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https://www.readbyqxmd.com/read/28712806/structures-of-human-a1-and-a2a-adenosine-receptors-with-xanthines-reveal-determinants-of-selectivity
#1
Robert K Y Cheng, Elena Segala, Nathan Robertson, Francesca Deflorian, Andrew S Doré, James C Errey, Cédric Fiez-Vandal, Fiona H Marshall, Robert M Cooke
The adenosine A1 and A2A receptors belong to the purinergic family of G protein-coupled receptors, and regulate diverse functions of the cardiovascular, respiratory, renal, inflammation, and CNS. Xanthines such as caffeine and theophylline are weak, non-selective antagonists of adenosine receptors. Here we report the structure of a thermostabilized human A1 receptor at 3.3 Å resolution with PSB36, an A1-selective xanthine-based antagonist. This is compared with structures of the A2A receptor with PSB36 (2...
July 3, 2017: Structure
https://www.readbyqxmd.com/read/28668513/toll-like-receptors-nf-%C3%AE%C2%BAb-and-il-27-mediate-adenosine-a2a-receptor-signaling-in-btbr-t-itpr3-tf-j-mice
#2
Sheikh F Ahmad, Mushtaq A Ansari, Ahmed Nadeem, Saleh A Bakheet, Laila Yousef Al-Ayadhi, Sabry M Attia
Autism is a predominant neurodevelopmental disorder characterized by impaired communication, social deficits, and repetitive behaviors. Recent research has proposed that the impairment of innate immunity may play an important role in autism. Toll-like receptors (TLRs) are potential therapeutic targets against neuroinflammation. The BTBR T(+) Itpr3(tf/)J (BTBR) mouse is a well-known model of autism, showing repetitive behaviors such as cognitive inflexibility and increased grooming as compared to C57BL/6 (B6) mice...
June 29, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28667836/adenosine-a2a-receptor-blockade-diminishes-wnt-%C3%AE-catenin-signaling-in-a-murine-model-of-bleomycin-induced-dermal-fibrosis
#3
Jin Zhang, Carmen Corciulo, Hailing Liu, Tuere Wilder, Mayumi Ito, Bruce Cronstein
Adenosine A2a receptor (A2aR) stimulation promotes the synthesis of collagens I and III, and we have recently demonstrated that there is crosstalk between the A2aR and WNT/β-catenin signaling pathway. In in vitro studies, A2aR signaling for collagen III expression was mediated by WNT/β-catenin signaling in human dermal fibroblasts; we further verified whether the crosstalk between A2aR and Wnt/β-catenin signaling was involved in diffuse dermal fibrosis in vivo. Wnt-signaling reporter mice (Tcf/Lef:H2B-GFP) were challenged with bleomycin and treated with the selective A2aR antagonist istradefylline (KW6002) or vehicle...
June 28, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28661196/design-synthesis-and-evaluation-of-2-aryl-benzoxazoles-as-promising-hit-for-the-a2a-receptor
#4
Romain Duroux, Nicolas Renault, Joana Esteves Cuelho, Laurence Agouridas, David Blum, Luisa V Lopes, Patricia Melnyk, Saïd Yous
The development of adenosine A2A receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A2AR antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A2A receptor. Compound F1, with an affinity of 1 μm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184 μm) without being cytotoxic at 100 μm...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28660236/expression-purification-and-crystallisation-of-the-adenosine-a2a-receptor-bound-to-an-engineered-mini-g-protein
#5
Byron Carpenter, Christopher G Tate
G protein-coupled receptors (GPCRs) promote cytoplasmic signalling by activating heterotrimeric G proteins in response to extracellular stimuli such as light, hormones and nucleosides. Structure determination of GPCR-G protein complexes is central to understanding the precise mechanism of signal transduction. However, these complexes are challenging targets for structural studies due to their conformationally dynamic and inherently transient nature. We recently developed an engineered G protein, mini-Gs, which addressed these problems and allowed the formation of a stable GPCR-G protein complex...
