British Journal of Pharmacology最新文献

{"title":"Preface to the Review Series Neuropharmacology of addiction","authors":"Andrew J. Lawrence, Christopher J. Langmead","doi":"10.1111/bph.17339","DOIUrl":"10.1111/bph.17339","url":null,"abstract":"<p>Alcohol use disorder (AUD) is the third leading cause of preventable deaths in the United States (White et al., <span>2020</span>), costing the US economy around $250 billion per annum (Sacks et al., <span>2015</span>). Despite this, data from the 2022 National Survey on Drug Use and Health suggest that only 7.6% of people aged 12 and over with an AUD received treatment for this condition within the last year (SAMSHA, <span>2022</span>). At present, there are only three drugs approved by the FDA specifically for the treatment of AUD, namely, disulfiram, naltrexone (both oral and long-acting injectable) and acamprosate; with nalmefene also being approved by the European Medicines Agency. While some clients find benefit from the available treatment options, none of them are universally effective and new, mechanism-based treatments are sorely needed.</p><p>In this context, Walker and colleagues review the growing evidence suggesting that muscarinic M<sub>4</sub> receptors may represent a novel therapeutic target for AUD (Walker et al., <span>2024</span>). Indeed, evidence aligns from human post-mortem data showing a down-regulation of M<sub>4</sub> mRNA and protein in the putamen from people with AUD, with analogous findings in rodent dorsolateral striatum (Walker et al., <span>2020</span>). Moreover, targeting M<sub>4</sub> receptors with a tool molecule positive allosteric modulator (PAM) reduced alcohol self-administration and seeking in rats (Walker et al., <span>2020</span>; Walker et al., <span>2021</span>), while M<sub>4</sub> knockout mice show elevated voluntary alcohol intake (de la Cour et al., <span>2015</span>). Of note, several pharmaceutical companies are actively pursuing compounds that are either M<sub>4</sub> receptor agonists or PAMs for the indication of schizophrenia. One example is KarXT, a drug that has already reported positive Phase III results (Kaul et al., <span>2024</span>) and is likely to be FDA approved as a novel treatment for schizophrenia. Such approval would open up the way for repurposing KarXT into the AUD space relatively rapidly—something that would certainly appear worth testing.</p><p>The striatum therefore appears to be one of the key loci where M<sub>4</sub> receptors are impacted by alcohol use. Another article in this issue canvasses a more general role of GPCRs in the modulation of striatal dopamine release and how this pertains to the mechanism(s) of action of psychoactive drugs (Littlepage-Saunders et al., <span>2024</span>). Dopamine transmission within the basal ganglia is a common target for many drugs of abuse. The team from the Johnson lab review the evidence surrounding modulation of striatal dopamine release, including that mediated by drugs of abuse, by a range of GPCRs such as dopamine receptors, metabotropic glutamate receptors, cannabinoid, muscarinic and opioid receptors. They also explore the implications of co-release of dopamine with other transmitters, such as glutamate and GABA and ","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17339","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating the beneficial impact of exercise on chronic obstructive pulmonary disease and its comorbidities: Integrating proteomic and immunological insights.","authors":"Xishuai Wang, Cong Liu, Ruining Liang, Yuehui Zhou, Xiliang Kong, Weichao Wang, Hongwei Wang, Lunan Zhao, Weina Niu, Chao Yi, Fugao Jiang","doi":"10.1111/bph.17328","DOIUrl":"https://doi.org/10.1111/bph.17328","url":null,"abstract":"<p><strong>Background and purpose: </strong>Physical activity is an effective therapeutic protocol for treating chronic obstructive pulmonary disease (COPD). However, the mechanisms underlying the benefits of physical activity in COPD are not fully elucidated.</p><p><strong>Experimental approach: </strong>In a mouse model of COPD, analysis of biological markers and lung proteomics identified the molecular pathways through which exercise ameliorates COPD.