British Journal of Pharmacology最新文献

{"title":"AMP-activated protein kinase in the amygdala and hippocampus contributes to enhanced fear memory in diabetic mice","authors":"Aimi Yamagishi, Naomi Yonemochi, Ai Kimura, Fumiko Takenoya, Seiji Shioda, John L. Waddington, Hiroko Ikeda","doi":"10.1111/bph.17338","DOIUrl":"https://doi.org/10.1111/bph.17338","url":null,"abstract":"Diabetic patients have an increased risk of psychiatric disorders. Because hyperglycaemia increases L-lactate in the brain and L-lactate inhibits AMP-activated protein kinase (AMPK), this study investigated the role of L-lactate and AMPK in strengthened fear memory, a model for human psychiatric disorders, in diabetic mice.","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":"142266040","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":"Mitigating off-target effects of small RNAs: conventional approaches, network theory and artificial intelligence","authors":"Zoltán Bereczki, Bettina Benczik, Olivér M. Balogh, Szandra Marton, Eszter Puhl, Mátyás Pétervári, Máté Váczy-Földi, Zsolt Tamás Papp, András Makkos, Kimberly Glass, Fabian Locquet, Gerhild Euler, Rainer Schulz, Péter Ferdinandy, Bence Ágg","doi":"10.1111/bph.17302","DOIUrl":"https://doi.org/10.1111/bph.17302","url":null,"abstract":"Three types of highly promising small RNA therapeutics, namely, small interfering RNAs (siRNAs), microRNAs (miRNAs) and the RNA subtype of antisense oligonucleotides (ASOs), offer advantages over small-molecule drugs. These small RNAs can target any gene product, opening up new avenues of effective and safe therapeutic approaches for a wide range of diseases. In preclinical research, synthetic small RNAs play an essential role in the investigation of physiological and pathological pathways as silencers of specific genes, facilitating discovery and validation of drug targets in different conditions. Off-target effects of small RNAs, however, could make it difficult to interpret experimental results in the preclinical phase and may contribute to adverse events of small RNA therapeutics. Out of the two major types of off-target effects we focused on the hybridization-dependent, especially on the miRNA-like off-target effects. Our main aim was to discuss several approaches, including sequence design, chemical modifications and target prediction, to reduce hybridization-dependent off-target effects that should be considered even at the early development phase of small RNA therapy. Because there is no standard way of predicting hybridization-dependent off-target effects, this review provides an overview of all major state-of-the-art computational methods and proposes new approaches, such as the possible inclusion of network theory and artificial intelligence (AI) in the prediction workflows. Case studies and a concise survey of experimental methods for validating <i>in silico</i> predictions are also presented. These methods could contribute to interpret experimental results, to minimize off-target effects and hopefully to avoid off-target-related adverse events of small RNA therapeutics.","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":"142266036","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":"Ulinastatin attenuated cardiac ischaemia/reperfusion injury by suppressing activation of the tissue kallikrein-kinin system","authors":"Qin Zhang, Hang Ruan, Xiaochuan Wang, Ailin Luo, Xiao Ran","doi":"10.1111/bph.16477","DOIUrl":"https://doi.org/10.1111/bph.16477","url":null,"abstract":"Ulinastatin has beneficial effects in patients undergoing coronary artery bypass grafting (CABG) surgery due to its anti-inflammatory properties, but the underlying mechanism remains unclear.","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":"142266208","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":"Comparative analysis of formyl peptide receptor 1 and formyl peptide receptor 2 reveals shared and preserved signalling profiles","authors":"Denise Pajonczyk, Merle F. Sternschulte, Oliver Soehnlein, Marcel Bermudez, Carsten A. Raabe, Ursula Rescher","doi":"10.1111/bph.17334","DOIUrl":"https://doi.org/10.1111/bph.17334","url":null,"abstract":"The pattern recognition receptors, formyl peptide receptors, FPR1 and FPR2, are G protein-coupled receptors that recognize many different pathogen- and host-derived ligands. While FPR1 conveys pro-inflammatory signals, FPR2 is linked with pro-resolving outcomes. To analyse how the two very similar FPRs exert opposite effects in modulating inflammatory responses despite their high homology, a shared expression profile on immune cells and an overlapping ligand repertoire, we questioned whether the signalling profile differs between these two