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Agonist triggering

Khiyam Hussain, Chantal E Hargreaves, Tania F Rowley, Joshua M Sopp, Kate V Latham, Pallavi Bhatta, John Sherington, Rona M Cutler, David P Humphreys, Martin J Glennie, Jonathan C Strefford, Mark S Cragg
Monoclonal antibody (mAb) immunotherapy has transformed the treatment of allergy, autoimmunity, and cancer. The interaction of mAb with Fc gamma receptors (FcγR) is often critical for efficacy. The genes encoding the low-affinity FcγR have single nucleotide polymorphisms (SNPs) and copy number variation that can impact IgG Fc:FcγR interactions. Leukocyte-based in vitro assays remain one of the industry standards for determining mAb efficacy and predicting adverse responses in patients. Here we addressed the impact of FcγR genetics on immune cell responses in these assays and investigated the importance of assay format...
2019: Frontiers in Immunology
Pavel V Avdonin, Alexander D Nadeev, Galina Yu Mironova, Irina L Zharkikh, Piotr P Avdonin, Nikolay V Goncharov
Hydrogen peroxide, formed in the endothelium, acts as a factor contributing to the relaxation of blood vessels. The reason for this vasodilatory effect could be modulation by H2 O2 of calcium metabolism, since mobilization of calcium ions in endothelial cells is a trigger of endothelium-dependent relaxation. The aim of this work was to investigate the influence of H2 O2 on the effects of Ca2+ -mobilizing agonists in human umbilical vein endothelial cells (HUVEC). We have found that H2 O2 in concentration range 10-100  μ M increases the rise of [Ca2+ ]i induced by 5-hydroxytryptamine (5-HT) and carbachol and does not affect the calcium signals of ATP, agonist of type 1 protease-activated receptor SFLLRN, histamine and bradykinin...
2019: Oxidative Medicine and Cellular Longevity
Jesús Gálvez, Juan J Gálvez, Pilar García-Peñarrubia
On the T-cell surface the TCR is the only molecule that senses antigen, and the engagement of TCR with its specific antigenic peptide (agonist)/MHC complex (pMHC) is determined by the biochemical parameters of the TCR-pMHC interaction. This interaction is the keystone of the adaptive immune response by triggering intracellular signaling pathways that induce the expression of genes required for T cell-mediated effector functions, such as T cell proliferation, cytokine secretion and cytotoxicity. To study the TCR-pMHC interaction one of its properties most extensively analyzed has been TCR-pMHC affinity...
2019: Frontiers in Immunology
Catherine McLaughlin, John Clements, Ana-Maria Oprişoreanu, Sergiy Sylantyev
KEY POINTS: A T258F mutation of the glycine receptor increases the receptor affinity to endogenous agonists, modifies single-channel conductance and shapes response decay kinetics. Glycine receptors of cerebellar granule cells play their functional role not continuously, but when granule cell layer starts receiving high amount of excitatory inputs. Despite their relative scarcity, tonically active glycine receptors of cerebellar granule cells make a significant impact on action potential generation, inter-neuronal crosstalk, and modulate synaptic plasticity in neural networks; extracellular glycine increases probability of postsynaptic response occurrence acting at NMDA receptors and decreases this probability acting at glycine receptors...
March 15, 2019: Journal of Physiology
Guangya Zhang, Jiangping He, Xiaofei Ye, Jing Zhu, Xi Hu, Minyan Shen, Yuru Ma, Ziming Mao, Huaidong Song, Fengling Chen
Hepatocellular carcinoma (HCC), a common liver malignancy worldwide, has high morbidity and mortality. β-Thujaplicin, a tropolone derivative, has been used in some health-care products and clinical adjuvant drugs, but its use for HCC is unknown. In this study, we found that β-Thujaplicin inhibits the growth of HCC cells, but not normal liver cells, with nanomolar potency. Mechanistically, we found that β-Thujaplicin could induce autophagy, as judged by western blot, confocal microscopy, and transmission electron microscopy...