April 20, 2017: Bio-protocol
https://www.readbyqxmd.com/read/28652244/targeting-adenosine-in-braf-mutant-melanoma-reduces-tumor-growth-and-metastasis
#6
Arabella Young, Shin Foong Ngiow, Jason Madore, Julia Reinhardt, Jennifer Landsberg, Arash Chitsazan, Jai Rautela, Tobias Bald, Deborah Barkauskas, Elizabeth Ahern, Nicholas Huntington, Dirk Schadendorf, Georgina V Long, Glen M Boyle, Michael Hölzel, Richard A Scolyer, Mark J Smyth
Increasing evidence exists for the role of immunosuppressive adenosine in promoting tumor growth and spread in a number of cancer types, resulting in poor clinical outcomes. In this study, we assessed whether the CD73-adenosinergic pathway is active in melanoma patients and whether adenosine restricts the efficacy of clinically approved targeted therapies for commonly mutated BRAF(V600E) melanoma. In AJCC Stage III melanoma patients, CD73 expression (the enzyme that generates adenosine) correlated significantly with patients presenting nodal metastatic melanoma, suggesting that targeting this pathway may be effective in advanced stage disease...
June 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28638737/selective-activation-of-anti-cd73-mechanisms-in-control-of-primary-tumors-and-metastases
#7
Dipti Vijayan, Deborah S Barkauskas, Kimberley Stannard, Erin Sult, Rebecca Buonpane, Kazuyoshi Takeda, Michele W L Teng, Kris Sachsenmeier, Carl Hay, Mark J Smyth
The emerging role for CD73 in driving cancer growth and metastasis has presented opportunities to develop anti-CD73 monoclonal antibodies (mAbs) in the treatment of human cancers. Blockade of CD73 by antagonistic CD73 mAbs ameliorates tumor growth and metastasis via the inhibition of enzymatic and non-enzymatic CD73 pathways. In this study, we investigated whether Fc-receptor cross-linking represented a non-redundant mechanism by which anti-CD73 mAbs exert potent suppression of solid tumors and metastases. We engineered four anti-CD73 mAbs, each different in their ability to modulate CD73 enzymatic function and bind Fc receptors...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28629145/synthesis-and-evaluation-of-phenylxanthine-derivatives-as-potential-dual-a2ar-antagonists-mao-b-inhibitors-for-parkinson-s-disease
#8
Xuebao Wang, Chao Han, Yong Xu, Kaiqi Wu, Shuangya Chen, Mangsha Hu, Luyao Wang, Yun Ye, Faqing Ye
The aim of this research was to prove the speculation that phenylxanthine (PX) derivatives possess adenosine A2A receptor (A2AR)-blocking properties and to screening and evaluate these PX derivatives as dual A2AR antagonists/MAO-B inhibitors for Parkinson's disease. To explore this hypothesis, two series of PX derivatives were prepared and their antagonism against A2AR and inhibition against MAO-B were determined in vitro. In order to evaluate further the antiparkinsonian properties, pharmacokinetic and haloperidol-induced catalepsy experiments were carried out in vivo...
June 17, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28612530/-minocycline-prevent-microglial-activation-via-suppression-of-adenosine-a-2a-receptor-in-a-rat-stroke-ischemia-reperfusion-model
#9
Tao Tao, Jie Fu, Yong-Gang Liu, Zuo-Xiao Li, Xiao-Gang Li
OBJECTIVES: To investigate whether minocycline could inhibit neuroinflammation induced by microglia activation through suppression of adenosine A2Areceptor (A2AR)expression in rats after cerebral ischemia/reperfusion (I/R) injury. METHODS: Thirty male Sprageue-Dawley rats were randomly divided into 3 groups: sham group, I/R group and minocycline group. The rats were subjected to occlusion of the right middle cerebral artery (MCAO) for 2 h to establish stroke I/R model, and 3 mg/kg minocycline was injected intravenously immediately after reperfusion twice a day in minocycline group...
March 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28592285/blockade-of-adenosine-a2a-receptor-enhances-cd8-t-cells-response-and-decreases-regulatory-t-cells-in-head-and-neck-squamous-cell-carcinoma
#10
Si-Rui Ma, Wei-Wei Deng, Jian-Feng Liu, Liang Mao, Guang-Tao Yu, Lin-Lin Bu, Ashok B Kulkarni, Wen-Feng Zhang, Zhi-Jun Sun
BACKGROUND: Cancer immunotherapy offers a promising approach in cancer treatment. The adenosine A2A receptor (A2AR) could protect cancerous tissues from immune clearance via inhibiting T cells response. To date, the role of A2AR in head and neck squamous cell carcinoma (HNSCC) has not been investigated. Here, we sought to explore the expression and immunotherapeutic value of A2AR blockade in HNSCC. METHODS: The expression of A2AR was evaluated by immunostaining in 43 normal mucosae, 48 dysplasia and 165 primary HNSCC tissues...
