Hong-Xia Li, Xiao-Yan Liang, Jiong-He Wu, Ya-Ping Yuan, Yue Gao, Shao-Hua Cai
To explore the protective mechanism of simvastatin in acute lung injury (ALI), the lipopolysaccharide (LPS) induced (5 mg/kg) ALI rat model was used to examine the effects of simvastatin. Following simvastatin treatment, the histopathological evaluation of lung tissues was made using hematoxylin and eosin (H&E) staining. Also, myeloperoxidase (MPO) activity and the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-10 were determined by ELISA. Blood gas analyses of arterial blood samples were performed to assess the pulmonary gas exchange...
March 24, 2021: Toxicology and Applied Pharmacology
Shaojie Ding, Xinyue Guo, Libo Zhu, Jianzhang Wang, Tiantian Li, Qin Yu, Xinmei Zhang
Background: Endometriosis-associated pain can be considered a type of neuropathic pain. Netrin-1 is an axon guidance cue that regulates axonal attraction or rejection in neural injury and regeneration. However, whether netrin-1 plays a role in endometriosis-associated pain remains unclear. This study aimed to determine the role of netrin-1 in endometriosis-related pain. Methods: Peripheral blood, peritoneal fluid, and endometrial tissues were sampled from women with (n=37) and without endometriosis (n=23)...
January 2021: Annals of Translational Medicine
Eleonora Spinozzi, Cecilia Baldassarri, Laura Acquaticci, Fabio Del Bello, Mario Grifantini, Loredana Cappellacci, Petrelli Riccardo
The ocular drug discovery arena has undergone a significant improvement in the last few years culminating in the FDA approvals of 8 new drugs. However, despite a large number of drugs, generics, and combination products available, it remains an urgent need to find breakthrough strategies and therapies for tackling ocular diseases. Targeting the adenosinergic system may represent an innovative strategy for discovering new ocular therapeutics. This review focused on the recent advance in the field and described the numerous nucleoside and non-nucleoside modulators of the four adenosine receptors (ARs) used as potential tools or clinical drug candidates...
January 25, 2021: Medicinal Chemistry Research
Yulan Ren, Zhihan Chen, Rui Wang, Yang Yu, Dehua Li, Yonggang He
Electroacupuncture (EA) can improve myocardial ischemia (MI) injury; nevertheless, the mechanism is not entirely clear. And there were disagreements about whether the effect of EA at acupoint in disease-affected meridian is better than EA at acupoint in non-affected meridian and sham acupoint. Here, we showed that the effect of EA at Neiguan (PC6) is better than EA at Hegu (LI4) and sham acupoint in affecting RPP and ECG, increasing ATP and ADO production, decreasing AMP production, and upregulating the mRNA expression levels of A1AR, A2aAR, and A2bAR; knockdown of A1AR or A2bAR reversed the effect of EA at PC6 in alleviating MI injury; knockdown of A2aAR had no influence on the cardiac protection of EA at PC6; thus, the cardioprotective effect of EA at PC6 needs A1AR and A2bAR, instead of A2aAR; considering that the cardio protection of adenosine receptor needs activation of other adenosine receptors, one of the reasons may be that after silence of A1AR or A2bAR, EA at PC6 could not impact the expression levels of the other two adenosine receptors, and after silence of A2aAR, EA at PC6 could impact the expression levels of A1AR and A2bAR...
July 6, 2020: Purinergic Signalling
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
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
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