March 15, 2019: Cell Death & Disease
Soaad Alfaqaan, Tomoki Yoshida, Hiromi Imamura, Chihiro Tsukano, Yoshiji Takemoto, Akira Kakizuka
Fluctuations in food availability and shifts in temperature are typical environmental changes experienced by animals. These environmental shifts sometimes portend more severe changes; e.g., chilly north winds precede the onset of winter. Such telltale signs may be indicators for animals to prepare for such a shift. Here we show that HEK293A cells, cultured under starvation conditions, can "memorize" a short exposure to cold temperature (15 °C), which was evidenced by their higher survival rate compared to cells continuously grown at 37 °C...
March 14, 2019: Scientific Reports
Xavier Pillois, Alexandre Guy, Émeline Choquet, Chloé James, Marie Tuffigo, Jean-François Viallard, Cédric Garcia, Jean-Claude Bordet, Martine Jandrot-Perrus, Bernard Payrastre, Mathieu Fiore
BACKGROUND: Acquired Glanzmann thrombasthenia (GT) is a bleeding disorder generally caused by anti-αII b β3 autoantibodies. OBJECTIVES: We aimed to characterize the molecular mechanism leading to a progressive GT-like phenotype in a patient with chronic immune thrombocytopenia. PATIENT, METHODS AND RESULTS: The patient suffered from repeated episodes of gastrointestinal bleedings and further studies indicated a moderate platelet aggregation defect...
March 13, 2019: Journal of Thrombosis and Haemostasis: JTH
Soheila Borhani, Carmen Corciulo, Ane Larranaga-Vera, Bruce N Cronstein
Osteoblast differentiation and proliferation are regulated by several modulators, among which are adenosine A2A receptors (A2ARs) and Wingless/Integrated-β-catenin pathways. Cytosolic β-catenin stabilization promotes its nuclear translocation and transcriptional activity. In the present study, we seek to determine whether there is a connection between A2AR stimulation and cellular β-catenin levels in osteoblasts. Osteoblast precursor cell line (MC3T3-E1) and primary murine osteoblasts were treated with CGS21680, a highly selective A2AR agonist...
March 13, 2019: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Maria Francesca Santolla, Adele Vivacqua, Rosamaria Lappano, Damiano Cosimo Rigiracciolo, Francesca Cirillo, Giulia Raffaella Galli, Marianna Talia, Giuseppe Brunetti, Anna Maria Miglietta, Antonino Belfiore, Marcello Maggiolini
The FGF2/FGFR1 paracrine loop is involved in the cross-talk between breast cancer cells and components of the tumor stroma as cancer-associated fibroblasts (CAFs). By quantitative PCR (qPCR), western blot, immunofluorescence analysis, ELISA and ChIP assays, we demonstrated that 17β-estradiol (E2) and the G protein estrogen receptor (GPER) agonist G-1 induce the up-regulation and secretion of FGF2 via GPER together with the EGFR/ERK/c-fos/AP-1 signaling cascade in (ER)-negative primary CAFs. Evaluating the genetic alterations from METABRIC and TCGA datasets, we then assessed that FGFR1 is the most frequently amplified FGFRs family member and its amplification/expression associates with shorter survival rates in breast cancer patients...
March 7, 2019: Cells
Barbara Lawrenz, Carol Coughlan, Human M Fatemi
PURPOSE OF REVIEW: The aim of this review is to summarize the different aspects of luteal phase deficiency in IVF treatment and the possibilities of individualized luteal phase support. RECENT FINDINGS: After the application of human chorionic gonadotrophin (hCG) for final oocyte maturation, the vaginal route for progesterone administration is sufficient to maintain an adequate luteal phase support. New data point toward the possibility of oral medication; however, those data have yet to be confirmed in larger studies...
February 21, 2019: Current Opinion in Obstetrics & Gynecology
Zhipeng Chen, Xiaohong Cen, Junjie Yang, Zhiman Lin, Meihuan Liu, Kui Cheng
Previous high throughput virtual screening of 10 million-compound and following cell based validation led to the discovery of a novel, nonlipopeptide-like chemotype ZINC 6662436, as toll-like receptor 2 (TLR2) agonists. In this report, compounds belonging to four areas of structural modification of ZINC6662436 were evaluated for biological activity using human HEK-Blue TLR2 reporter cells, and human THP-1 monocytic cells, yield SMU-C13 as an optimized, direct and high potent (EC50  = 160 nM) agonist of human TLR2...
