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https://www.readbyqxmd.com/read/28077335/omega-3-fatty-acids-regulate-nlrp3-inflammasome-activation-and-prevent-behavior-deficits-after-traumatic-brain-injury
#1
Chao Lin, Honglu Chao, Zheng Li, Xiupeng Xu, Yinlong Liu, Zhongyuan Bao, Lijun Hou, Yan Liu, Xiaoming Wang, Yongping You, Ning Liu, Jing Ji
Omega-3 fatty acids (ω-3 FAs) attenuate inflammation and improve neurological outcome in response to traumatic brain injury (TBI), but the specific anti-inflammatory mechanisms remain to be elucidated. Here we found that NLRP3 inflammasome and subsequent pro-inflammatory cytokines were activated in human brains after TBI. Rats treated with ω-3 FAs had significantly less TBI-induced caspase-1 cleavage and IL-1β secretion than those with vehicle. G protein-coupled receptor 40 (GPR40) was observed to be involved in this anti-inflammation...
January 8, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28062183/%C3%AE-arrestin-is-critical-for-early-shear-stress-induced-akt-enos-activation-in-human-vascular-endothelial-cells
#2
Ana Paula Carneiro, Miriam Helena Fonseca-Alaniz, Luís Alberto Oliveira Dallan, Ayumi Aurea Miyakawa, Jose Eduardo Krieger
Recent evidence suggests that β-arrestins, which are involved in G protein-coupled receptors desensitization, may influence mechanotransduction. Here, we observed that nitric oxide (NO) production was abrogated in human saphenous vein endothelial cells (SVECs) transfected with siRNA against β-arrestin 1 and 2 subjected to shear stress (SS, 15 dynes/cm(2), 10 min). The downregulation of β-arrestins 1/2 in SVECs cells also prevented the SS-induced rise in levels of phosphorylation of Akt and endothelial nitric oxide synthase (eNOS, Serine 1177)...
January 3, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28059509/pyrimidinyl-biphenylureas-identification-of-new-lead-compounds-as-allosteric-modulators-of-the-cannabinoid-receptor-cb1
#3
Leepakshi Khurana, Boqiao Fu, Anantha L Duddupudi, Yu-Hsien Liao, Sri Sujana Immadi, Debra A Kendall, Dai Lu
The allosteric modulator 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 2) bound the cannabinoid receptor 1 (CB1) and antagonized G protein coupling. This compound demonstrated potent anorectic effects similar to the CB1 antagonist rimonabant that once was marketed for the treatment of obesity suggesting a new chemical entity for the discovery of anti-obesity drugs. To increase structural diversity of this class of CB1 ligands, we designed and synthesized two classes of novel analogs, in which the pyridine ring of 2 was replaced by a pyrimidine ring...
January 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28035404/arrb1-enhances-the-chemosensitivity-of-lung-cancer-through-the-mediation-of-dna-damage-response
#4
Hongchang Shen, Liguang Wang, Jiangang Zhang, Wei Dong, Tiehong Zhang, Yang Ni, Hongxin Cao, Kai Wang, Yun Li, Yibing Wang, Jiajun Du
ARRB1 (also known as β-arrestin-1) serves as a multifunctional adaptor contributing to the regulation of signaling pathways. ARRB1 may be involved in DNA damage accumulation; however the underlying mechanism involved is unclear. In the present study, non-small cell lung cancer (NSCLC) cell lines (H520 and SK-MES-1) were transfected with ARRB1 plasmids or small interfering ribonucleic acid (siRNA) and received treatment with DNA-damaging agents (cisplatin and etoposide). A mouse xenograft model was used to assess the impact of ARRB1 on the efficacy of cisplatin in vivo...
