British Journal of Pharmacology最新文献

{"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":"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":" ","pages":"5133-5150"},"PeriodicalIF":6.8,"publicationDate":"2024-12-01","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":"Targeting the NLRP3 inflammasome signalling for the management of atrial fibrillation.","authors":"Alisha Niskala, Jordi Heijman, Dobromir Dobrev, Thomas Jespersen, Arnela Saljic","doi":"10.1111/bph.16470","DOIUrl":"10.1111/bph.16470","url":null,"abstract":"<p><p>Inflammatory signalling via the nod-like receptor (NLR) family pyrin domain-containing protein-3 (NLRP3) inflammasome has recently been implicated in the pathophysiology of atrial fibrillation (AF). However, the precise role of the NLRP3 inflammasome in various cardiac cell types is poorly understood. Targeting components or products of the inflammasome and preventing their proinflammatory consequences may constitute novel therapeutic treatment strategies for AF. In this review, we summarise the current understanding of the role of the inflammasome in AF pathogenesis. We first review the NLRP3 inflammasome pathway and inflammatory signalling in cardiomyocytes, (myo)fibroblasts and immune cells, such as neutrophils, macrophages and monocytes. Because numerous compounds targeting NLRP3 signalling are currently in preclinical development, or undergoing clinical evaluation for other indications than AF, we subsequently review known therapeutics, such as colchicine and canakinumab, targeting the NLRP3 inflammasome and evaluate their potential for treating AF.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":"4939-4957"},"PeriodicalIF":6.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320624","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":"Evidence generation throughout paediatric medicines life cycle: findings from collaborative work between European Medicines Agency (EMA) and EUnetHTA on use of extrapolation.","authors":"Dominik Karres, María José Pino-Barrio, Sylvie Benchetrit, Norbert Benda, Pierre Cochat, Sara Galluzzo, Alejandro García-Solís, Sara Gonzalez, Roberto de Lisa, David Khan, Rita Lankester, Frederike Lentz, Pilar Angustias Martínez-Ortega, Simona Montilla, Daniel R Morales, Flora Musuamba Tshinanu, Sonia Pulido Sánchez, Ana Rossignoli Montero, Sabine Scherer, Andrew Thomson, Belén Torres Garrido, Denise Umuhire, Siri Wang, Ralph Bax, Niklas Hedberg","doi":"10.1111/bph.17396","DOIUrl":"https://doi.org/10.1111/bph.17396","url":null,"abstract":"<p><p>Drug development for children presents unique challenges and is highly regulated. Novel approaches, such as the use of extrapolation to address, for example, the need to avoid unethical studies, whilst supporting robust evidence generation have been developed in support of benefit/risk considerations by regulatory authorities. This is only one step in the decision-making process towards access, which in Europe also includes health technology assessment (HTA) bodies. Discussions related to evidentiary requirements in small populations using scientific evidence transfer have been identified as a priority action by European Medicines Agency/European Network for Health Technology Assessment 21 (EMA/EUnetHTA 21). We describe the outcome of this work and reflect on the discussions that had taken place on how to leverage prior knowledge through identifying and addressing uncertainties during life cycle management to support regulatory and HTA decision-making. Using examples, we explore the range of applications for evidence generation and offer regulatory and HTA insights on key design considerations for producing better evidence, reflecting our shared ambition. Early interactions with all respective stakeholders, particularly between regulators and HTA bodies are key to optimise data generation and utility in children. In Europe, the HTA regulation will offer opportunities for collaborations, which are important for all development efforts. We collaboratively explored the unique specific challenges relating to paediatric drug development, ethically and in its ability to leverage prior knowledge, as exemplified using extrapolation. Learnings from these offer opportunities to further develop methodology on how to leverage uncertainties across a product's life cycle for small populations generally.