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The inhibitory effect of Adenosine on tumor adaptive immunity and intervention strategies

Acta Pharmaceutica Sinica B 2024年第5期14卷 1951-1964页

作者： Longsheng Wang Jie Zhang Wenxin Zhang Mingming Zheng Hongjie Guo Xiaohui Pan Wen Li Bo Yang Ling Ding Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Nanhu Brain-Computer Interface Institute Hangzhou 311100China

Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal tissues.It binds to Adenosine receptors(AdoRs),suppressing tumor antigen presentation and immune cell activation,thereby inhibiting tumor adaptive immunity.Ado downregulates major histocompatibility complex II(MHC II)and co-stimulatory factors on dendritic cells(DCs)and macrophages,inhibiting antigen presentation.It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor(TCR)binding and signal transduction.Ado also inhibits chemokine secretion and KCa3.1 channel activity,impeding effector T cell trafficking and infiltration into the tumor site.Furthermore,Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion,upregulating immune checkpoint proteins,and enhancing immune-suppressive cell activity.Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies.Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway.Therefore,this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity,as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

关键词： Adenosine Adenosine receptors Adenosine-generating enzymes Tumor microenvironment Immune suppression Immune escape Clinical treatment Targeting drugs

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Dietary Adenosine supplementation improves placental angiogenesis in IUGR piglets by up-regulating Adenosine A2a receptor

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Animal Nutrition 2023年第2期13卷 282-288页

作者： Zifang Wu Jiawei Nie Deyuan Wu Shuangbo Huang Jianzhao Chen Huajin Liang Xiangyu Hao Li Feng Hefeng Luo Chengquan Tan Guangdong Provincial Key Laboratory of Animal Nutrition Control National Engineering Research Center for Breeding Swine IndustryInstitute of Subtropical Animal Nutrition and FeedCollege of Animal ScienceSouth China Agricultural UniversityGuangzhouGuangdong 510642China Dekon Food and Agriculture Group ChengduChina

Abnormal placental angiogenesis is associated with the occurrence of intrauterine growth restriction(IUGR)in piglets,and effective treatment strategies against this occurrence remain to be explored.Adenosine has been reported to play an important role in angiogenesis,but its role in placental angio-genesis is still unknown.Here,we investigated the effect of dietary Adenosine supplementation on IUGR occurrence in piglets by analyzing the role of Adenosine in placental angiogenesis for Normal and IUGR piglets.Specifically,88 sows were allotted to 2 treatments(n=44)and fed a basal diet supplemented with 0%or 0.1%of Adenosine from day 65 of gestation until farrowing,followed by collecting the placental samples of Normal and IUGR piglets,and recording their characteristics.The results showed that Adenosine supplementation increased the mean birth weight of piglets(PAdenosine supplementation promoted angiogenesis(PAdenosine A2a receptor(ADORA2A)was lower(PAdenosine treatment could significantly increase ADORA2A expression,and also had an interaction effect between factors IUGR and Ado.Collectively,placentae for IUGR piglets showed impaired angiogenesis and down-regulated expression level of ADORA2A,while dietary Adenosine supplementation could activate ADORA2A expression,improve the placental angio-genesis,and ultimately decrease the occurrence of IUGR in piglets.

关键词： Angiogenesis IUGR Placenta Adenosine ADORA2A

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Ticagrelor Protects against Sepsis-Induced Acute Kidney Injury through an Adenosine Receptor-Dependent Pathway

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Current Medical Science 2022年第3期42卷 505-512页

作者： Yu-han CAO Qian-cheng XU Yu-wei WANG Yang LING Cong FU Department of Nephrology Yi Ji Shan Hospital affiliated to Wan Nan Medical CollegeWuhu 241000China Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution Wan Nan Medical CollegeWuhu 241000China Department of Critical Care Medicine Yi Ji Shan Hospital affiliated to Wan Nan Medical CollegeWuhu 241000China Department of Cardiology Yi Ji Shan Hospital Affiliated to Wan Nan Medical CollegeWuhu 241000China

