British Journal of Pharmacology最新文献

{"title":"EXPRESSION OF CONCERN: Superoxide from NADPH Oxidase Upregulates Type 5 Phosphodiesterase in Human Vascular Smooth Muscle Cells: Inhibition with Iloprost and NONOate.","authors":"","doi":"10.1111/bph.70042","DOIUrl":"https://doi.org/10.1111/bph.70042","url":null,"abstract":"","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P2Y₁₄ receptor activation of platelets induces Ca²⁺ mobilization and Rho-GTPase-dependent motility that requires an interaction with P2Y₁ receptors.","authors":"Md Monir Hossain, Dingxin Pan, Kate L Arkless, Khondaker Miraz Rahman, Clive P Page, Kalwant S Authi, Simon C Pitchford","doi":"10.1111/bph.70024","DOIUrl":"https://doi.org/10.1111/bph.70024","url":null,"abstract":"<p><strong>Background and purpose: </strong>Platelet function during inflammation is dependent on activation by endogenous nucleotides acting on purinergic receptors. The P2Y₁₄ receptor has been reported to be expressed on platelets and is involved in leukocyte recruitment during inflammation. However, a role for P2Y₁₄ receptors in platelet function has not yet been determined.</p><p><strong>Experimental approach: </strong>Platelets obtained from healthy human volunteers were incubated with the P2Y₁₄ receptor agonist, UDP-Glucose (UDP-G), and PPTN, a selective P2Y₁₄ receptor antagonist. Platelet activation was quantified using Ca²⁺ mobilization, aggregation and chemotaxis assays. Cooperativity with P2Y₁ receptor activation was also assessed after stimulation with UDP-G in the presence of MRS2500, a selective P2Y₁ receptor antagonist.</p><p><strong>Key results: </strong>Ca²⁺ mobilization occurred in platelets after incubation with UDP-G in a concentration-dependent manner, and this was suppressed in platelets treated with PPTN. Platelets did not aggregate, or bind to fibrinogen after incubation with UDP-G. However, platelet chemotaxis towards f-MLP was dependent on P2Y₁₄ receptor stimulation with UDP-G and this was reduced by Rho-GTPase inhibitors. Furthermore, UDP-G-induced Ca²⁺ mobilization and chemotaxis were also inhibited when platelets were pretreated with MRS2500. Conversely, ADP-induced Ca²⁺ mobilization, chemotaxis and aggregation were not affected by the incubation with PPTN.</p><p><strong>Conclusion and implications: </strong>Platelets can be activated via P2Y₁₄ receptor stimulation to induce chemotaxis but not aggregation. Furthermore, this was dependent on concomitant activation of P2Y₁ receptor. Activation of P2Y₁₄ receptors on platelets may therefore be relevant during inflammation, but cooperation with P2Y₁ receptor activation is required.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural products and cancer: From drug discovery to prevention and therapy.","authors":"Angelo A Izzo, Barbara Stefanska","doi":"10.1111/bph.70014","DOIUrl":"https://doi.org/10.1111/bph.70014","url":null,"abstract":"","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-throughput screening identifies bazedoxifene as a potential therapeutic for dysferlin-deficient limb girdle muscular dystrophy.","authors":"Celine Bruge, Nathalie Bourg, Emilie Pellier, Johana Tournois, Jerome Polentes, Manon Benabides, Noella Grossi, Anne Bigot, Anthony Brureau, Isabelle Richard, Xavier Nissan","doi":"10.1111/bph.70017","DOIUrl":"https://doi.org/10.1111/bph.70017","url":null,"abstract":"<p><strong>Background and purpose: </strong>Limb-girdle muscular dystrophy R2 (LGMD R2) is a rare genetic disorder characterised by progressive weakness and wasting of proximal muscles. LGMD R2 is caused by the loss of function of dysferlin, a transmembrane protein crucial for plasma membrane repair in skeletal muscles. This study aimed to identify drugs that could improve the localisation and restore the function of an aggregated mutant form of dysferlin (DYSF^L1341P).</p><p><strong>Experimental approach: </strong>We developed an in vitro high-throughput assay to monitor the expression and reallocation of aggregated mutant dysferlin (DYSF^L1341P) in immortalised myoblasts. After screening 2239 clinically approved drugs and bioactive compounds, the ability of the more promising candidates to improve cell survival following hypo-osmotic shock was assessed. Their protective effects were evaluated on immortalised myoblasts carrying other dysferlin mutations and on dysferlin-deficient muscle fibres from Bla/J mice.