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686190","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":"EDITORIAL for BJP themed issue \"noncoding RNA therapeutics\".","authors":"Yvan Devaux, Serena Zacchigna, Rainer Schulz","doi":"10.1111/bph.17365","DOIUrl":"https://doi.org/10.1111/bph.17365","url":null,"abstract":"","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686188","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":"Plasma miR-1-3p levels predict severity in hospitalized COVID-19 patients.","authors":"Paola Di Pietro, Angela Carmelita Abate, Carmine Izzo, Anna Laura Toni, Maria Rosaria Rusciano, Veronica Folliero, Federica Dell'Annunziata, Giovanni Granata, Valeria Visco, Benedetta Maria Motta, Alfonso Campanile, Carolina Vitale, Valeria Prete, Cristina Gatto, Giuliana Scarpati, Paolo Poggio, Gennaro Galasso, Pasquale Pagliano, Ornella Piazza, Gaetano Santulli, Gianluigi Franci, Albino Carrizzo, Carmine Vecchione, Michele Ciccarelli","doi":"10.1111/bph.17392","DOIUrl":"https://doi.org/10.1111/bph.17392","url":null,"abstract":"","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686062","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":"Disruption of survivin protein expression by treatment with YM155 accelerates the resolution of neutrophilic inflammation.","authors":"Débora de Oliveira Fernandes, Jessica Rayssa Machado, Vinicius Amorim Beltrami, Anna Clara Paiva Menezes Dos Santos, Celso Martins Queiroz-Junior, Juliana Priscila Vago, Frederico Marianetti Soriani, Flávio Almeida Amaral, Mauro Martins Teixeira, Franciel Batista Felix, Vanessa Pinho","doi":"10.1111/bph.17375","DOIUrl":"https://doi.org/10.1111/bph.17375","url":null,"abstract":"<p><strong>Background and purpose: </strong>Prolonged survival of neutrophils is essential for determining the progression and severity of inflammatory and immune-mediated disorders, including gouty arthritis. Survivin, an anti-apoptotic molecule, has been described as a regulator of cell survival. This study aims to examine the effects of YM155 treatment, a survivin selective suppressant, in maintaining neutrophil survival in vitro and in vivo experimental settings of neutrophilic inflammation.</p><p><strong>Experimental approach: </strong>BALB/c mice were injected with monosodium urate (MSU) crystals and treated with YM155 (intra-articularly) at the peak of inflammatory response. Leukocyte recruitment, apoptosis neutrophil and efferocytosis were determined by knee joint wash cell morphology counting and flow cytometry. Resolution interval (Ri) was quantified by neutrophil infiltration, monitoring the amplitude and duration of the inflammation. Cytokine production was measured by ELISA. Mechanical hypernociception was assessed using an electronic von Frey aesthesiometer. Efferocytosis was evaluated in zymosan-induced neutrophilic peritonitis. Survivin and cleaved caspase-3 expression was determined in human neutrophils by flow cytometry.</p><p><strong>Key results: </strong>Survivin was expressed in neutrophils during MSU-induced gout, and the treatment with YM155 reduced survivin expression and shortened Ri from ∼8 h observed in vehicle-treated mice to ∼5.5 h, effect accompanied by increased neutrophil apoptosis and efferocytosis, both crucial for the inflammation resolution. Reduced IL-1β and CXCL1 levels were also observed in periarticular tissue. YM155 reduced histopathological score and hypernociceptive response. In human neutrophils, lipopolysaccharide (LPS) increased survivin expression, whereas survivin inhibition with YM155 induced neutrophil apoptosis, with activation of caspase-3.</p><p><strong>Conclusions and implications: </strong>Survivin may be a promising therapeutic target to control neutrophilic inflammation.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680800","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":"GraphCPP: The new state-of-the-art method for cell-penetrating peptide prediction via graph neural networks.","authors":"Attila Imre, Balázs Balogh, István Mándity","doi":"10.1111/bph.17388","DOIUrl":"https://doi.org/10.1111/bph.17388","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cell-penetrating peptides (CPPs) are short amino acid sequences that can penetrate cell membranes and deliver molecules into cells. Several models have been developed for their discovery, yet these models often face challenges in accurately predicting membrane penetration due to the complex nature of peptide-cell interactions. Hence, there is a need for innovative approaches that can enhance predictive performance.