March 1, 2019: European Journal of Medicinal Chemistry
Thomas Vain, Sara Raggi, Noel Ferro, Deepak Kumar Barange, Martin Kieffer, Qian Ma, Siamsa M Doyle, Mattias Thelander, Barbora Pařízková, Ondřej Novák, Alexandre Ismail, Per-Anders Enquist, Adeline Rigal, Małgorzata Łangowska, Sigurd Ramans Harborough, Yi Zhang, Karin Ljung, Judy Callis, Fredrik Almqvist, Stefan Kepinski, Mark Estelle, Laurens Pauwels, Stéphanie Robert
Auxin phytohormones control most aspects of plant development through a complex and interconnected signaling network. In the presence of auxin, AUXIN/INDOLE-3-ACETIC ACID (AUX/IAA) transcriptional repressors are targeted for degradation by the SKP1-CULLIN1-F-BOX (SCF) ubiquitin-protein ligases containing TRANSPORT INHIBITOR RESISTANT 1/AUXIN SIGNALING F-BOX (TIR1/AFB). CULLIN1-neddylation is required for SCFTIR1/AFB functionality, as exemplified by mutants deficient in the NEDD8-activating enzyme subunit AUXIN-RESISTANT 1 (AXR1)...
March 8, 2019: Proceedings of the National Academy of Sciences of the United States of America
Lai Jin, Yuanyuan Qian, Jun Zhou, Li Dai, Chunxuan Cao, Chao Zhu, Shengnan Li
Clinical studies have elucidated the negative correlation between microtubules-associated protein 1 light chain 3-B (LC3B) protein expression and overall survival of breast cancer patients. Our previous data demonstrated corticortropin-releasing hormone family (CRHs) suppressed migration of breast cancer cells via CRH receptors (CRHRs). Here, we showed that the activation of CRHRs (CRHR1 and CRHR2) remarkably reduced the conversion of LC3BI to LC3BII and hence repressed macroautophagy/autophagy, resulting in migration inhibition...
March 5, 2019: Cellular Signalling
Giovanna Antonaci, Luca Giulio Cossa, Antonella Muscella, Carla Vetrugno, Sandra Angelica De Pascali, Francesco Paolo Fanizzi, Santo Marsigliante
We have demonstrated the cytotoxic effects of [Pt( O , O '-acac)(γ-acac)(dimethyl sulfide (DMS))] on various immortalized cell lines, in primary cultures, and in murine xenograft models in vivo. Recently, we also showed that [Pt( O,O' -acac)(γ-acac)(DMS)] is able to kill Caki-1 renal cells both in vivo and in vitro. In the present paper, apoptotic and autophagic effects of [Pt( O , O '-acac)(γ-acac)(DMS)] and cisplatin were studied and compared using Caki-1 cancerous renal cells. The effects of cisplatin include activation of caspases, proteolysis of enzyme poly ADP ribose polymerase (PARP), control of apoptosis modulators B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and BH3-interacting domain death agonist (Bid), and cell cycle arrest in G2/M phase...
March 6, 2019: Biomolecules
Liwen Jiang, Dongqing Ma, Blair D Grubb, Minyan Wang
OBJECTIVES: The transient receptor potential ankyrin A 1 (TRPA1) channel and calcitonin gene-related peptide (CGRP) are targets for migraine prophylaxis. This study aimed to understand their mechanisms in migraine by investigating the role of TRPA1 in cortical spreading depression (CSD) in vivo and exploring how reactive oxygen species (ROS)/TRPA1/CGRP interplay in regulating cortical susceptibility to CSD. METHODS: Immunohistochemistry was used for detecting TRPA1 expression...
