keyword
https://read.qxmd.com/read/32573250/a-nitrogen-walk-approach-to-explore-bioisosteric-replacements-in-a-series-of-potent-a2b-adenosine-receptor-antagonists
#21
JOURNAL ARTICLE
Ana Mallo-Abreu, Ruben Prieto-Diaz, Willem Jespers, Jhonny Azuaje, Maria Majellaro, Carmen Velando, Xerardo García-Mera, Olga Caamaño, José M Brea, María Isabel Loza, Hugo Gutiérrez-de-Terán, Eddy Sotelo
A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A2BAR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 different pentagonal heterocyclic frameworks at position 4, was synthesized and evaluated. This study enabled the identication of new ligands that combine remarkable affinity (Ki < 30 nM) and exquisite selectivity...
June 23, 2020: Journal of Medicinal Chemistry
https://read.qxmd.com/read/32476256/intraluminal-nutrients-acutely-strengthen-rat-intestinal-mrp2-barrier-function-by-a-glucagon-like-peptide-2-mediated-mechanism
#22
JOURNAL ARTICLE
Guillermo N Tocchetti, Camila J Domínguez, Felipe Zecchinati, Maite R Arana, Juan P Rigalli, María L Ruiz, Silvina S M Villanueva, Aldo D Mottino
AIM: MRP2 is an intestinal ABC transporter that prevents the absorption of dietary xenobiotics. The aims of this work were: (1) to evaluate whether a short-term regulation of intestinal MRP2 barrier function takes place in vivo after luminal incorporation of nutrients and (2) to explore the underlying mechanism. METHODS: MRP2 activity and localization were assessed in an in vivo rat model with preserved irrigation and innervation. Nutrients were administered into distal jejunum...
June 1, 2020: Acta Physiologica
https://read.qxmd.com/read/32207522/late-protective-effect-of-netrin-1-in-the-murine-acetaminophen-hepatotoxicity-model
#23
JOURNAL ARTICLE
Luqi Duan, Benjamin L Woolbright, Hartmut Jaeschke, Anup Ramachandran
Acetaminophen (APAP) overdose induced acute liver failure is an important clinical problem in the United States and the current antidote N-acetylcysteine, has a short early therapeutic window. Since most patients present late to the clinic, there is need for novel late acting therapeutic options. Though the neuronal guidance cue netrin-1, has been shown to promote hepatic repair and regeneration during liver ischemia/reperfusion injury, its effect in APAP - induced hepatotoxicity is unknown. In the quest for a late-acting therapeutic intervention in APAP-induced liver injury, we examined the role of netrin-1 in a mouse model of APAP overdose...
March 24, 2020: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://read.qxmd.com/read/32129084/adenosine-a2bar-activation-stimulates-alveolar-fluid-clearance-through-alveolar-epithelial-sodium-channel-via-camp-pathway-in-endotoxin-induced-lung-injury
#24
JOURNAL ARTICLE
Mengnan Wang, Xiaoxia Guo, Huiying Zhao, Jie Lv, Huixia Wang, Youzhong An
Clinical studies have established that the capacity of removing excess fluid from alveoli is impaired in most patients with ARDS. Impaired AFC correlated with poor outcomes. Adenosine A2BAR has the lowest affinity with adenosine among four adenosine receptors. It is documented that A2BAR can activate AC resulting in elevated cAMP. Based on the understanding that cAMP is a key regulator of ENaC, which is the limited step in sodium transport, we hypothesized that A2BAR signaling may affect AFC in ALI through regulating ENaC via cAMP, thus attenuating pulmonary edema...
March 4, 2020: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://read.qxmd.com/read/31333092/adenosine-receptors-as-novel-targets-for-the-treatment-of-various-cancers
#25
JOURNAL ARTICLE
Bapi Gorain, Hira Choudhury, Gan Sook Yee, Subrat Kumar Bhattamisra
Adenosine is a ubiquitous signaling nucleoside molecule, released from different cells within the body to act on vasculature and immunoescape. Physiological action on the proliferation of tumour cell has been reported by the presence of high concentration of adenosine within the tumour microenvironment, which results in the progression of the tumour, and even leading to metastases. The activity of adenosine exclusively depends upon interaction with four subtypes of heterodimeric G-protein-coupled adenosine receptors (AR), A1, A2A, A2B, and A3-ARs on the cell surface...
