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Xiaojiaoyang Li, Runping Liu, Linxi Yu, Zihang Yuan, Rong Sun, Hang Yang, Luyong Zhang, Zhenzhou Jiang
Alpha-naphthylisothiocyanate (ANIT) is widely used to induce cholestasis in basic researches. Although direct damage induced by ANIT to bile duct epithelial cells has been documented in previous studies, few works investigated ANIT-induced effects on hepatocytes. Our previous study indicated that activated AMP-activated protein kinase (AMPK) inhibited farnesoid X receptor (FXR) expression and further participated in the pathogenesis of estrogen-induced cholestasis. However, whether ANIT has effects on bile acid homeostasis in hepatocytes, and the role of AMPK-FXR pathway played in these effects remain unclear...
October 1, 2016: Toxicology
Anh Tn Nguyen, Jo-Anne Baltos, Trayder Thomas, Toan D Nguyen, Laura Lopez Munoz, Karen J Gregory, Paul J White, Patrick M Sexton, Arthur Christopoulos, Lauren T May
The adenosine A1 G protein-coupled receptor (A1AR) is an important therapeutic target implicated in a wide range of cardiovascular and neuronal disorders. Although it is well established that the A1AR orthosteric site is located within the receptor's transmembrane (TM) bundle, prior studies have implicated extracellular loop 2 (ECL2) as having a significant role in contributing to orthosteric ligand affinity and signaling for various G protein-coupled receptors (GPCRs). We thus performed extensive alanine scanning mutagenesis of the A1AR-ECL2 to explore the role of this domain on A1AR orthosteric ligand pharmacology...
September 28, 2016: Molecular Pharmacology
Anh Tn Nguyen, Elizabeth A Vecchio, Trayder Thomas, Toan D Nguyen, Luigi Aurelio, Peter J Scammells, Paul J White, Patrick M Sexton, Karen J Gregory, Lauren T May, Arthur Christopoulos
Allosteric modulation of adenosine A1 receptors (A1ARs) offers a novel therapeutic approach for the treatment of numerous central and peripheral disorders. However, despite decades of research, there is a relative paucity of structural information regarding the A1AR allosteric site and mechanisms governing cooperativity with orthosteric ligands. We combined alanine-scanning mutagenesis of the A1AR second extracellular loop (ECL2) with radioligand binding and functional interaction assays to quantify effects on allosteric ligand affinity, cooperativity and efficacy...
September 28, 2016: Molecular Pharmacology
Pengfei Cheng, Xuzheng Zuo, Yifei Ren, Shunjie Bai, Weiju Tang, Xiuying Chen, Gong Wang, Haoxiang Wang, Wen Huang, Peng Xie
We sought to investigate the role of the adenosine A1 receptors (A1ARs) in white matter lesions under chronic cerebral hypoperfusion (CCH) and explore the potential repair mechanisms by activation of the receptors. A right unilateral common carotid artery occlusion (rUCCAO) method was used to construct a CCH model. 2-chloro-N6-cyclopentyladenosine (CCPA), a specific agonist of A1ARs, was used to explore the biological mechanisms of repair in white matter lesions under CCH. The expression of mammalian target of rapamycin (mTOR), phosphorylation of mTOR (P-mTOR), myelin basic protein (MBP, a marker of white matter myelination) were detected by Western-blot...
September 23, 2016: Neurochemical Research
Fabrizio Vincenzi, Annalisa Ravani, Silvia Pasquini, Stefania Merighi, Stefania Gessi, Romeo Romagnoli, Pier Giovanni Baraldi, Pier Andrea Borea, Katia Varani
Activation of A1 adenosine receptors (ARs) has been associated with anxiolytic-like effects in different behavioral tests, but development of A1AR agonists for therapeutic use has been hampered, most likely due to the presence of side effects. With the aim to identify a safer approach for the treatment of anxiety, we investigated, in mice, the anxiolytic-like properties of a novel A1AR positive allosteric modulator, TRR469. Acute administration of TRR469 (0.3-3 mg/kg) resulted in robust anxiolytic-like effects in the elevated plus maze, the dark/light box, the open field and the marble burying tests...
December 2016: Neuropharmacology
Zhaoqun Liu, Zhi Zhou, Lingling Wang, Limei Qiu, Huan Zhang, Hao Wang, Linsheng Song
We have now cloned an alpha-1 adrenergic receptor (A1AR) from the cDNA library of oyster Crassostrea gigas, designating as CgA1AR-1. The full length of CgA1AR-1 was 1149 bp and it encodes a protein of 382 amino acids containing a 7 transmembrane domain, whose putative topology was similar to the A1ARs in higher organisms and shared similarity of 19% with mammalian A1ARs according to the phylogenic analysis. After cell transfection of CgA1AR-1 into HEK293T cells and the incubation with its specific agonist norepinephrine (NE), the concentration of second messenger Ca(2+) increased significantly (p < 0...