December 28, 2016: Oncology Reports
https://www.readbyqxmd.com/read/28035080/multifactorial-regulation-of-g-protein-coupled-receptor-endocytosis
#5
REVIEW
Xiaohan Zhang, Kyeong-Man Kim
Endocytosis is a process by which cells absorb extracellular materials via the inward budding of vesicles formed from the plasma membrane. Receptor-mediated endocytosis is a highly selective process where receptors with specific binding sites for extracellular molecules internalize via vesicles. G protein-coupled receptors (GPCRs) are the largest single family of plasma-membrane receptors with more than 1000 family members. But the molecular mechanisms involved in the regulation of GPCRs are believed to be highly conserved...
January 1, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28035079/biased-g-protein-coupled-receptor-signaling-new-player-in-modulating-physiology-and-pathology
#6
REVIEW
Zuzana Bologna, Jian-Peng Teoh, Ahmed S Bayoumi, Yaoliang Tang, Il-Man Kim
G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas β-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of β-arrestins in regulating GPCR signaling have been discovered...
January 1, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28018341/differential-ccr7-targeting-in-dendritic-cells-by-three-naturally-occurring-cc-chemokines
#7
Gertrud M Hjortø, Olav Larsen, Anne Steen, Viktorija Daugvilaite, Christian Berg, Suzan Fares, Morten Hansen, Simi Ali, Mette M Rosenkilde
The CCR7 ligands CCL19 and CCL21 are increasingly recognized as functionally different (biased). Using mature human dendritic cells (DCs), we show that CCL19 is more potent than CCL21 in inducing 3D chemotaxis. Intriguingly, CCL21 induces prolonged and more efficient ERK1/2 activation compared with CCL19 and a C-terminal truncated (tailless) CCL21 in DCs. In contrast, tailless-CCL21 displays increased potency in DC chemotaxis compared with native CCL21. Using a CCL21-specific antibody, we show that CCL21, but not tailless-CCL21, accumulates at the cell surface...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/28017720/retinal-expression-and-localization-of-mef2c-support-its-important-role-in-photoreceptor-gene-expression
#8
Anne Wolf, Alexander Aslanidis, Thomas Langmann
Photoreceptor-specific gene expression is controlled by a hierarchical network of transcription factors, including the master regulators cone-rod homeobox (Crx) and neural retina leucine zipper (Nrl). Myocyte-enhancer factor 2c (Mef2c) is an ubiquitously expressed transcription factor with important functions in the cardiovascular system. Here, we performed a detailed analysis of Mef2c expression, localization and function in the retina to further elucidate its potential role for photoreceptor gene regulation...
December 23, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28009774/effect-of-plasmapheresis-and-passage-of-anti-retinal-antibodies-through-the-placenta-in-a-case-of-non-paraneoplastic-autoimmune-retinopathy
#9
David I Sierpina, David M Skale, Joseph T Fan
PURPOSE: To present a case of nonparaneoplastic autoimmune retinopathy in association with myasthenia gravis in a young woman, and to report the effect of plasmapheresis as well as passage of antiretinal antibodies through the placenta. METHODS: Case report. RESULTS: A 31-year-old woman presented with a history of myasthenia gravis and rapidly progressive vision loss at the age of 23. Funduscopic appearance and fluorescein angiographic findings on presentation were consistent with an autoimmune retinopathy...
January 2017: Retinal Cases & Brief Reports
https://www.readbyqxmd.com/read/28008933/class-b-%C3%AE-arrestin2-dependent-ccr5-signalosome-retention-with-natural-antibodies-to-ccr5
#10
Assunta Venuti, Claudia Pastori, Rosamaria Pennisi, Agostino Riva, Maria Teresa Sciortino, Lucia Lopalco
CCR5 stimulation with natural ligands, such as RANTES, classically induces short-term internalization with transient activation of β-arrestins and rapidly recycling on the cell surface. Here we discovered that, in T cells, natural CCR5 antibodies induce a CCR5-negative phenotype with the involvement of β-arrestin2, which leads to the formation of a stable CCR5 signalosome with both β-arrestin2 and ERK1. The activation of β-arrestin2 is necessary to CCR5 signaling for the signalosome formation and stabilization...