</p><p><strong>Key results: </strong>Exercise improved pulmonary function, emphysema, small airway disease, pulmonary inflammation, glucose metabolic dysregulation, and insulin resistance in COPD mice. Proteomic analysis revealed 430 differentially expressed proteins (DEPs) between the COPD and COPD + Exercise (COPD + Ex) groups. GO analysis indicated that the enriched pathways were predominantly related to the immune response, inflammatory processes, insulin secretion, and glucose metabolic processes. GO analysis revealed IL-33 as a crucial target for the exercise-related amelioration of COPD. KEGG analysis showed that DEPs were significantly enriched in primary immunodeficiency, the intestinal immune network for IgA production, and the NF-κB signalling pathway. Exercise inhibited NF-κB activation by suppressing the CD14/TLR4/MyD88 and TNF-α/TNF-R1/TRAF2/5 pathways in COPD mice. Exercise inhibited expression of BCR, IgM, IgD, IgG, IgE, and IgA by suppressing B-cell receptor signalling. Exercise attenuated glucose metabolic dysregulation and insulin resistance through the suppression of proinflammatory mediators, including MHC I, MHC II, TNF-α, IFN-γ, and IL-1β, while concurrently increasing insulin expression. The qRT-PCR results were consistent with the proteomic results.</p><p><strong>Conclusion and implications: </strong>In a mouse model, exercise improved COPD and its metabolic comorbidities through immune system regulation and inflammation suppression, offering insights into potential therapeutic targets.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342053","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":"Contribution of hypothalamic orexin (hypocretin) circuits to pathologies of motivation","authors":"Aida Mohammadkhani,&nbsp;Caitlin Mitchell,&nbsp;Morgan H. James,&nbsp;Stephanie L. Borgland,&nbsp;Christopher V. Dayas","doi":"10.1111/bph.17325","DOIUrl":"10.1111/bph.17325","url":null,"abstract":"<p>The orexin (also known as hypocretin) system, consisting of neuropeptides orexin-A and orexin-B, was discovered over 25 years ago and was immediately identified as a central regulator of sleep and wakefulness. These peptides interact with two G-protein coupled receptors, orexin 1 (OX₁) and orexin 2 (OX₂) receptors which are capable of coupling to all heterotrimeric G-protein subfamilies, but primarily transduce increases in calcium signalling. Orexin neurons are regulated by a variety of transmitter systems and environmental stimuli that signal reward availability, including food and drug related cues. Orexin neurons are also activated by anticipation, stress, cues predicting motivationally relevant information, including those predicting drugs of abuse, and engage neuromodulatory systems, including dopamine neurons of the ventral tegmental area (VTA) to respond to these signals. As such, orexin neurons have been characterized as motivational activators that coordinate a range of functions, including feeding and arousal, that allow the individual to respond to motivationally relevant information, critical for survival. This review focuses on the role of orexins in appetitive motivation and highlights a role for these neuropeptides in pathologies characterized by inappropriately high levels of motivated arousal (overeating, anxiety and substance use disorders) versus those in which motivation is impaired (depression).</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11458361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oroxylin A attenuates psoriasiform skin inflammation by direct targeting p62 (sequestosome 1) via suppressing M1 macrophage polarization.","authors":"Yuxiang Ma, Yunyao Liu, You Zhong, Xiangzheng Li, Yujiao Xu, Leyi Chen, Litong Gong, He Huang, Xu Chen, Yuan He, Lei Qiang","doi":"10.1111/bph.17349","DOIUrl":"https://doi.org/10.1111/bph.17349","url":null,"abstract":"<p><strong>Background and purpose: </strong>Psoriasis results from the interplay of innate and adaptive immunity in the skin. Oroxylin A (OA) has shown anti-inflammatory effects in various disorders. This study explores oroxylin A potential in treating psoriasis, particularly its impact on type I macrophage (Mφ1) polarization.</p><p><strong>Experimental approach: </strong>Oroxylin A-mediated therapeutic effects were evaluated using imiquimod-induced or IL-23-injected psoriatic mice models, followed by proteomics assays to predict potential signalling and targeting proteins. Immunofluorescence and immunoblot assays verified that oroxylin A suppresses NF-kB signalling in M1 macrophages. Co-immunoprecipitation and microscale thermophoresis (MST) assays further demonstrated that p62 (sequestosome 1) is the target protein for oroxylin A in macrophages. Oroxylin A-p62-mediated suppression of psoriasis was validated in an imiquimod-induced p62 conditional knockout (cKO) mice model.</p><p><strong>Key results: </strong>Oroxylin A demonstrated therapeutic efficacy in murine models induced by imiquimod or IL-23 by attenuating cutaneous inflammation and mitigating Mφ1 polarization via NF-κB signalling. Proteomics analysis suggested SQSTM1/p62 as a key target, confirmed to interact directly with oroxylin A. Oroxylin A disrupted the p62-PKCζ interaction by binding to PB1 domain of p62. Its anti-inflammatory effects were significantly reduced in macrophages from p62 cKO mice compared to the wild-type (WT) mice in psoriasis model, supporting oroxylin A role in suppressing Mφ1 polarization through its interaction with p62.