September 12, 2016: Fish & Shellfish Immunology
Vishal R Yadav, Ka L Hong, Darryl C Zeldin, Mohammed A Nayeem
Soluble epoxide hydrolase (sEH) converts epoxyeicosatrienoic acids that are endothelium-derived hyperpolarizing factors into less active dihydroxyeicosatrienoic acids. Previously, we reported a decrease in adenosine A1 receptor (A1AR) protein levels in sEH knockout (sEH(-/-)) and an increase in sEH and A1AR protein levels in A2AAR(-/-) mice. Additionally, KATP channels are involved in adenosine receptor (AR)-dependent vascular relaxation. Thus, we hypothesize that a potential relationship may exist among sEH over-expression, A1AR upregulation, inactivation of KATP channels, and increased in vascular tone...
November 2016: Molecular and Cellular Biochemistry
Kenneth A Jacobson, Mortimer M Civan
Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A1, A2A, and A3...
October 2016: Journal of Ocular Pharmacology and Therapeutics
Elizabeth A Vecchio, Chung Hui Chuo, Jo-Anne Baltos, Leigh Ford, Peter J Scammells, Bing H Wang, Arthur Christopoulos, Paul J White, Lauren T May
We have recently described the rationally-designed adenosine receptor agonist, 4-(5-amino-4-benzoyl-3-(3-(trifluoromethyl)phenyl)thiophen-2-yl)-N-(6-(9-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxylmethyl)tetrahydro-furan-2-yl)-9H-purin-6-ylamino)hexyl)benzamide (VCP746), a hybrid molecule consisting of an adenosine moiety linked to an adenosine A1 receptor (A1AR) allosteric modulator moiety. At the A1AR, VCP746 mediated cardioprotection in the absence of haemodynamic side effects such as bradycardia. The current study has now identified VCP746 as an important pharmacological tool for the adenosine A2B receptor (A2BAR)...
October 1, 2016: Biochemical Pharmacology
L Graham, D Graham, M W McBride, A F Dominiczak, S Padmanabhan
OBJECTIVE: UMOD-/- mice have low blood pressure and decreased salt-sensitivity indicating interactions between UMOD and sodium transport in the TAL. However, it's unclear whether the effect of UMOD is solely through interaction with cognate molecules in the TAL or whether the perturbations in physiology are more complex with involvement of both TAL and other parts of the nephron. We propose to answer this by profiling mRNA expression levels of the main ion transporters and signalling molecules in tubules from UMOD+/+ and UMOD-/- mice...
September 2016: Journal of Hypertension
Domenico Tupone, Justin S Cetas, Shaun F Morrison
The positive outcome that hypothermia contributes to brain and cardiac protection following ischemia has stimulated research in the development of pharmacological approaches to induce a hypothermic/hypometabolic state. Pharmacological manipulation of central autonomic thermoregulatory circuits could represent a potential target for the induction of a hypothermic state. Here we present a brief description of the CNS thermoregulatory centers and how the manipulation of these circuits can be useful in the treatment of pathological conditions such as stroke or brain hemorrhage...
April 2016: Nihon Shinkei Seishin Yakurigaku Zasshi, Japanese Journal of Psychopharmacology
Tejbeer Kaur, Vikrant Borse, Sandeep Sheth, Kelly Sheehan, Sumana Ghosh, Srinivasan Tupal, Sarvesh Jajoo, Debashree Mukherjea, Leonard P Rybak, Vickram Ramkumar
UNLABELLED: Cisplatin is a commonly used antineoplastic agent that produces ototoxicity that is mediated in part by increasing levels of reactive oxygen species (ROS) via the NOX3 NADPH oxidase pathway in the cochlea. Recent studies implicate ROS generation in mediating inflammatory and apoptotic processes and hearing loss by activating signal transducer and activator of transcription (STAT1). In this study, we show that the adenosine A1 receptor (A1AR) protects against cisplatin ototoxicity by suppressing an inflammatory response initiated by ROS generation via NOX3 NADPH oxidase, leading to inhibition of STAT1...
April 6, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Patrycja Koszałka, Monika Gołuńska, Aleksandra Urban, Grzegorz Stasiłojć, Marcin Stanisławowski, Marceli Majewski, Andrzej C Składanowski, Jacek Bigda
CD73 (ecto-5'-nucleotidase), a cell surface enzyme hydrolyzing AMP to adenosine, was lately demonstrated to play a direct role in tumor progression including regulation of tumor vascularization. It was also shown to stimulate tumor macrophage infiltration. Interstitial adenosine, accumulating in solid tumors due to CD73 enzymatic activity, is recognized as a main mediator regulating the production of pro- and anti-angiogenic factors, but the engagement of specific adenosine receptors in tumor progression in vivo is still poorly researched...
