) towards dibenzoyl-ATP (Bz-ATP). The glutamatergic agonists NMDA and AMPA, as well as the purinergic agonist ATP also increased the Bz-ATP-induced current amplitudes (IBzATP )...
August 6, 2018: Neuropharmacology
Lizhen Wu, Jian Cao, Wesley L Cai, Sabine M Lang, John R Horton, Daniel J Jansen, Zongzhi Z Liu, Jocelyn F Chen, Meiling Zhang, Bryan T Mott, Katherine Pohida, Ganesha Rai, Stephen C Kales, Mark J Henderson, Xin Hu, Ajit Jadhav, David J Maloney, Anton Simeonov, Shu Zhu, Akiko Iwasaki, Matthew D Hall, Xiaodong Cheng, Gerald S Shadel, Qin Yan
Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection and cancer. STING agonists induce both innate and adaptive immune responses and are a new class of cancer immunotherapy agents tested in multiple clinical trials. However, STING is commonly silenced in cancer cells via unclear mechanisms, limiting the application of these agonists. Here, we report that the expression of STING is epigenetically suppressed by the histone H3K4 lysine demethylases KDM5B and KDM5C and is activated by the opposing H3K4 methyltransferases...
August 6, 2018: PLoS Biology
Cheryl L Limebeer, Erin M Rock, Keith A Sharkey, Linda A Parker
Using the rat conditioned gaping model of nausea, the interoceptive insular cortex (IIC) has been identified as a critical site for the regulation of lithium chloride (LiCl)-induced nausea. Indirect evidence supports a model where serotonin (5-HT) acts on postsynaptic 5-HT3 receptors and its release is suppressed by elevating 2-arachidonylglycerol (2-AG) by monoacylglycerol lipase (MAGL) inhibition to suppress nausea. Here, we directly test the hypothesis that systemic LiCl elevates 5-HT in the IIC, and this is prevented by pretreatments that reduce 5-HT release...
July 2018: ENeuro
Ronit Beck-Fruchter, Shira Baram, Yoel Geslevich, Amir Weiss
BACKGROUND/AIMS: Gonadotropin releasing hormone (GnRH) agonist triggering results in an endogenous gonadotropin flare. Although it effectively stimulates ovulation, GnRH agonist triggers results in an early luteolysis and requires modification of the luteal support. The current study aims to evaluate GnRH agonist triggering with exclusive human chorionic gonadotropin (hCG) luteal support. METHODS: In this prospective observational study, 56 normogonadotropic-assisted reproductive technology patients, stimulated using a GnRH-antagonist protocol, were studied...
July 26, 2018: Gynecologic and Obstetric Investigation
Ewelina Bratek, Apolonia Ziembowicz, Agnieszka Bronisz, Elzbieta Salinska
Birth asphyxia resulting in brain hypoxia-ischemia (H-I) can cause neonatal death or lead to persistent brain damage. Recent investigations have shown that group II metabotropic glutamate receptor (mGluR2/3) activation can provide neuroprotection against H-I but the mechanism of this effect is not clear. The aim of this study was to investigate whether mGluR2/3 agonists applied a short time after H-I reduce brain damage in an experimental model of birth asphyxia, and whether a decrease in oxidative stress plays a role in neuroprotection...
2018: PloS One
Xiaoting Du, Yang Zhang, Jingyi Zou, Zhenghong Yuan, Zhigang Yi
Replication of the positive-strand RNA viruses generates double-stranded RNAs (dsRNAs) that are recognized by host pattern recognition receptors (PRRs) to trigger innate immune responses. Formation of the viral replication complex (RC) has been thought to shield dsRNA from being recognized by innate sensors. To elucidate the RC-mediated evasion of innate recognition, we selected poliovirus (PV) as a model. We first found that RNAs generated during PV replication were potent interferon (IFN) inducers upon transfection, while there was no obvious IFN production detected in PV-replicating cells...
July 24, 2018: Journal of General Virology
Christian Carpéné, Jean Galitzky, Chloé Belles, Alexia Zakaroff-Girard
Tyramine is found in foodstuffs, the richest being cheeses, sausages, and wines. Tyramine has been recognized to release catecholamines from nerve endings and to trigger hypertensive reaction. Thereby, tyramine-free diet is recommended for depressed patients treated with irreversible inhibitors of monoamine oxidases (MAO) to limit the risk of hypertension. Tyramine is a substrate of amine oxidases and also an agonist at trace amine-associated receptors. Our aim was to characterize the dose-dependent effects of tyramine on human adipocyte metabolic functions...
July 23, 2018: Journal of Physiology and Biochemistry
Yu-Qiang Li
Oct4 is uniformly expressed by all types of pluripotent cells and is essential for pluripotency. Oct4 is also the central reprogramming factor that is constant in most transcription factor cocktails used to generate iPS cells. This article discusses the mechanisms of regulating Oct4 expression by confluence-based Hgf and hypoxia signalling in mouse somatic cells. Stat3 is activated ligand-independently in confluent cells and triggers the formation of cell aggregates. Hgf signalling is preserved after confluence, stimulating β-catenin and Stat3 activity, which are both crucial for Oct4 transcription...