July 15, 2019: Current Pharmaceutical Design
https://read.qxmd.com/read/30952101/the-role-of-netrin-1-in-the-mouse-cornea-during-aspergillus-fumigatus-infection
#26
JOURNAL ARTICLE
Yifan Zhou, Jing Lin, Xudong Peng, Cui Li, Jie Zhang, Qian Wang, Guoqiang Zhu, Jia You, Guiqiu Zhao
PURPOSE: To explore the effects of netrin-1 on inflammation in Aspergillus fumigatus-infected mouse corneas and on proliferation and migration in human corneal epithelial cells (HCECs). METHODS: Netrin-1 and the receptor A2BAR were detected in normal and infected corneas from C57BL/6 mice and RAW 264.7 cells. The mice were injected subconjunctivally with recombinant netrin-1. The severity of the disease was determined by clinical scores, photography with a slit lamp, RT-PCR, western blotting, myeloperoxidase (MPO) assays and immunofluorescence staining of polymorphonuclear neutrophilic leukocytes (PMNs)...
April 2, 2019: International Immunopharmacology
https://read.qxmd.com/read/30835463/a2b-adenosine-receptor-antagonists-with-picomolar-potency
#27
JOURNAL ARTICLE
Jie Jiang, Catharina Seel, Ahmed Temirak, Vigneshwaran Namasivayam, Antonella Arridu, Jakub Schabikowski, Younis Baqi, Sonja Hinz, Jörg Hockemeyer, Christa E Müller
The A2B adenosine receptor (A2BAR) was proposed as a novel target for the (immuno)therapy of cancer since A2BAR blockade results in antiproliferative, anti-angiogenic, anti-metastatic, and immu-no-stimulatory effects. In this study, we explored the structure-activity relationships of xan-thin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established which facilitated the synthesis of the target compounds...
March 5, 2019: Journal of Medicinal Chemistry
https://read.qxmd.com/read/30530591/g2a-protects-mice-against-sepsis-by-modulating-kupffer-cell-activation-cooperativity-with-adenosine-receptor-2b
#28
JOURNAL ARTICLE
Hong-Mei Li, Ji Hye Jang, Jun-Sub Jung, Jiseon Shin, Chul O Park, Yeon-Ja Kim, Won-Gyun Ahn, Ju-Suk Nam, Chang-Won Hong, Jongho Lee, Yu-Jin Jung, Jiang-Fan Chen, Katya Ravid, H Thomas Lee, Won-Ki Huh, Janusz H Kabarowski, Dong-Keun Song
G2A is a GPCR abundantly expressed in immune cells. G2A-/- mice showed higher lethality, higher plasma cytokines, and an impaired bacterial clearance in response to a murine model of sepsis (cecal ligation and puncture), which were blocked by GdCl3 , an inhibitor of Kupffer cells. Anti-IL-10 Ab reversed the impaired bacterial clearance in G2A-/- mice. Indomethacin effectively blocked both the increased i.p. IL-10 levels and the impaired bacterial clearance, indicating that disturbed PG system is the proximal cause of these phenomena...
December 10, 2018: Journal of Immunology
https://read.qxmd.com/read/29898376/a2bar-activation-attenuates-acute-lung-injury-by-inhibiting-alveolar-epithelial-cell-apoptosis-both-in-vivo-and-in-vitro
#29
JOURNAL ARTICLE
Xiaotao Xu, Qingwei Zhu, Fangfang Niu, Rong Zhang, Yan Wang, Wenying Wang, Dawei Sun, Xintao Wang, Aizhong Wang
The epithelial barrier of the lung is destroyed during acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) due to the apoptosis of alveolar epithelial cells (AECs). Therefore, treatments that block AEC apoptosis might be a therapeutic strategy to ameliorate ALI. Based on recent evidence, A2B adenosine receptor (A2BAR) plays an important role in ALI in several different animal models, but its exact function in AECs has not been clarified. We investigated the role of A2BAR in AEC apoptosis in a mouse model of oleic acid (OA)-induced ALI and in hydrogen peroxide (H2 O2 )-induced AEC (A549 cells and MLE-12 cells) injury...
June 13, 2018: American Journal of Physiology. Cell Physiology
https://read.qxmd.com/read/29681156/fluorescent-labeled-selective-adenosine-a-2b-receptor-antagonist-enables-competition-binding-assay-by-flow-cytometry
#30
JOURNAL ARTICLE
Meryem Köse, Sabrina Gollos, Tadeusz Karcz, Amelie Fiene, Fabian Heisig, Andrea Behrenswerth, Katarzyna Kieć-Kononowicz, Vigneshwaran Namasivayam, Christa E Müller
Fluorescent ligands represent powerful tools for biological studies and are considered attractive alternatives to radioligands. In this study, we developed fluorescent antagonists for A2B adenosine receptors (A2B ARs), which are targeted by antiasthmatic xanthines and were proposed as novel targets in immuno-oncology. Our approach was to merge a small borondipyrromethene (BODIPY) derivative with the pharmacophore of 8-substituted xanthine derivatives. On the basis of the design, synthesis, and evaluation of model compounds, several fluorescent ligands were synthesized...