</p><p><strong>Key results: </strong>We identified two compounds, saracatinib and bazedoxifene, that increase dysferlin content in cells carrying the DYSF^L1341P mutation. Both drugs improved cell survival and plasma membrane resistance following osmotic shock. Whereas saracatinib acts specifically on misfolded L1341P dysferlin, bazedoxifene shows an additional protective effect on dysferlin KO immortalised myoblasts and mice muscle fibres. Further analysis revealed that bazedoxifene induces autophagy flux, which may enhance the survival of LGMD R2 myofibres.</p><p><strong>Conclusion and implications: </strong>Our drug screening identified saracatinib and bazedoxifene as potential treatments for LGMD R2, especially for patients with the L1341P mutation. The widespread protective effect of bazedoxifene reveals a new avenue toward genotype-independent treatment of LGMD R2 patients.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sub-chronic administration of AM6545 enhances cognitive performance and induces hippocampal synaptic plasticity changes in naïve mice.","authors":"Araceli Bergadà-Martínez, Lucía de Los Reyes-Ramírez, Sara Martínez-Torres, Laura Ciaran-Alfano, Irene Martínez-Gallego, Rafael Maldonado, Antonio Rodríguez-Moreno, Andrés Ozaita","doi":"10.1111/bph.70015","DOIUrl":"https://doi.org/10.1111/bph.70015","url":null,"abstract":"<p><strong>Background and purpose: </strong>There is evidence of crosstalk between the brain and peripheral tissues. However, how the periphery contributes to brain function is not well understood. The cannabinoid CB₁ receptor is classically pictured to have a relevant role in cognitive function. We previously demonstrated a novel mechanism where acute administration of the CB₁ receptor antagonist AM6545, largely restricted to the periphery, prolonged memory persistence in mice. Here, we have assessed the effects of repeated exposure to AM6545 on cognitive improvements.</p><p><strong>Experimental approach: </strong>We evaluated, in young adult male and female mice, the behavioural consequences of sub-chronic treatment with AM6545. An unbiased transcriptomic analysis, as well as electrophysiological and biochemical studies, was carried out to elucidate the central cellular and molecular consequences of such action at peripheral receptors.</p><p><strong>Key results: </strong>Sub-chronic AM6545 enhanced memory in low and high arousal conditions in male and female mice. Executive function was facilitated after repeated AM6545 administration in male mice. Transcriptional analysis of hippocampal synaptoneurosomes from treated mice revealed a preliminary, sex-dependent, modulation of synaptic transcripts by AM6545. Notably, AM6545 occluded long-term potentiation in CA3-CA1 synapses while enhancing input-output relation in male mice. This was accompanied by an increase in hippocampal expression of Bdnf and Ngf.</p><p><strong>Conclusion and implications: </strong>Our results showed that repeated administration of AM6545 contributed to the modulation of memory persistence, executive function and hippocampal synaptic plasticity in mice, further indicating that peripheral CB₁ receptors could act as a target for a novel class of nootropic compounds.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TLR2 activates AP-1 to facilitate CTGF transcription and stimulate doxorubicin-induced myocardial injury.","authors":"Lang Hong, Xinyong Cai, Yuliang Zhan, Songtao Liu, Pengtao Zou, Yanmei Chen, Liang Shao","doi":"10.1111/bph.17423","DOIUrl":"https://doi.org/10.1111/bph.17423","url":null,"abstract":"<p><strong>Background and purpose: </strong>Our study aimed to explore the mechanistic network of toll-like receptor 2 (TLR2)/activator protein-1 (AP-1) combined with SOX10 activation of the mitogen-activated protein kinase (MAPK) pathway via connective tissue growth factor (CTGF) in doxorubicin (Dox)-induced myocardial injury.</p><p><strong>Experimental approach: </strong>Rats with Dox-induced myocardial injury were treated with a TLR2 inhibitor or CTGF silencing lentiviral vector. H9c2 cells were treated with genetic vectors or MAPK pathway activators. Cardiac function was tested using echocardiography and serum markers. H&E, Sirius red and TUNEL staining were used to detect myocardial pathological changes, collagen accumulation and apoptosis. Western blot was used to detect proteins related to cardiac hypertrophy, fibrosis, apoptosis and the MAPK pathway. H9c2 cell injury was assessed by testing cell viability, lactate dehydrogenase (LDH) release and mitochondrial membrane potential.</p><p><strong>Key results: </strong>TLR2 and CTGF were highly expressed in patients with heart failure, and Dox treatment further increased their expression. Inhibiting TLR2 or silencing CTGF improved cardiac function and reduced myocardial fibrosis and apoptosis in Dox-treated rats. Silencing of TLR2 alleviated Dox-induced H9c2 cell injury, which was nullified by CTGF overexpression. TLR2 activated AP-1, which cooperated with SOX10 to promote CTGF transcription. MAPK activation aggravated H9c2 cells against Dox-induced injury.