Objective Ticagrelor is a widely used anti-platelet drug.However,the mechanisms by which ticagrelor protects against sepsis-induced acute kidney injury(AKI)have not been clearly demonstrated.We designed this study to explore the protective effect of ticagrelor on sepsis-induced AKI and to explore the underlying mechanisms.Methods C57BL6J mice received oral ticagrelor(20 mg/kg and 50 mg/kg)for 7 days,and then caecal ligation and puncture(CLP)were performed.An Adenosine receptor antagonist,CGS15943,was administered(10 mg/kg,intraperitoneal injection)to block the Adenosine pathway 2 h before CLP.After 24 h,serum creatinine levels were measured.Periodic acid-Schiff(PAS)staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL)staining were employed to analyze pathological changes and cell apoptosis.Serum concentrations of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),and mRNA expression of tissue TNF-αand IL-1βwere detected.Western blotting analysis was used to determine AKT and mammalian target of rapamycin(mTOR)protein expression in the kidney.Results PAS staining showed less swelling of renal tubules,and TUNEL staining revealed less cell apoptosis in the ticagrelor group than in the CLP group.Serum creatinine levels were significantly lower in the ticagrelor group than in the CLP group.Moreover,significantly lower serum and kidney levels of TNF-αand IL-1βwere observed in the ticagrelor group.CGS15943 blocked the effects of ticagrelor.Western blotting analysis showed increased phosphorylation of AKT and mTOR in the kidneys of the 50 mg/kg ticagrelor group.The Adenosine receptor antagonist inhibited the activation of AKT and mTOR.Conclusion This study demonstrates that the protective effect of ticagrelor on sepsis-induced AKI depends on Adenosine receptor activation and the subsequent increase of AKT and mTOR phosphorylation.

关键词： sepsis acute kidney injury Adenosine phosphatidyl-inositol 3-kinase mammalian target of rapamycin

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Adenosine monophosphate enhances callus regeneration competence for de novo plant organogenesis

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Molecular Plant 2023年第12期16卷 1867-1870页

作者： Hong Gil Lee Seo Young Jang Eun Yee Jie Seung Hee Choi Ok-Sun Park Soon Hyung Bae Hyun-Soon Kim Suk Weon Kim Geum-Sook Hwang Pil Joon Seo Department of Chemistry Seoul National UniversitySeoul 08826Korea Plant Genomics and Breeding Institute Seoul National UniversitySeoul 08826Korea Integrated Metabolomics Research Group Western Seoul CenterKorea Basic Science InstituteSeoul 03759Korea Biological Resource Center Korea Research Institute of Bioscience and BiotechnologyJeongeup56212Korea Plant Systems Engineering Research Center Korea Research Institute of Bioscience and BiotechnologyDaejeon 34141Korea College of Pharmacy Chung-Ang UniversitySeoul 06974Korea

Dear Editor,Plant tissue culture involves callus formation and de novo shoot regeneration.First,explants from differentiated tissues are used to generate a pluripotent cell mass,called callus,on auxin-rich callus-inducing medium(CIM),followed by shoot regeneration on cytokinin-rich shoot-inducing medium(SiM).Callus results from division of pericycle-like cells(Atta et al.,2009;Sugimoto et al.,2010);its cellular identity resembles that of lateral root primordia(Atta et al.,2009;Sugimoto et al.,2010).Callus acquires cellular pluripotency by forming root stem cell niches on CIM(Sugimoto et al.,2010)。

关键词： Adenosine callus

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Unlocking antitumor immunity with Adenosine receptorblockers

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Cancer Drug Resistance 2023年第4期6卷 748-767页

作者： Victoria A.Remley Joel Linden Todd W.Bauer Julien Dimastromatteo Department of Surgery University of VirginiaCharlottesvilleVA 22903USA Adovate CharlottesvilleVA 22901USA University of Virginia Comprehensive Cancer Center CharlottesvilleVA 22903USA