May 24, 2018: Journal of Medicinal Chemistry
https://read.qxmd.com/read/29473361/-effects-of-electroacupuncture-on-the-expression-of-adenosine-receptors-in-the-heart-tissue-of-myocardial-ischemia-rats
#31
JOURNAL ARTICLE
Shengfeng Lu, Yuexia Tang, Yajuan Ding, Meiling Yu, Shuping Fu, Bingmei Zhu
OBJECTIVE: To explore the impact of electroacupuncture (EA) on the protein expression of adenosine receptors in the heart of the rats with myocardial ischemia (MI). METHODS: Thirty healthy male SD rats were divided randomly into a control group ( n =6), a model group ( n =12) and an EA group ( n =12). We ligated the left anterior descending artery (LAD) for MI model in the model group and EA group, and exposed the heart after opening the chest without ligation in the control group...
February 12, 2018: Zhongguo Zhen Jiu, Chinese Acupuncture & Moxibustion
https://read.qxmd.com/read/29387112/estrogen-stimulates-adenosine-receptor-expression-subtypes-in-human-breast-cancer-mcf-7-cell-line
#32
JOURNAL ARTICLE
Azam Mohamadi, Mahmoud Aghaei, Mojtaba Panjehpour
Estrogen is a steroid hormone that plays a key role in the development and regulation of reproductive system. It has been shown that estrogen is related to breast cancer development through binding to its receptors. In order to uncover the estrogen effects on adenosine receptor expression, estrogen-positive MCF-7 cells were used to treat with agonist and antagonist of estrogen and then the mRNA expression of adenosine receptor subtypes were evaluated. Estrogen-positive MCF-7 cells were treated with various concentrations of 17β estradiol (E2) as an estrogen agonist, and ICI 182,780 as an estrogen antagonist...
February 2018: Research in Pharmaceutical Sciences
https://read.qxmd.com/read/29225130/on-the-g-protein-coupling-selectivity-of-the-native-a-2b-adenosine-receptor
#33
JOURNAL ARTICLE
Zhan-Guo Gao, Asuka Inoue, Kenneth A Jacobson
A2B adenosine receptor (A2B AR) activation induces Gs-dependent cyclic AMP accumulation. However, A2B AR G protein-coupling to other signaling events, e.g. ERK1/2 and calcium, is not well documented. We explored Gi, Gq/11 and Gs coupling in 1321 N1 astrocytoma, HEK293, and T24 bladder cancer cells endogenously expressing human A2B AR, using NECA or nonnucleoside BAY60-6583 as agonist, selective Gi, Gs and Gq/11 blockers, and CRISPR/Cas9-based Gq- and Gs-null HEK293 cells. In HEK293 cells, A2B AR-mediated ERK1/2 activity occurred via both Gi and Gs, but not Gq/11...
May 2018: Biochemical Pharmacology
https://read.qxmd.com/read/29218545/a2b-adenosine-receptor-agonist-induces-cell-cycle-arrest-and-apoptosis-in-breast-cancer-stem-cells-via-erk1-2-phosphorylation
#34
JOURNAL ARTICLE
Seyyed Mehdi Jafari, Hamid Reza Joshaghani, Mojtaba Panjehpour, Mahmoud Aghaei
PURPOSE: It has been reported that cancer stem cells (CSCs) may play a crucial role in the development, recurrence and metastasis of breast cancer. Targeting signaling pathways in CSCs is considered to be a promising strategy for the treatment of cancer. Here, we investigated the role of the A2B adenosine receptor (A2BAR) and its associated signaling pathways in governing the proliferation and viability of breast cancer cell line derived CSCs. METHODS: CSCs were isolated from the breast cancer cell lines MCF-7 and MDA-MB-231 using a mammosphere assay...
February 2018: Cellular Oncology (Dordrecht)
https://read.qxmd.com/read/29149731/purinergic-drug-targets-for-gastrointestinal-disorders
#35
REVIEW
Geoffrey Burnstock, Kenneth A Jacobson, Fievos L Christofi
Purinergic receptors are implicated in the pathogenesis of gastrointestinal disorders and are being explored as potential therapeutic targets. Gut inflammation releases ATP that acts on neuronal, glial, epithelial and immune cells. Purinergic signalling in glia and neurons is implicated in enteric neuropathies. Inflammation activates glia to increase ATP release and alter purinergic signalling. ATP release causes neuron death and gut motor dysfunction in colitis via a P2X7-dependent neural-glial pathway and a glial purinergic-connexin-43 pathway...