</p><p><strong>Conclusions and implications: </strong>TLR2 activates AP-1 which cooperates with SOX10 to promote CTGF transcription and subsequently activate the MAPK pathway, thereby stimulating Dox-induced myocardial injury.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rescue of loss-of-function long QT syndrome-associated mutations in K_V7.1/KCNE1 by the endocannabinoid N-arachidonoyl-L-serine (ARA-S).","authors":"Irene Hiniesto-Iñigo, Akshay Sridhar, Julien Louradour, Alicia De la Cruz, Siri Lundholm, Amaia Jauregi-Miguel, Federica Giannetti, Luca Sala, Katja E Odening, H Peter Larsson, Nina E Ottosson, Sara I Liin","doi":"10.1111/bph.70008","DOIUrl":"10.1111/bph.70008","url":null,"abstract":"<p><strong>Background and purpose: </strong>Congenital long QT syndrome (LQTS) involves genetic mutations affecting ion channels, leading to a prolonged QT interval and increased risk of potentially lethal ventricular arrhythmias. Mutations in the genes encoding K_V7.1/KCNE1 are the most frequent, with channel loss-of-function contributing to LQTS. The endocannabinoid N-arachidonoyl-L-serine (ARA-S) has been shown to facilitate activation of wild type K_V7.1/KCNE1 channels and to counteract a prolonged QT interval in isolated guinea pig hearts. In this study, we examine the ability of ARA-S to facilitate activation of LQTS-associated mutations, in various regions of the channel, and hence to counteract loss-of-function.</p><p><strong>Experimental approach: </strong>The two-electrode voltage clamp technique on Xenopus oocytes expressing human K_V7.1/KCNE1 channels was used to investigate the effects of ARA-S in 20 LQTS type 1-associated mutations distributed across the channel. Thereafter, different electrophysiology was used to assess ARA-S effects in mammalian cells.</p><p><strong>Key results: </strong>ARA-S enhanced the function of all mutated channels by shifting V₅₀ and increasing current amplitude. However, the magnitude of effect varied, related to whether mutations were in one of the two putative ARA-S binding sites on the channel as suggested by molecular dynamics simulations. ARA-S displayed translational potential by facilitating channel opening in mammalian cells and shortening the action potential duration in cardiomyocytes.</p><p><strong>Conclusions and implications: </strong>This study demonstrates the rescuing capability of ARA-S on a diverse set of LQTS mutants. These insights may aid in developing drug compounds using ARA-S sites and mechanisms and guide interpretation of which LQTS mutants respond well to such compounds.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-likeness evaluation and inhibitory mechanism of the emodin derivative on cardiac fibrosis based on metastasis-associated protein 3.","authors":"Heng Liu, Runze Li, Zhixia Wang, Weina Han, Xiuxiu Sun, Xinxin Dong, Han Lou, Run Xu, Ange Hu, Denis Baranenko, Xue Bai, Dan Xiao, Weihong Lu","doi":"10.1111/bph.70012","DOIUrl":"https://doi.org/10.1111/bph.70012","url":null,"abstract":"<p><strong>Background and purpose: </strong>Emodin inhibits cardiac fibrosis through metastasis-associated protein 3 (MTA3), but its limited bioavailability hinders clinical application. To enhance emodin's clinical potential, a new derivative, emodin succinyl ethyl ester, was synthesised by modifying the 3'-OH position. This study assessed its drug-likeness, anti-fibrotic properties and molecular mechanisms involving MTA3.</p><p><strong>Experimental approach: </strong>Drug-likeness properties of the emodin derivative were evaluated using computational-aided drug design (CADD). Transverse aortic constriction (TAC)-induced cardiac fibrosis and Angiotensin II (Ang II)-stimulated cardiac fibroblasts were used in vivo and ex vivo, respectively, to determine the effects of the emodin derivative on cardiac fibrosis and fibroblast transdifferentiation. Bioinformatics analysis, CADD, chromatin immunoprecipitation (ChIP), luciferase reporter assays and functional experiments were employed to predict, identify and validate the relationship between MTA3 and its upstream transcription factors.</p><p><strong>Key results: </strong>The emodin derivative exhibited superior drug-likeness and anti-fibrotic effects compared to emodin by effectively inhibiting cardiac fibroblast transdifferentiation and restored MTA3 expression. E2F1 was identified and validated as a transcriptional regulator, promoting α-SMA and COL1A2 expression, and directly reducing MTA3 expression in cardiac fibroblasts. The emodin derivative demonstrated stronger binding to the E2F1 transcription site than emodin, reducing E2F1 expression and enhancing anti-fibrotic action.