Tumors survive by creating a tumor microenvironment(TME)that suppresses antitumor immunity.The TME suppresses the immune system by limiting antigen presentation,inhibiting lymphocyte and natural killer(NK)cell activation,and facilitating T cell exhaustion.Checkpoint inhibitors like anti-PD-1 and anti-CTLA4 are immunostimulatory antibodies,and their blockade extends the survival of some but not all cancer patients.Extracellular Adenosine triphosphate(ATP)is abundant in inflamed tumors,and its metabolite,Adenosine(ADO),is a driver of immunosuppression mediated by Adenosine A2A receptors(A2AR)and Adenosine A2B receptors(A2BR)found on tumor-associated lymphoid and myeloid cells.This review will focus on Adenosine as a key checkpoint inhibitor-like immunosuppressive player in the TME and how reducing Adenosine production or blocking A2AR and A2BR enhances antitumor immunity.

关键词： Immunotherapy Adenosine Adenosine receptors Adenosine A2A receptors(A2AR) Adenosine A2B receptors(A2BR) tumor cells immune cells tumor microenvironment

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Comparative efficacy and safety of Adenosine and regadenoson for assessment of fractional flow reserve:A systematic review and meta-analysis

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World Journal of Cardiology 2022年第5期14卷 319-328页

作者： Gauravpal Singh Gill Akshaya Gadre Arun Kanmanthareddy Cardiovascular Medicine Creighton University School of MedicineOmahaNE 68124United States Internal Medicine Western Michigan University Homer Stryker MD School of MedicineKalamazooMI 49007United States

BACKGROUND Adenosine is a coronary hyperemic agent used to measure invasive fractional flow reserve(FFR)of intermediate severity coronary stenosis.AIM To compare FFR assessment using Adenosine with an alternate hyperemic agent,regadenoson.METHODS PubMed,Google Scholar,CINAHL and Cochrane databases were queried for studies comparing Adenosine and regadenoson for assessment of FFR.Data on FFR,correlation coefficient and adverse events from the selected studies were extracted and analyzed by means of random effects model.Two tailed P-value less than 0.05 was considered significant.Heterogeneity was assessed using I2 test.RESULTS Five studies with 248 patients were included in the final analysis.All included patients and coronary lesions underwent FFR assessment using both Adenosine and regadenoson.There was no significant mean difference between FFR measurement by the two agents[odds ratio(OR)=-0.00;95%confidence interval(CI):(-0.02)-0.01,P=0.88].The cumulative correlation coefficient was 0.98(0.96-0.99,PAdenosine compared to regadenoson(OR=2.39;95%CI:1.22-4.67,P=0.01),which most commonly included bradycardia and hypotension.Vast majority of the adverse events associated with both agents were transient.CONCLUSION The performance of regadenoson in inducing maximal hyperemia was comparable to that of Adenosine.There was excellent correlation between the FFR measurements by both the agents.The use of Adenosine,was however associated with higher risk of adverse events and longer time to FFR compared to regadenoson.

关键词： Adenosine Regadenoson Fractional flow reserve Meta-analysis

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Electroacupuncture improves neuropathic pain Adenosine, Adenosine 5'-triphosphate disodium and their receptors perhaps change simultaneously

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Neural Regeneration Research 2012年第33期7卷 2618-2623页

作者： Wen Ren Wenzhan Tu Songhe Jiang Ruidong Cheng Yaping Du Institute of Social & Family Medicine Zhejiang University Hangzhou 310058 Zhejiang Province China Department of Physical Medicine and Rehabilitation The Second Affiliated Hospital of Wenzhou Medical College Wenzhou 325000Zhejiang Province China

Applying a stimulating current to acupoints through acupuncture needles–known as electroacupuncture–has the potential to produce analgesic effects in human subjects and experimental animals. When acupuncture was applied in a rat model, Adenosine 5-triphosphate disodium in the extracellular space was broken down into Adenosine, which in turn inhibited pain transmission by means of an Adenosine A1 receptor-dependent process. Direct injection of an Adenosine A1 receptor agonist enhanced the analgesic effect of acupuncture. The analgesic effect of acupuncture appears to be mediated by activation of A1 receptors located on ascending nerves. In neuropathic pain, there is upregulation of P2X purinoceptor 3 （P2X3） receptor expression in dorsal root ganglion neurons. Conversely, the onset of mechanical hyperalgesia was diminished and established hyperalgesia was significantly reversed when P2X3 receptor expression was downregulated. The pathways upon which electroacupuncture appear to act are interwoven with pain pathways, and electroacupuncture stimuli converge with impulses originating from painful areas. Electroacupuncture may act via purinergic A1 and P2X3 receptors simultaneously to induce an analgesic effect on neuropathic pain.