June 7, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28583881/altered-adenosine-2a-and-dopamine-d2-receptor-availability-in-the-6-hydroxydopamine-treated-rats-with-and-without-levodopa-induced-dyskinesia
#11
X Zhou, J Doorduin, P H Elsinga, R A J O Dierckx, E F J de Vries, C Casteels
Several lines of evidence imply alterations in adenosine signaling in Parkinson's disease (PD). Here, we investigated cerebral changes in adenosine 2A receptor (A2AR) availability in 6-hydroxydopamine (6-OHDA)-lesioned rats with and without levodopa-induced dyskinesia (LID) using positron-emission tomography (PET) with [(11)C]preladenant. In parallel dopamine type 2 receptor (D2R) imaging with [(11)C]raclopride PET and behavioral tests for motor and cognitive function were performed. METHODS: Parametric A2AR and D2R binding potential (BPND) images were reconstructed using reference tissue models with midbrain and cerebellum as reference tissue, respectively...
June 2, 2017: NeuroImage
https://www.readbyqxmd.com/read/28582704/a-novel-antagonist-of-the-immune-checkpoint-protein-adenosine-a2a-receptor-restores-tumor-infiltrating-lymphocyte-activity-in-the-context-of-the-tumor-microenvironment
#12
Melanie Mediavilla-Varela, Julio Castro, Alberto Chiappori, David Noyes, Dalia C Hernandez, John Stagg, Scott J Antonia
BACKGROUND: Therapeutic strategies targeting immune checkpoint proteins have led to significant responses in patients with various tumor types. The success of these studies has led to the development of various antibodies/inhibitors for the different checkpoint proteins involved in immune evasion of the tumor. Adenosine present in high concentrations in the tumor microenvironment activates the immune checkpoint adenosine A2a receptor (A2aR), leading to the suppression of antitumor responses...
June 2, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28554302/new-cardiac-expression-of-two-adenosine-2a-receptor-isoforms-in-dysfunctioning-minipigs
#13
Manuela Cabiati, Benedetta Svezia, Marco Matteucci, Luca Panchetti, Silvia Burchielli, Maria-Aurora Morales, Silvia Del Ry
PURPOSE: Eight A2AR variants are reported in humans while no A2AR isoforms in pigs. The aim of this study was to evaluate potential isoforms presence in cardiac pig tissue to better define possible involvement of A2AR in the cardiovascular pathophysiology. MATERIALS AND METHODS: In adult male minipigs (n = 4) left ventricular dysfunction (LVD) was induced by pacing at 200 bpm in the right ventricular (RV) apex. In these animals and in sham operated pigs (C-SHAM, n = 4) cardiac tissue was collected from LV-septal wall (LV-SW)-close to pacing site-and from lateral (opposite) site (LV-OSW)...
August 2017: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/28536931/guanosine-promotes-cytotoxicity-via-adenosine-receptors-and-induces-apoptosis-in-temozolomide-treated-a172-glioma-cells
#14
Karen A Oliveira, Tharine A Dal-Cim, Flávia G Lopes, Cláudia B Nedel, Carla Inês Tasca
Gliomas are a malignant tumor group whose patients have survival rates around 12 months. Among the treatments are the alkylating agents as temozolomide (TMZ), although gliomas have shown multiple resistance mechanisms for chemotherapy. Guanosine (GUO) is an endogenous nucleoside involved in extracellular signaling that presents neuroprotective effects and also shows the effect of inducing differentiation in cancer cells. The chemotherapy allied to adjuvant drugs are being suggested as a novel approach in gliomas treatment...
May 23, 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/28533515/perivascular-aqp4-dysregulation-in-the-hippocampal-ca1-area-after-traumatic-brain-injury-is-alleviated-by-adenosine-a2a-receptor-inactivation
#15
Zi-Ai Zhao, Ping Li, Shi-Yang Ye, Ya-Lei Ning, Hao Wang, Yan Peng, Nan Yang, Yan Zhao, Zhuo-Hang Zhang, Jiang-Fan Chen, Yuan-Guo Zhou
Traumatic brain injury (TBI) can induce cognitive dysfunction due to the regional accumulation of hyperphosphorylated tau protein (p-tau). However, the factors that cause p-tau to concentrate in specific brain regions remain unclear. Here, we show that AQP4 polarization in the perivascular astrocytic end feet was impaired after TBI, which was most prominent in the ipsilateral brain tissue surrounding the directly impacted region and the contralateral hippocampal CA1 area and was accompanied by increased local p-tau, changes in dendritic spine density and morphology, and upregulation of the adenosine A2A receptor (A2AR)...