</p><p><strong>Conclusion and implications: </strong>Our findings demonstrated oroxylin A suppressed psoriasiform skin inflammation in mouse models by blocking the PKCζ-p62 interaction, subsequently inhibiting the activation of NF-κB p65 phosphorylation in macrophages.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307083","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":"Therapeutic and pharmacological applications of extracellular vesicles and lipoproteins","authors":"Krisztina Németh,&nbsp;Brachyahu M. Kestecher,&nbsp;Sayam Ghosal,&nbsp;Bernadett R. Bodnár,&nbsp;Ágnes Kittel,&nbsp;Szabolcs Hambalkó,&nbsp;Csenger Kovácsházi,&nbsp;Zoltán Giricz,&nbsp;Péter Ferdinandy,&nbsp;Xabier Osteikoetxea,&nbsp;Ralph Burkhardt,&nbsp;Edit I. Buzas,&nbsp;Evelyn Orsó","doi":"10.1111/bph.17336","DOIUrl":"10.1111/bph.17336","url":null,"abstract":"<p>In recent years, various approaches have been undertaken to eliminate lipoproteins co-isolated with extracellular vesicles, as they were initially regarded as contaminating entities. However, novel discoveries are reshaping our perspective. In body fluids, these distinct particles not only co-exist, but also interactions between them are likely to occur. Extracellular vesicles and lipoproteins can associate with each other, share cargo, influence each other's functions, and jointly have a role in the pathomechanisms of diseases. Additionally, their association carries important implications for therapeutic and pharmacological aspects of lipid-lowering strategies. Extracellular vesicles and lipoprotein particles may have roles in the elimination of each other from the circulation. The objective of this minireview is to delve into these aspects. Here, we show that under certain physiological and pathological conditions, extracellular vesicles and lipoproteins are ‘partners’ rather than ‘strangers’ or ‘rivals’.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17336","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetrabenazine, a vesicular monoamine transporter 2 inhibitor, inhibits vesicular storage capacity and release of monoamine transmitters in mouse brain tissue.","authors":"Pál Tod, Anita Varga, Viktor Román, Balázs Lendvai, Roland Pálkovács, Beáta Sperlágh, E Sylvester Vizi","doi":"10.1111/bph.17348","DOIUrl":"https://doi.org/10.1111/bph.17348","url":null,"abstract":"<p><strong>Background and purpose: </strong>Tetrabenazine (TBZ), used for treating hyperkinetic disorders, inhibits vesicular monoamine transporter-2 (VMAT-2), which sequesters monoamines into vesicles for exocytosis. However, our knowledge of the effect of TBZ on monoaminergic transmission is limited. Herein, we provide neurochemical evidence regarding the effect of VMAT-2 inhibition on vesicular neurotransmitter release from the prefrontal cortex (PFC) and striatum (STR) (brain regions involved in characteristic TBZ treatment side effects). The interaction between TBZ and MDMA was also assessed regarding motor behaviour in mice.</p><p><strong>Experimental approach: </strong>Vesicular storage capacity and release of [³H]-noradrenaline ([³H]-NA), [³H]-dopamine ([³H]-DA), [³H]-serotonin ([³H]-5-HT), and [³H]-acetylcholine ([³H]-ACh) was studied in mouse PFC and STR ex vivo slice preparations using electrical field stimulation. Additionally, locomotor activity was assessed in vehicle-treated mice and compared with that of MDMA, TBZ, and co-administered animals (n = 6) using the LABORAS system.</p><p><strong>Key results: </strong>TBZ lowered the storage capacity and inhibited the vesicular release of [³H]-NA and [³H]-DA from the PFC, and [³H]-DA and [³H]-5-HT from the STR in a concentration-dependent manner. Unlike vesamicol (vesicular ACh uptake inhibitor), TBZ failed to inhibit the vesicular release of [³H]-ACh from the PFC. When the vesicular storage of the investigated monoamines was inhibited by TBZ in the PFC and STR, MDMA induced the release of transmitters through transporter reversal; MDMA dose dependently increased locomotor activity in vivo.</p><p><strong>Conclusion and implications: </strong>Our observations provide neurochemical evidence explaining the mechanism of VMAT-2 inhibitors in the brain and support the involvement of dopaminergic and noradrenergic transmission in hyperkinetic movement disorders.