receptors.","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":"142266039","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":"Immune regulatory and anti-resorptive activities of tanshinone IIA sulfonate attenuates rheumatoid arthritis in mice","authors":"Preety Panwar, Pierre Marie Andrault, Dipon Saha, Dieter Brömme","doi":"10.1111/bph.17312","DOIUrl":"https://doi.org/10.1111/bph.17312","url":null,"abstract":"Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and painful joint destruction. Current treatments are helpful in RA remission, but strong immunosuppressive activity and patient resistance are clinical issues. This study explores a dual-action inhibitor, possessing both anti-inflammatory and anti-resorptive properties, as a novel treatment for RA.","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":"142266037","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":"Cardioprotective microRNAs (protectomiRs) in a pig model of acute myocardial infarction and cardioprotection by ischaemic conditioning: MiR-450a","authors":"Regina N. Nagy, András Makkos, Tamás Baranyai, Zoltán Giricz, Márta Szabó, Bernadett Kravcsenko-Kiss, Zoltán Bereczki, Bence Ágg, László G. Puskás, Nóra Faragó, Rainer Schulz, Mariann Gyöngyösi, Dominika Lukovic, Zoltán V. Varga, Anikó Görbe, Péter Ferdinandy","doi":"10.1111/bph.17313","DOIUrl":"https://doi.org/10.1111/bph.17313","url":null,"abstract":"Cardioprotective miRNAs (protectomiRs) are promising therapeutic tools. Here, we aimed to identify protectomiRs in a translational porcine model of acute myocardial infarction (AMI) and to validate their cardiocytoprotective effect.","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":"142266038","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":"Advances in binding kinetics and mechanistic PK/PD modelling","authors":"Bharath Srinivasan","doi":"10.1111/bph.17340","DOIUrl":"10.1111/bph.17340","url":null,"abstract":"&lt;p&gt;It has been a year since we held the ‘Binding Kinetics and Mechanistic PK/PD modelling’ meeting in Cambridge. The event was a roaring success with some of the best mechanistic enzymologists and PK/PD modellers attending and presenting their work at the event. Now, it gives me immense pleasure to present to you these three reviews summarising the advances discussed at the meeting, covering the highlights and nuances of how binding kinetics has played a major role in redefining the quantification of drug–target interactions and PK/PD modelling.&lt;/p&gt;&lt;p&gt;For small-molecule drug discovery, binding kinetics is critical in understanding how the matrix events of small-molecule association, small-molecule dissociation (and the attendant residence time), small-molecule half-life in systemic circulation (and, as an extension, at the site of action) and the half-life of the protein target coalesce together to give us the therapeutic index and window. The latter parameters are essential to appreciate efficacy in light of toxicity (the latter could be on-target and/or off-target dependent on the affinity and kinetics of the small molecule's interaction with the target of interest versus other proteins). As we transition from small molecules to large molecules and from predominantly reversible equilibrium inhibition to other modalities such as non-equilibrium irreversible and degradation, these tenets are becoming all the more relevant in quantifying efficacy weighed against potential toxicity. The correct assessment of the concentration of a small molecule at its site of action is very important. This would depend on (1) intravascular versus extravascular administration with potential first pass depletion, (2) deciding on the strategy of administration as a single bolus dose versus infusion, (3) measuring the outcomes of diuretic effects in clearing the small molecule from systemic circulation as a function of dose concentration, (4) dose frequency and dosing mode and (5) assessing the effects of type I and type II mechanisms in metabolizing the small molecule with potential excretion; and are factors that have been traditionally considered very critical in understanding the concentration and, thus, efficacy of the action of small molecules and have been historically classed as aspects of pharmacokinetic modelling. Likewise, the equilibrium measure of affinity, signifying the potency of the small molecule's interaction with its target of interest, has been quantified by pharmacodynamic measures. These measures, in spite of their limitation in understanding the time evolution of the small molecule's interaction with their target of interest, have supported decision making for small-molecule drug discovery cascades.