关键词： electroacupuncture analgesia Adenosine Adenosine 5＇-triphosphate disodium A1 receptors P2Xpudnoceptor 3 receptors neuropathic pain peripheral nervous system central nervous system regeneration neural regeneration.

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N-terminal pro-B-type natriuretic peptide and diastolic function measurements by Adenosine stress echocardiography in prediction of coronary stenosis in patients

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Chinese Medical Journal 2011年第14期124卷 2089-2095页

作者： ZHENG Ping WANG Hao TIAN Yue-qin GUO Yuan-lin HE Zuo-xiang LU Ye ZHENG Xin MA Wen-jun XU Nan SUN Xin ZHANG Ling Department of Echocardiography Cardiovascular Institute and Fuwai Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100037 China Department of Nuclear Medicine Cardiovascular Institute and Fuwai Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100037 China Center of Coronary Heart Diseases Cardiovascular Institute and Fuwai Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100037 China Center of Hypertension Cardiovascular Institute and Fuwai Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100037 China

Background Stress echocardiography is mainly used in detection of coronary artery disease （CAD） and to assess risk.This study aimed to use Adenosine stress echocardiography （ASE） and N-terminal pro-B-type natriuretic peptide （NT-proBNP） to noninvasively assess coronary stenosis in patients with chest pain syndromes or anginal equivalent.Methods NT-proBNP was measured after overnight fast in fifty patients, 42 males and 8 females, who were （57＋11）years old. They then underwent echocardiography before and during Adenosine administration. Left ventricular （LV）diastolic function analyzed included mitral annular early （E＇） and late velocity （A＇） both at the mitral septal and lateral level and the mitral inflow to annulus ratio （E/E＇）. Coronary angiography was performed the following day after which patients were assigned to three groups： normal results （16 patients）, stenosis 50%-69%（17 patients） and stenosis≥70% （17 patients）.Results NT-proBNP levels in the groups of stenosis 50%-69% and≥ 70% were significantly higher than that in the group with normal results （P=0.014 and P=0.040）. During Adenosine stress, the E/E＇ in the group of stenosis≥70% was higher than in the group of normal results （P=0.024）. E＇lateral/A＇lateral in the group of stenosis 50%-69% and E＇septal/A＇septal and E＇lateral/A＇lateral in the group of stenosis≥70% were also decreased during stress compared with baseline （P=0.003,P=0.001, P=0.022）. The variation of E＇septal/A＇septal before and during Adenosine stress （△E＇septal/A＇septal） between the groups of normal results and stenosis ≥70% were significantly different （P=0.001）. By receiver operating characteristic （ROC）, the specificity of △E＇septal/A＇septal ≥0.037 predicting coronary stenosis ＜70% was 94%. The sensitivity and specificity of NT-proBNP≥544.6 fmol/ml in predicting coronary stenosis ≥70% were 93% and 75%, respectively.NT-proBNP inversely correlated with E＇lateral/A＇lateral （r=-0.390, P=0.014） and positively correlated with E/E＇lateral（r=0.550,P=0.001）.Conclusions Adenosine might induce di

关键词： Adenosine echocardiography diastole coronary stenosis N-terminal pro-B-type natriuretic peptide

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Synergistic myoprotection of L-arginine and Adenosine in a canine model of global myocardial ischaemic reperfusion injury

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Chinese Medical Journal 2007年第22期120卷 1975-1981页

作者： DU Lei DIAN Ke CHEN Hui-jiao AN Qi JIA Meng-xing YANG Ping-liang WANG Wei DENG Shuo-zeng LIU Jin Department of Anaesthesiology West China Hospital Sichuan University Chengdu 610041 China Department of Thoracic and Cardiovascular Surgery West China Hospital Sichuan University Chengdu 610041 China Department of Pathology West China Hospital Sichuan University Chengdu 610041 China