May 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28512397/leukocyte-expression-of-type-1-and-type-2-purinergic-receptors-and-pro-inflammatory-cytokines-during-total-sleep-deprivation-and-or-sleep-extension-in-healthy-subjects
#16
Mounir Chennaoui, Pierrick J Arnal, Catherine Drogou, Damien Leger, Fabien Sauvet, Danielle Gomez-Merino
The purinergic type P1 (adenosine A1 and A2A) receptors and the type P2 (X7) receptor have been suggested to mediate physiological effects of adenosine and adenosine triphosphate on sleep. We aimed to determine gene expression of A1R (receptor), A2AR, and P2RX7 in leukocytes of healthy subjects during total sleep deprivation followed by sleep recovery. Expression of the pro-inflammatory cytokines IL-1β and TNF-α were also determined as they have been characterized as sleep regulatory substances, via P2RX7 activation...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28500295/angiotensin-ii-type-1-adenosine-a-2a-receptor-oligomers-a-novel-target-for-tardive-dyskinesia
#17
Paulo A de Oliveira, James A R Dalton, Marc López-Cano, Adrià Ricarte, Xavier Morató, Filipe C Matheus, Andréia S Cunha, Christa E Müller, Reinaldo N Takahashi, Víctor Fernández-Dueñas, Jesús Giraldo, Rui D Prediger, Francisco Ciruela
Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells...
May 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28499635/adenosine-a2a-receptors-are-up-regulated-and-control-the-activation-of-human-alveolar-macrophages
#18
Tiago Manuel Alfaro, Diana Isabel Rodrigues, Ângelo Ribeiro Tomé, Rodrigo Antunes Cunha, Carlos Robalo Cordeiro
Chronic inflammatory lung diseases remain a health concern and new anti-inflammatory treatments are needed. Targeting adenosine A2A receptors (A2AR) affords robust anti-inflammatory effects in animal models, but the translation of this promising strategy to humans has been challenging, possibly due to interspecies differences in receptor distribution and effects. Thus, we now assessed the efficiency of a selective A2AR agonist to control the activation of fresh human alveolar inflammatory cells. We collected bronchoalveolar lavage fluid from patients with interstitial lung disease and loaded alveolar cells with the intracellular free calcium probe FURA-2/AM...
May 9, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28495790/systemic-inflammatory-response-syndrome-related-lymphopenia-is-associated-with-adenosine-a1-receptor-dysfunction
#19
Reut Riff, Yair Cohen, Hadar Eini-Rider, Oshri Naamani, Julia Mazar, Yosef S Haviv, Cidio Chaimovitz, Amos Douvdevani
SIRS is associated with lymphopenia, and prolonged lymphopenia of septic patients has been associated with increased mortality risk. We hypothesize that elevated adenosine during SIRS down-regulates Gi-coupled A1R, which signals an effect that sensitizes a cAMP-dependent lymphotoxic response. In this study, we evaluate the role of adenosine in SIRS-mediated lymphopenia and impaired IL-15 production. Cecal ligation and puncture was used to induce sepsis-associated SIRS in mice. BMDCs were cultured and used to measure the effect of adenosine on IL-15...
May 11, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28492224/endogenous-adenosine-maintains-cartilage-homeostasis-and-exogenous-adenosine-inhibits-osteoarthritis-progression
#20
Carmen Corciulo, Matin Lendhey, Tuere Wilder, Hanna Schoen, Alexander Samuel Cornelissen, Gregory Chang, Oran D Kennedy, Bruce N Cronstein
Osteoarthritis (OA) is characterized by cartilage destruction and chondrocytes have a central role in this process. With age and inflammation chondrocytes have reduced capacity to synthesize and maintain ATP, a molecule important for cartilage homeostasis. Here we show that concentrations of ATP and adenosine, its metabolite, fall after treatment of mouse chondrocytes and rat tibia explants with IL-1β, an inflammatory mediator thought to participate in OA pathogenesis. Mice lacking A2A adenosine receptor (A2AR) or ecto-5'nucleotidase (an enzyme that converts extracellular AMP to adenosine) develop spontaneous OA and chondrocytes lacking A2AR develop an 'OA phenotype' with increased expression of Mmp13 and Col10a1...
May 11, 2017: Nature Communications
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