&lt;/p&gt;&lt;p&gt;However, with emergent modalities such as PROTAC (where a bivalent ligand recruits the protein of interest to an E3 ligase resulting in its ubiquitination and subsequent degradation), molecular glues (where a small molecule facilitates protein","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17340","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266041","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":"Network medicine and systems pharmacology approaches to predicting adverse drug effects","authors":"Alessio Funari, Giulia Fiscon, Paola Paci","doi":"10.1111/bph.17330","DOIUrl":"https://doi.org/10.1111/bph.17330","url":null,"abstract":"Identifying and understanding the relationships between drug intake and adverse effects that can occur due to inadvertent molecular interactions between drugs and targets is a difficult task, especially considering the numerous variables that can influence the onset of such events. The ability to predict these side effects in advance would help physicians develop strategies to avoid or counteract them. In this article, we review the main computational methods for predicting side effects caused by drug molecules, highlighting their performance, limitations and application cases. Furthermore, we provide an overall view of resources, such as databases and tools, useful for building side effect prediction analyses.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219162","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":"Progress on the development of Class A GPCR‐biased ligands","authors":"Paula Morales, Magdalena M. Scharf, Marcel Bermudez, Attila Egyed, Rafael Franco, Olivia K. Hansen, Nadine Jagerovic, Jan Jakubík, György M. Keserű, Dóra Judit Kiss, Pawel Kozielewicz, Olav Larsen, Maria Majellaro, Ana Mallo‐Abreu, Gemma Navarro, Rubén Prieto‐Díaz, Mette M. Rosenkilde, Eddy Sotelo, Holger Stark, Tobias Werner, Laura M. Wingler","doi":"10.1111/bph.17301","DOIUrl":"https://doi.org/10.1111/bph.17301","url":null,"abstract":"Class A G protein‐coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR‐biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219163","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":"An adenosinergic positive feedback loop extends pharmacological cardioprotection duration","authors":"Gerald Wölkart,&nbsp;Simon Gissing,&nbsp;Heike Stessel,&nbsp;Erin K. Fassett,&nbsp;Burkhard Klösch,&nbsp;Robert W. Greene,&nbsp;Bernd Mayer,&nbsp;John T. Fassett","doi":"10.1111/bph.17331","DOIUrl":"10.1111/bph.17331","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Adenosine receptor activation induces delayed, sustained cardioprotection against ischaemia–reperfusion (IR) injury (24–72 h), but the mechanisms underlying extended cardioprotection duration remain unresolved. We hypothesized that a positive feedback loop involving adenosine receptor-induced proteasomal degradation of adenosine kinase (ADK) and decreased myocardial adenosine metabolism extends the duration of cardioprotection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Mice were administered an ADK inhibitor, ABT-702, to induce endogenous adenosine signalling. Cardiac ADK protein and mRNA levels were analysed 24–120 h later. Theophylline or bortezomib was administered 24 h after ABT-702 to examine the late roles of adenosine receptors or proteasomal activity, respectively, in ADK expression and cardioprotection at 72 h. Coronary flow and IR tolerance were analysed by Langendorff technique. The potential for continuous adenosinergic cardioprotection was examined using heterozygous, cardiac-specific ADK KO (cADK^+/−) mice. Cardiac ADK expression was also examined after A₁ or A₃ receptor agonist, phenylephrine, lipopolysaccharide or sildenafil administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key results</h3>\u0000 \u0000 <p>ABT-702 treatment decreased ADK protein content and provided cardioprotection from 24 to 72 h. ADK mRNA upregulation restored ADK protein after 96–120 h. Adenosine receptor or proteasome inhibition at 24 h reversed ABT-702-induced ADK protein deficit and cardioprotection at 72 h. cADK^+/− hearts exhibited continuous cardioprotection. Diverse preconditioning agents also diminished cardiac ADK protein expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>A positive feedback loop driven by adenosine receptor-induced ADK degradation and renewed adenosine signalling extends the duration of cardioprotection by ABT-702 and possibly other preconditioning agents. The therapeutic potential of continuous adenosinergic cardioprotection is demonstrated in cADK^+/− hearts.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17331","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219164","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}