July 22, 2018: Current Stem Cell Research & Therapy
Shireen Nigar, Yoshinari Yamamoto, Takuma Okajima, Takashi Sato, Tasuku Ogita, Takeshi Shimosato
Bacterial genomic DNA has recently been shown to elicit a highly evolved immune defense. This response can be selectively triggered for a wide range of therapeutic applications, including use as a vaccine adjuvant to immunotherapies for allergy, cancer, and infectious diseases. Previously, we identified a low-concentration immune synergistic oligodeoxynucleotide (iSN-ODN, named iSN34) from Lactobacillus rhamnosus GG that has immunosynergistic activity upon costimulation of target cells with ligands of Toll-like receptor 9 (TLR9)...
July 23, 2018: Animal Science Journal, Nihon Chikusan Gakkaihō
Susanne Mommert, Derya Aslan, Lisanne Ratz, Holger Stark, Ralf Gutzmer, Thomas Werfel
The anaphylatoxin C3a triggers inflammation by binding to its specific G-protein-coupled C3a receptor (C3aR). Since the number of C3aR, which is expressed on the cell surface, affects the response to C3a, we investigated the expression levels of C3aR on human M2 macrophages in allergic situations where high levels of the Th2 cytokine IL-4 and histamine are present in a local microenvironment. The histamine H1 receptor (H1R), H2R and the H4R mRNA expressions were induced or up-regulated during the differentiation process of M2 macrophages...
July 20, 2018: Journal of Innate Immunity
Bindu N Chimote, Natchandra M Chimote
Steroid hormones form an integral part of normal development in mammalian organisms. Cholesterol is the parent compound from which all steroid hormones are synthesized. The product pregnenolone formed from cholesterol serves as precursor for mineralocorticoids, glucocorticoids, as well as dehydroepiandrosterone (DHEA) and its derived sexual hormones. DHEA assumes the prohormone status of a predominant endogenous precursor and a metabolic intermediate in ovarian follicular steroidogenesis. DHEA supplementation has been used to enhance ovarian reserve...
2018: Vitamins and Hormones
Xinchun Li, Li Zhong, Zhuo Wang, Huiming Chen, Dan Liao, Ruhua Zhang, Hongyu Zhang, Tiebang Kang
IRS4, a member of the insulin receptor substrate protein family, can induce constitutive PI3K/AKT hyperactivation and cell proliferation even in the absence of insulin or growth factors and promote tumorigenesis, but its regulation has only been explored at the transcriptional level. Methods: Scansite was used to predict the potential protein kinases that may regulate the functions of IRS4, and mass spectrometry was used to identify the E3 ligase for IRS4. The protein interaction was carried out by immunoprecipitation, and protein stability was measured by cycloheximide treatment...
2018: Theranostics
Michael Chavez, Matthew T Silvestrini, Elizabeth S Ingham, Brett Z Fite, Lisa M Mahakian, Sarah M Tam, Asaf Ilovitsh, Arta M Monjazeb, William J Murphy, Neil E Hubbard, Ryan R Davis, Clifford G Tepper, Alexander D Borowsky, Katherine W Ferrara
Both adjuvants and focal ablation can alter the local innate immune system and trigger a highly effective systemic response. Our goal is to determine the impact of these treatments on directly treated and distant disease and the mechanisms for the enhanced response obtained by combinatorial treatments. Methods: We combined RNA-sequencing, flow cytometry and TCR-sequencing to dissect the impact of immunotherapy and of immunotherapy combined with ablation on local and systemic immune components. Results: With administration of a toll-like receptor agonist agonist (CpG) alone or CpG combined with same-site ablation, we found dramatic differences between the local and distant tumor environments, where the directly treated tumors were skewed to high expression of F4/80 , Cd11b and Tnf and the distant tumors to enhanced Cd11c , Cd3 and Ifng ...
2018: Theranostics
Alexander Stumpf, Daniel Parthier, Rosanna P Sammons, A Vanessa Stempel, Jörg Breustedt, Benjamin R Rost, Dietmar Schmitz
Endogenous cannabinoids are diffusible lipid ligands of the main cannabinoid receptors type 1 and 2 (CB1 R and CB2 R). In the central nervous system endocannabinoids are produced in an activity-dependent manner and have been identified as retrograde modulators of synaptic transmission. Additionally, some neurons display a cell-autonomous slow self-inhibition (SSI) mediated by endocannabinoids. In these neurons, repetitive action potential firing triggers the production of endocannabinoids, which induce a long-lasting hyperpolarization of the membrane potential, rendering the cells less excitable...
September 1, 2018: Neuropharmacology
Jieun Kang, Jisun Park, Dawn Chung, San Hui Lee, Eun Young Park, Kyung-Hee Han, Seoung Jin Choi, In-Bai Chung, Hyuck Dong Han, Yeon Soo Jung
Objective: To describe the clinical outcomes of frozen-thawed embryo transfer (FET) with artificial preparation of the endometrium, using a combination of estrogen (E2) and progesterone (P4) with or without a gonadotropin-releasing hormone agonist (GnRHa), and the modified natural cycle (MNC) with human chorionic gonadotropin (hCG) trigger. Methods: In this retrospective study, we evaluated 187 patients during 3 years (February 2012-April 2015). The patients were allocated to the following treatment groups: group A, comprising 113 patients (181 cycles) who received GnRHa+E2+P4; group B, comprising 49 patients (88 cycles) who received E2+P4; and group C, comprising 25 patients (42 cycles) who received hCG+P4...
July 2018: Obstetrics & Gynecology Science
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