2016: PloS One
Enrique Guzmán-Gutiérrez, Axel Armella, Fernando Toledo, Fabián Pardo, Andrea Leiva, Luis Sobrevia
Gestational diabetes mellitus (GDM) associates with increased L-arginine transport and extracellular concentration of adenosine in human umbilical vein endothelial cells (HUVECs). In this study we aim to determine whether insulin reverses GDM-increased L-arginine transport requiring adenosine receptors expression in HUVECs. Primary cultured HUVECs from full-term normal (n = 38) and diet-treated GDM (n = 38) pregnancies were used. Insulin effect was assayed on human cationic amino acid transporter 1 (hCAT1) expression (protein, mRNA, SLC7A1 promoter activity) and activity (initial rates of L-arginine transport) in the absence or presence of adenosine receptors agonists or antagonists...
March 2016: Purinergic Signalling
Kenneth A Jacobson, Christa E Müller
Pharmacological tool compounds are now available to define action at the adenosine (ARs), P2Y and P2X receptors. We present a selection of the most commonly used agents to study purines in the nervous system. Some of these compounds, including A1 and A3 AR agonists, P2Y1R and P2Y12R antagonists, and P2X3, P2X4 and P2X7 antagonists, are potentially of clinical use in treatment of disorders of the nervous system, such as chronic pain, neurodegeneration and brain injury. Agonists of the A2AAR and P2Y2R are already used clinically, P2Y12R antagonists are widely used antithrombotics and an antagonist of the A2AAR is approved in Japan for treating Parkinson's disease...
May 2016: Neuropharmacology
Jian-Xi Ye, Dao-Zhong Chen
The use of ischemic preconditioning (IPC) to protect the myocardium is usually not effective in elderly patients. The aim of the present study was to design new methods to achieve enhanced myocardial protection, based on the differential role of endogenous adenosine (ADO) and ADO receptors (ARs) in the effects of IPC on young and old animals. An improved New Zealand white rabbit model of ischemia/reperfusion was established based on the Langendorff model. Adult or elderly rabbit hearts, with or without exposure to IPC, were used in order to assess the roles of ADO and ARs in the different effects of IPC...
October 2015: Experimental and Therapeutic Medicine
Jesse Lea Carlin, Dilip K Tosh, Cuiying Xiao, Ramón A Piñol, Zhoumou Chen, Daniela Salvemini, Oksana Gavrilova, Kenneth A Jacobson, Marc L Reitman
Adenosine can induce hypothermia, as previously demonstrated for adenosine A1 receptor (A1AR) agonists. Here we use the potent, specific A3AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A3AR. The hypothermic effect of A3AR agonists is independent of A1AR activation, as the effect was fully intact in mice lacking A1AR but abolished in mice lacking A3AR. A3AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A3AR hypothermia is mediated, at least in part, via mast cells...
February 2016: Journal of Pharmacology and Experimental Therapeutics
Jo-Anne Baltos, Karen J Gregory, Paul J White, Patrick M Sexton, Arthur Christopoulos, Lauren T May
Adenosine A1 receptor (A1AR) stimulation is a powerful protective mechanism in cerebral and cardiac ischemia-reperfusion injury. Despite this, therapeutic targeting of the A1AR for the treatment of ischemia-reperfusion injury has been largely unsuccessful, as high concentrations of prototypical A1AR agonists impart significant hemodynamic effects, particularly pronounced bradycardia, atrioventricular block and hypotension. Exploiting the phenomenon of biased agonism to develop ligands that promote A1AR cytoprotection in the absence of adverse hemodynamic effects remains a relatively unexplored, but exciting, approach to overcome current limitations...
January 1, 2016: Biochemical Pharmacology
Romeo Romagnoli, Pier Giovanni Baraldi, Allan R Moorman, Pier Andrea Borea, Katia Varani
Adenosine is an ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1, A2A, A2B and A3 adenosine receptors (ARs). Allosteric enhancers to A1ARs may represent novel therapeutic agents because they increase the activity of these receptors by mediating a shift to their active form in the A1AR-G protein ternary complex. In this manner, they are able to amplify the action of endogenous adenosine, which is produced in high concentrations under conditions of metabolic stress...
2015: Future Medicinal Chemistry
Mohamad Wessam Alnouri, Stephan Jepards, Alessandro Casari, Anke C Schiedel, Sonja Hinz, Christa E Müller
Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclinical studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species. In the present study, we selected a set of frequently used standard AR ligands, 8 agonists and 16 antagonists, and investigated them in radioligand binding studies at all four AR subtypes, A1, A2A, A2B, and A3, of three species, human, rat, and mouse...
September 2015: Purinergic Signalling
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