December 2017: Current Opinion in Pharmacology
https://read.qxmd.com/read/29125553/structure-based-design-of-potent-and-selective-ligands-at-the-four-adenosine-receptors
#36
JOURNAL ARTICLE
Willem Jespers, Ana Oliveira, Rubén Prieto-Díaz, María Majellaro, Johan Åqvist, Eddy Sotelo, Hugo Gutiérrez-de-Terán
The four receptors that signal for adenosine, A₁, A2A , A2B and A₃ ARs, belong to the superfamily of G protein-coupled receptors (GPCRs). They mediate a number of (patho)physiological functions and have attracted the interest of the biopharmaceutical sector for decades as potential drug targets. The many crystal structures of the A2A , and lately the A₁ ARs, allow for the use of advanced computational, structure-based ligand design methodologies. Over the last decade, we have assessed the efficient synthesis of novel ligands specifically addressed to each of the four ARs...
November 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/29108754/extracellular-adenosine-produced-by-ecto-5-nucleotidase-cd73-regulates-macrophage-pro-inflammatory-responses-nitric-oxide-production-and-favors-salmonella-persistence
#37
JOURNAL ARTICLE
Matthew G Costales, Mohammad Samiul Alam, Christopher Cavanaugh, Kristina M Williams
Surface enzymes CD39 (nucleoside triphosphate dephosphorylase) and CD73 (ecto-5'-nucleotidase) mediate the synthesis of extracellular adenosine that can regulate immune responses. Adenosine produced by CD39/CD73 acts via adenosine receptors (ARs). CD73 is expressed by a variety of cell types and mediates anti-inflammatory responses. Because efficient innate immune responses are required for clearance of Salmonella infection, we investigated the role of CD73 in macrophage function, including phagocytosis, intracellular killing of Salmonella, and anti-bacterial pro-inflammatory responses to Salmonella-whole cell lysate (ST-WCL) or Salmonella infection...
January 30, 2018: Nitric Oxide: Biology and Chemistry
https://read.qxmd.com/read/29106905/characterisation-of-endogenous-a-2a-and-a-2b-receptor-mediated-cyclic-amp-responses-in-hek-293-cells-using-the-glosensor%C3%A2-biosensor-evidence-for-an-allosteric-mechanism-of-action-for-the-a-2b-selective-antagonist-psb-603
#38
JOURNAL ARTICLE
Joelle Goulding, Lauren T May, Stephen J Hill
Endogenous adenosine A2B receptors (A2B AR) mediate cAMP accumulation in HEK 293 cells. Here we have used a biosensor to investigate the mechanism of action of the A2B AR antagonist PSB 603 in HEK 293 cells. The A2A agonist CGS 21680 elicited a small response in these cells (circa 20% of that obtained with NECA), suggesting that they also contain a small population of A2A receptors. The responses to NECA and adenosine were antagonised by PSB 603, but not by the selective A2A AR antagonist SCH 58261. In contrast, CGS 21680 responses were not antagonised by high concentrations of PSB 603, but were sensitive to inhibition by SCH 58261...
January 2018: Biochemical Pharmacology
https://read.qxmd.com/read/29047264/the-inactivation-of-erk1-2-p38-and-nf-kb-is-involved-in-the-down-regulation-of-osteoclastogenesis-and-function-by-a2b-adenosine-receptor-stimulation
#39
JOURNAL ARTICLE
Bo Hyun Kim, Ju Hee Oh, Na Kyung Lee
A2B adenosine receptor (A2BAR) is known to be the regulator of bone homeostasis, but its regulatory mechanisms in osteoclast formation are less well-defined. Here, we demonstrate the effect of A2BAR stimulation on osteoclast differentiation and activity by RANKL. A2BAR was expressed in bone marrow-derived monocyte/macrophage (BMM) and RANKL increased A2BAR expression during osteoclastogenesis. A2BAR stimulation with its specific agonist BAY 60-6583 was sufficient to inhibit the activation of ERK1/2, p38 MAP kinases and NF-κB by RANKL as well as it abrogated cell-cell fusion in the late stage of osteoclast differentiation...
October 2017: Molecules and Cells
https://read.qxmd.com/read/28982732/adenosine-receptors-differentially-regulate-type-2-cytokine-production-by-il-33-activated-bone-marrow-cells-ilc2s-and-macrophages
#40
JOURNAL ARTICLE
Balázs Csóka, Zoltán H Németh, Claudia U Duerr, Jörg H Fritz, Pál Pacher, György Haskó
Group 2 innate lymphoid cells (ILC2s) represent a rapid source of type 2 cytokines, such as IL-5 and IL-13, and play an important role in orchestrating type 2 immune response. Adenosine is an endogenous purine nucleoside, a catabolite of ATP that binds and activates ≥1 of 4 transmembrane G protein-coupled cell-surface adenosine receptors (ARs)-A1 , A2A , A2B , and A3 . Here, we studied the role of ARs in the regulation of cytokine production by ILC2s. We found that A2B ARs suppress the production of both IL-5 and IL-13 by ILC2s, whereas A2A ARs augment IL-5 production and fail to affect IL-13 release...
February 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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