December 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28004760/angiotensin-ii-increases-glomerular-permeability-by-%C3%AE-arrestin-mediated-nephrin-endocytosis
#11
Eva Königshausen, Ulf M Zierhut, Martin Ruetze, Sebastian A Potthoff, Johannes Stegbauer, Magdalena Woznowski, Ivo Quack, Lars C Rump, Lorenz Sellin
Glomerular permeability and subsequent albuminuria are early clinical markers for glomerular injury in hypertensive nephropathy. Albuminuria predicts mortality and cardiovascular morbidity. AT1 receptor blockers protect from albuminuria, cardiovascular morbidity and mortality. A blood pressure independent, molecular mechanism for angiotensin II (Ang II) dependent albuminuria has long been postulated. Albuminuria results from a defective glomerular filter. Nephrin is a major structural component of the glomerular slit diaphragm and its endocytosis is mediated by β-arrestin2...
December 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28004074/-research-progress-in-signal-bias-of-g-protein-coupled-receptor-and-its-mechanism
#12
Pei-Bin Zhai, Lan Ma, Xing Liu
G protein-coupled receptors (GPCRs) mediate signal transduction via G protein or β-arrestin. Several biased ligands and receptors that preferentially signal through either G protein- or β-arrestin-mediated pathways have been identified. These discoveries have redefined the classical GPCR signaling paradigm. Distinct ligand-receptor binding sites might be one of the main reasons for biased signal transduction. It is posited that multiple active conformations of receptors lead to distinct kinase phosphorylation patterns on C terminus of receptors...
December 25, 2016: Sheng Li Xue Bao: [Acta Physiologica Sinica]
https://www.readbyqxmd.com/read/27996211/gsk-3%C3%AE-interacts-with-dopamine-d1-receptor-to-regulate-receptor-function-implication-for-prefrontal-cortical-d1-receptor-dysfunction-in-schizophrenia
#13
Jing-Ru Wang, Pei-Hua Sun, Zhao-Xiang Ren, Herbert Y Meltzer, Xue-Chu Zhen
INTRODUCTION: Impaired dopamine D1 receptor (D1R) function in prefrontal cortex (PFC) is believed to contribute to the PFC hypofunction that has been hypothesized to be associated with negative symptoms and cognitive deficits in schizophrenia. It is therefore critical to understand the mechanisms for modulation of D1R function. AIMS: To investigate the physical interaction and functional modulation between D1R and GSK-3β. RESULTS: D1R and GSK-3β physically interact in cultured cells and native brain tissues...
December 20, 2016: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/27993970/identification-of-a-multifunctional-docking-site-on-the-catalytic-unit-of-phosphodiesterase-4-pde4-that-is-utilised-by-multiple-interaction-partners
#14
Kirsty F Houslay, Frank Christian, Ruth MacLeod, David R Adams, Miles D Houslay, George Scott Baillie
Cyclic AMP (cAMP) specific phosphodiesterase-4 (PDE4) enzymes underpin compartmentalised cAMP signalling by localising to distinct signalling complexes. PDE4 long isoforms can be phosphorylated by mitogen-activated protein kinase-activated protein kinase 2 (MK2), which attenuates activation of such enzymes through their phosphorylation by protein kinase A (PKA). Here we show that MK2 interacts directly with PDE4 long isoforms and define the sites of interaction. One is a unique site that locates within the regulatory UCR1 domain and contains a core Phe141, Leu142 and Tyr143 (FLY) cluster (PDE4A5 numbering)...
December 19, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27958743/synthetic-studies-of-neoclerodane-diterpenes-from-salvia-divinorum-identification-of-a-potent-and-centrally-acting-%C3%AE-opioid-analgesic-with-reduced-abuse-liability
#15
Rachel Saylor Crowley, Andrew P Riley, Alexander M Sherwood, Chad E Groer, Nirajmohan Shivaperumal, Miguel Biscaia, Kelly Paton, Sebastian Schneider, Davide Provasi, Bronwyn M Kivell, Marta Filizola, Thomas E Prisinzano
Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective μ-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands...