Background Endogenous nitric oxide and Adenosine increase simultaneously to keep the balance of energy demand and supply when the oxygen supply is insufficient, which suggests that nitric oxide and Adenosine might exert a synergistic myoprotection during tissue hypoxia. In this study, we tested this hypothesis utilizing a canine model of prolonged global myocardial ischaemic reperfusion injury. Methods In this double blind, controlled study, the hearts of 24 anaesthetized mongrel dogs were arrested for 2 hours with aortic cross clamping and blood cardioplegia. The treatment groups were those supplemented with 2 mmol/L L-arginine （ARG）, supplemented with 1 mmol/L Adenosine （ADO）, ARG ＋ ADO supplemented with both, and no supplementation （control）（n=6 in each group）. Haemodynamics, biochemical indices, Adenosine triphosphate （ATP） content and myeloperoxidase activities of myocardium were determined to evaluate myocardial injury. Statistical comparison was performed by two way ANOVA. Results Although the requirements for inotropic supports were higher, the cardiac outputs were lower in control group than in ARG, ADO and the combination groups. Plasma cardiac troponin I levels were higher and the areas of hydropic changes were larger in control group than in ARG and ADO groups. Combination of arginine and Adenosine provided further myoprotection with respect to better cardiac performance, lower release of cardiac troponin I, and smaller areas of hydropic changes compared with ARG and ADO groups. ATP content was higher, but myeloperoxidase activities of myocardium were significantly lower in the combination group than in control, ARG and ADO groups （P〈0.05）. Conclusions Combination of L-arginine and Adenosine provides synergistic myoprotection in a canine model of global myocardial ischaemia. Thus, the combination is recommended when the heart is exposed to a prolonged ischaemia during cardiac surgery.

关键词： nitric oxide Adenosine myocardium injury, ischaemic reperfusion

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Ischemic preconditioning protects post-ischemic renal function in anesthetized dogs:role of Adenosine and adenine nucleotides

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Acta Pharmacologica Sinica 2005年第7期26卷 851-859页

作者： ShojiKIMURA AkiraNISHIYAMA MatluburRAHMAN YouichiABE Department of Pharmacology Kagawa Medical University 1750-1 Ikenobe Japan Kagawa 761-0793

Aim:To investigate the effects of renal ischemic preconditioning(IPC)on bothrenal hemodynamics and the renal interstitial concentrations of Adenosine andadenine nucleotides induced by ischemia-reperfusion injury.Methods:Renalhemodynamics responses to ischemia-reperfusion injury in mongrel dog modelswere determined with or without multiple brief renal ischemic preconditioningtreatments,as well as the Adenosine A1receptor antagonist(KW-3902),respectively.The renal interstitial concentrations of Adenosine and adenine nucle-otides in response to ischemia-reperfusion injury,either following 1-3 cycles ofIPC or not,were measured simultaneously using microdialysis samplingtechnology.Results:One 10-min IPC,Adenosine A1receptor antagonist(KW-3902)also shortened the recovery time of renal blood flow(RBF)and urine flow(UF),as well as mean blood pressure(BP).Advanced renal IPC attenuated theincrement of Adenosine and adenine nucleotides,as well as recovery time duringthe 60-rain reperfusion which followed the 60-min renal ischemia.All of theserecovery times were dependent on the cycles of 10-min IPC.The renal interstitialconcentrations of Adenosine and adenine nucleotides increased and decreasedduring renal ischemia and reperfusion,respectively.Conclusion:A significantrelativity in dog models exists between the cycles of 10-min renal IPC and therecovery time of BP,UF,and RBF during the 60-min renal reperfusion following60-min renal ischemia,respectively.Renal IPC can protect against ischemia-reperfusion injury and the predominant effect of endogenous Adenosine inducedby prolonged renal ischemia;renal Adenosine A1receptor activation during therenal ischemia-reperfusion injury is detrimental to renal function.

关键词： microdialysis ischemia preconditioning reperfusion injury kidney Adenosine Adenosine A1 receptor

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