March 6, 2019: Journal of Headache and Pain
M F Nagoor Meeran, Hasan Al Taee, Sheikh Azimullah, Saeed Tariq, Ernest Adeghate, Shreesh Ojha
The cannabinoid type 2 receptor (CB2 ) has recently emerged as an important therapeutic target for cancer as well as cardiovascular diseases. The CB2 receptor downregulation has been reported in solid tumors and cardiovascular diseases, therefore the CB2 receptor activation has been considered as a viable strategy for chemotherapy as well as cardioprotection. In chemotherapy, doxorubicin (DOX) is an important drug that continues to be the mainstay of chemotherapy in solid tumors, leukemia, and lymphoma. However, the use of DOX is often limited due to its lethal cardiotoxicity...
March 2, 2019: Chemico-biological Interactions
Cing-Yu Chen, Mann-Jen Hour, Wen-Chuan Lin, Kar-Lok Wong, Lian-Ru Shiao, Ka-Shun Cheng, Paul Chan, Yuk-Man Leung
Ca2+ -sensing receptors (CaSR) are G protein-coupled receptors which are activated by a rise in extracellular Ca2+ . CaSR activation has been known to inhibit parathyroid hormone release and stimulate calcitonin release from parathyroid glands and thyroid parafollicular C cells, respectively. The roles of CaSR in other cell types including endothelial cells (EC) are much less understood. In this work, we demonstrated protein and functional expression of CaSR in mouse cerebral EC (bEND.3). Unexpectedly, CaSR response (high Ca2+ -elicited cytosolic [Ca2+ ] elevation) was unaffected by edelfosine or U73122 but strongly suppressed by SK&F 96365, ruthenium red, and 2-aminoethoxydiphenyl borate (2-APB), suggesting involvement of TRPV and TRPC channels but not Gq-phospholipase C...
March 2, 2019: Naunyn-Schmiedeberg's Archives of Pharmacology
Johannes A Eble
Snake venoms contain an astounding variety of different proteins. Among them are numerous C-type lectin family members, which are grouped into classical Ca2+ - and sugar-binding lectins and the non-sugar-binding snake venom C-type lectin-related proteins (SV-CLRPs), also called snaclecs. Both groups share the robust C-type lectin domain (CTLD) fold but differ in a long loop, which either contributes to a sugar-binding site or is expanded into a loop-swapping heterodimerization domain between two CLRP subunits...
March 1, 2019: Toxins
Sunjay Sethi, Rhianna Morgan, Wei Feng, Yanping Lin, Xueshu Li, Corey Luna, Madison Koch, Ruby Bansal, Michael W Duffel, Birgit Puschner, Thomas R Zoeller, Hans-Joachim Lehmler, Isaac N Pessah, Pamela J Lein
Polychlorinated biphenyls (PCBs) pose significant risk to the developing human brain; however, mechanisms of PCB developmental neurotoxicity (DNT) remain controversial. Two widely posited mechanisms are tested here using PCBs identified in pregnant women in the MARBLES cohort who are at increased risk for having a child with a neurodevelopmental disorder (NDD). As determined by gas chromatography-triple quadruple mass spectrometry, the mean PCB levels in maternal serum was 2.22 ng/mL. The 12 most abundant PCBs were tested singly and as a mixture mimicking the congener profile in maternal serum for activity at the thyroid hormone receptor (THR) and ryanodine receptor (RyR)...
March 1, 2019: Environmental Science & Technology
Yuantong Liu, Jianmin Li, Hao Li, Yue Shang, Yan Guo, Zhenzhong Li, Zhen Liu
STUDY DESIGN: Animal experiment: a rat model of lumbar disc herniation (LDH) induced painful radiculopathies. OBJECTIVE: To investigate the role and mechanism of AMP-activated protein kinase (AMPK) in dorsal root ganglia (DRG) neurons in LDH-induced painful radiculopathies. SUMMARY OF BACKGROUND DATA: Overactivation of multiple pain signals in DRG neurons triggered by LDH is crucial to the development of radicular pain. AMPK is recognized as a cellular energy sensor, as well as a pain sensation modulator, but its function in LDH-induced pain hypersensitivity remains largely unknown...
February 5, 2019: Spine
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