</p><p><strong>Conclusions and implications: </strong>The emodin derivative shows improved drug-likeness and potent inhibition of cardiac fibrosis by targeting E2F1, disrupting its pro-fibrotic function, restoring MTA3 expression and halting fibrosis progression. This advances emodin derivative's potential as a clinical therapy for cardiac fibrosis and provides insights into its anti-fibrotic mechanisms.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic EP4 receptor agonist and Arginase-1 therapy in a murine model of chronic asthma and influenza virus-induced asthma exacerbation.","authors":"Tim Lange, Tobias Brunn, Charlotte Vetter, Konstantin Bloch, Nora Vedder, Chiel van Geffen, Philipp Gercke, Saeed Kolahian","doi":"10.1111/bph.17473","DOIUrl":"https://doi.org/10.1111/bph.17473","url":null,"abstract":"<p><strong>Background and purpose: </strong>Myeloid-derived suppressor cells (MDSCs) play important roles in the pathogenesis of asthma. Recent studies demonstrate that their function can be modulated by different pharmacological approaches. In this study, we focussed on the effects of systemically administered prostaglandin EP₄ receptor agonist L-902,688 and pegylated human Arginase-1 on MDSCs in a murine model of chronic asthma and asthma exacerbation.</p><p><strong>Experimental approach: </strong>BALB/c mice were challenged with house dust mite (HDM) over a period of 5 weeks, establishing a chronic asthma phenotype. To induce asthma exacerbation, mice were infected with Influenza Virus H1N1 A/Puerto Rico/8/1934. In vivo lung function, lung inflammatory features, number and suppressive activity of MDSCs, number of different T cell subsets in lung and spleen and viral titer in the bronchoalveolar lavage fluid (BALF) were assessed.</p><p><strong>Key results: </strong>In asthmatic mice, treatment with the EP₄ receptor agonist or Arginase-1 significantly reduced the number of eosinophils in the BALF. Both treatments improved lung function and ameliorated airway hyperresponsiveness (AHR) in asthma exacerbation. The number and suppressive activity of MDSCs in the lung were increased by virus-induced asthma exacerbation.</p><p><strong>Conclusion and implications: </strong>We found beneficial effects of systemic EP₄ receptor agonist and Arginase-1 therapy in a murine model of chronic asthma and influenza virus-induced asthma exacerbation. Our findings highlight the potential efficacy of EP₄ receptor agonists, Arginase-1, and MDSCs, as novel therapeutic approaches in asthma and asthma exacerbation.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vestibular modulation by stimulant derivatives in a pentameric ligand-gated ion channel.","authors":"Emelia Karlsson, Olivia Andén, Chen Fan, Zaineb Fourati, Ahmed Haouz, Yuxuan Zhuang, Rebecca J Howard, Marc Delarue, Erik Lindahl","doi":"10.1111/bph.70011","DOIUrl":"https://doi.org/10.1111/bph.70011","url":null,"abstract":"<p><strong>Background and purpose: </strong>Allosteric modulation of pentameric ligand-gated ion channels (pLGICs) are critical for the action of neurotransmitters and many psychoactive drugs. However, details of their modulatory mechanisms remain unclear, especially beyond the orthosteric neurotransmitter-binding sites. The recently reported prokaryotic symbiont of Tevnia jerichonana ligand-gated ion channel (sTeLIC), a pH-gated homologue of eukaryotic receptors in the pLGIC family, is thought to be modulated by aromatic compounds via a relatively uncharacterised modulatory site in the extracellular vestibule.</p><p><strong>Experimental approach: </strong>We have characterised the effects of psychostimulant derivatives on sTeLIC using two-electrode voltage-clamp electrophysiology in the presence and absence of engineered mutations, and determined X-ray and cryo-EM structures of the channel in both closed and open states.</p><p><strong>Key results: </strong>We have shown that sTeLIC is sensitive to potentiation by several amphiphilic compounds, which preferentially bind to a vestibular pocket in the contracted open-state extracellular domain.</p><p><strong>Conclusions and implications: </strong>This work provides a detailed structure-function mechanism for allosteric potentiation via a noncanonical ligand site, with potential conservation of the eukaryotic pentameric ligand-gated ion channels.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}