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280537","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":"Contribution of T-type calcium channel isoforms to cold and mechanical sensitivity in naïve and oxaliplatin-treated mice of both sexes","authors":"Flavia T. T. Antunes, Maria A. Gandini, Vinicius M. Gadotti, Nara Lins Meira Quintão, José Roberto Santin, Ivana A. Souza, Laurence S. David, Terrance P. Snutch, Michael Hildebrand, Gerald W. Zamponi","doi":"10.1111/bph.17337","DOIUrl":"https://doi.org/10.1111/bph.17337","url":null,"abstract":"The chemotherapy agent oxaliplatin can give rise to oxaliplatin-induced peripheral neuropathy (OIPN). Here, we investigated whether T-type calcium channels (Ca_v3) contribute to OIPN.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266035","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":"Vortioxetine reduces the development of pain-related behaviour in a knee osteoarthritis model in rats: Involvement of nerve growth factor (NGF) down-regulation","authors":"Maja Tomić, Katarina Nastić, Miroslav Dinić, Emilija Brdarić, Jelena Kotur-Stevuljević, Uroš Pecikoza, David Pavićević, Ana Micov, Danijela Milenković, Aleksandar Jovanović, Radica Stepanović-Petrović","doi":"10.1111/bph.17342","DOIUrl":"https://doi.org/10.1111/bph.17342","url":null,"abstract":"Vortioxetine, a multimodal-acting antidepressant, has recently shown analgesic properties. We aimed to investigate its prophylactic effect in the osteoarthritis (OA) model and gain insights into the underlying molecular mechanisms. Duloxetine was studied as a reference.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266033","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":"Selective modulation of epileptic tissue by an adenosine A3 receptor-activating drug","authors":"Anwesha Ghosh, Leonor Ribeiro-Rodrigues, Gabriele Ruffolo, Veronica Alfano, Cátia Domingos, Nádia Rei, Dilip K. Tosh, Diogo M. Rombo, Tatiana P. Morais, Cláudia A. Valente, Sara Xapelli, Beatriz Bordadágua, Alexandre Rainha-Campos, Carla Bentes, Eleonora Aronica, Maria José Diógenes, Sandra H. Vaz, Joaquim A. Ribeiro, Eleonora Palma, Kenneth A. Jacobson, Ana M. Sebastião","doi":"10.1111/bph.17319","DOIUrl":"https://doi.org/10.1111/bph.17319","url":null,"abstract":"Adenosine, through the A₁ receptor (A₁R), is an endogenous anticonvulsant. The development of adenosine receptor agonists as antiseizure medications has been hampered by their cardiac side effects. A moderately A₁R-selective agonist, MRS5474, has been reported to suppress seizures without considerable cardiac action. Hypothesizing that this drug could act through other than A₁R and/or through a disease-specific mechanism, we assessed the effect of MRS5474 on the hippocampus.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266034","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":"Translational modelling to predict human pharmacokinetics and pharmacodynamics of a Bruton's tyrosine kinase‐targeted protein degrader BGB‐16673","authors":"Yue Wu, Bernd Meibohm, Taichang Zhang, Xinfeng Hou, Haitao Wang, Xiaona Sun, Ming Jiang, Bo Zhang, Wenjing Zhang, Ye Liu, Wei Jin, Fan Wang","doi":"10.1111/bph.17332","DOIUrl":"https://doi.org/10.1111/bph.17332","url":null,"abstract":"Background and PurposeBifunctional small molecule degraders, which link the target protein with E3 ubiquitin ligase, could lead to the efficient degradation of the target protein. BGB‐16673 is a Bruton's tyrosine kinase (BTK) degrader. A translational PK/PD modelling approach was used to predict the human BTK degradation of BGB‐16673 from preclinical in vitro and in vivo data.Experimental ApproachA simplified mechanistic PK/PD model was used to establish the correlation between the in vitro and in vivo BTK degradation by BGB‐16673 in a mouse model. Human and mouse species differences were compared using the parameters generated from in vitro human or mouse blood, and human or mouse serum spiked TMD‐8 cells. Human PD was then predicted using the simplified mechanistic PK/PD model.Key ResultsBGB‐16673 showed potent BTK degradation in mouse whole blood, human whole blood, and TMD‐8 tumour cells in vitro. Furthermore, BGB‐16673 showed BTK degradation in a murine TMD‐8 xenograft model in vivo. The PK/PD model predicted human PD and the observed BTK degradation in clinical studies both showed robust BTK degradation in blood and tumour at clinical dose range.Conclusion and ImplicationsThe presented simplified mechanistic model with reduced number of model parameters is practically easier to be applied to research projects compared with the full mechanistic model. It can be used as a tool to better understand the PK/PD behaviour for targeted protein degraders and increase the confidence when moving to the clinical stage.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266042","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}