December 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27957549/%C3%AE-arrestin-2-attenuates-cardiac-dysfunction-in-polymicrobial-sepsis-through-gp130-and-p38
#16
Hui Yan, Hui Li, James Denney, Christopher Daniels, Krishna Singh, Balvin Chua, Charles Stuart, Yi Caudle, Ronald Hamdy, Gene LeSage, Deling Yin
Sepsis is an exaggerated systemic inflammatory response to persistent bacteria infection with high morbidity and mortality rate clinically. β-arrestin 2 modulates cell survival and cell death in different systems. However, the effect of β-arrestin 2 on sepsis-induced cardiac dysfunction is not yet known. Here, we show that β-arrestin 2 overexpression significantly enhances animal survival following cecal ligation and puncture (CLP)-induced sepsis. Importantly, overexpression of β-arrestin 2 in mice prevents CLP-induced cardiac dysfunction...
September 2016: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/27956717/molecular-signature-that-determines-the-acute-tolerance-of-g-protein-coupled-receptors
#17
Chengchun Min, Xiaohan Zhang, Mei Zheng, Ningning Sun, Sirijan Archarya, Xiaowei Zhang, Kyeong-Man Kim
Desensitization and acute tolerance are terms used to describe the attenuation of receptor responsiveness by prolonged or intermittent exposure to an agonist. Unlike desensitization of G protein-coupled receptors (GPCRs), which is commonly explained by steric hindrance caused by the β-arrestins that are translocated to the activated receptors, molecular mechanisms involved in the acute tolerance of GPCRs remain unclear. Our studies with several GPCRs and related mutants showed that the acute tolerance of GPCRs could occur independently of agonist-induced β-arrestin translocation...
December 16, 2016: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/27956622/%C3%AE-2-adrenergic-receptor-dependent-chemokine-receptor-2-expression-regulates-leukocyte-recruitment-to-the-heart-following-acute-injury
#18
Laurel A Grisanti, Christopher J Traynham, Ashley A Repas, Erhe Gao, Walter J Koch, Douglas G Tilley
Following cardiac injury, early immune cell responses are essential for initiating cardiac remodeling and tissue repair. We previously demonstrated the importance of β2-adrenergic receptors (β2ARs) in the regulation of immune cell localization following acute cardiac injury, with deficient leukocyte infiltration into the damaged heart. The purpose of this study was to investigate the mechanism by which immune cell-expressed β2ARs regulate leukocyte recruitment to the heart following acute cardiac injury...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27956055/diverse-arrestin-recruiting-and-endocytic-profiles-of-tricyclic-antipsychotics-acting-as-direct-%C3%AE-2a-adrenergic-receptor-ligands
#19
Christopher Cottingham, Pulin Che, Wei Zhang, Hongxia Wang, Raymond X Wang, Stefanie Percival, Tana Birky, Lufang Zhou, Kai Jiao, Qin Wang
The therapeutic mechanism of action underlying many psychopharmacological agents remains poorly understood, due largely to the extreme molecular promiscuity exhibited by these agents with respect to potential central nervous system targets. Agents of the tricyclic chemical class, including both antidepressants and antipsychotics, exhibit a particularly high degree of molecular promiscuity; therefore, any clarification of how these agents interact with specific central nervous system targets is of great potential significance to the field...
December 9, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27927913/two-janus-cannabinoids-that-are-both-cb2-agonists-and-cb1-antagonists
#20
Amey Dhopeshwarkar, Natalia Murataeva, Alex Makriyannis, Alex Straiker, Ken P Mackie
The cannabinoid signaling system includes two G protein coupled receptors, CB1 and CB2. These receptors are widely distributed throughout the body and have each been implicated in many physiologically important processes. Though the cannabinoid signaling system has therapeutic potential, a persistent hurdle has remained the development of receptor-selective ligands. Because CB1 and CB2 are involved in diverse processes, it would be advantageous develop ligands that differentially engaging CB1 and CB2. We now report that GW405833 and AM1710, described as selective CB2 agonists, can antagonize CB1 receptor signaling...
December 7, 2016: Journal of Pharmacology and Experimental Therapeutics
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