</p><p><strong>Experimental approach: </strong>In this study, we present the application GraphCPP, a novel graph neural network (GNN) for the prediction of membrane penetration capability of peptides.</p><p><strong>Key results: </strong>A new comprehensive dataset-dubbed CPP1708-was constructed resulting in the largest reliable database of CPPs to date. Comparative analyses with previous methods, such as MLCPP2, C2Pred, CellPPD and CellPPD-Mod, demonstrated the superior predictive performance of our model. Upon testing against other published methods, GraphCPP performs exceptionally, achieving 0.5787 Matthews correlation coefficient and 0.8459 area under the curve (AUC) values on one dataset. This means a 92.8% and 23.3% improvement in Matthews correlation coefficient and AUC measures respectively compared with the next best model. The capability of the model to effectively learn peptide representations was demonstrated through t-distributed stochastic neighbour embedding plots. Additionally, the uncertainty analysis revealed that GraphCPP maintains high confidence in predictions for peptides shorter than 40 amino acids. The source code is available at https://github.com/attilaimre99/GraphCPP.</p><p><strong>Conclusion and implications: </strong>These findings indicate the potential of GNN-based models to improve CPP penetration prediction and it may contribute towards the development of more efficient drug delivery systems.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680736","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":"NaHS alters synaptic plasticity proteins and enhances dendritic arborization to improve cognitive and motor deficits after traumatic brain injury in mice.","authors":"Farheen Nasir, Priyanka Yadav, Thamil Mani Sivanandam","doi":"10.1111/bph.17386","DOIUrl":"https://doi.org/10.1111/bph.17386","url":null,"abstract":"<p><strong>Background and purpose: </strong>Traumatic brain injury (TBI) is a complex medical condition affecting people globally. Hydrogen sulfide (H₂S) is a recently discovered gaseous mediator and is dysregulated in the brain after TBI. Sodium hydrogen sulfide (NaHS), a known donor of H₂S, is beneficial in various biological processes involving aging and diseases, including injury. It is neuroprotective against oxidative stress, neuroinflammation, and other secondary injury processes. However, the NaHS-H₂S system has not been investigated as a regulator of injury-mediated synaptic plasticity proteins and the underlying mechanisms after TBI.</p><p><strong>Experimental approach: </strong>We developed a model of TBI in Swiss albino mice to study the effects of exogenous H₂S, administered as NaHS. We assessed cognitive function (Barnes maze and novel object recognition) and motor function (rotarod). Brain tissue was analysed with ELISA, qRT-PCR, immunoblotting, Golgi-cox staining, and immunofluorescence.</p><p><strong>Key results: </strong>NaHS administration restored the injury-caused decline in H₂S levels. Injury-mediated oxidative stress parameters were improved following NaHS. It down-regulated TBI biomarkers, ameliorated the synaptic marker proteins, and improved cognitive and motor deficits. These changes were accompanied by enhanced dendritic arborization and spine number. Restoration of N-methyl D-aspartate receptor subunits and diminished glutamate and calcium levels, along with marked changes in microtubule-associated protein 2 A and calcium/calmodulin-dependent protein kinase II, formed the basis of the underlying mechanism(s).</p><p><strong>Conclusion and implications: </strong>Our findings suggest that NaHS could have therapeutic activity against TBI, as it ameliorated cognitive and motor deficits caused by changes in synaptic plasticity proteins and dendritic arborisation, in our model.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675210","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":"The endocannabinoid anandamide mediates anti-inflammatory effects through activation of NR4A nuclear receptors.","authors":"Tom Teichmann, Beatrice Pflüger-Müller, Virna Margarita Martín Giménez, Fiona Sailer, Henrik Dirks, Simonida Zehr, Timothy Warwick, Felix Brettner, Paola Munoz-Tello, Andreas Zimmer, Irmgard Tegeder, Dominique Thomas, Robert Gurke, Stefan Günther, Jan Heering, Ewgenij Proschak, Gerd Geisslinger, Iris-S Bibli, Dagmar Meyer Zu Heringdorf, Walter Manucha, Maike Windbergs, Stefan Knapp, Andreas Weigert, Matthias S Leisegang, Douglas Kojetin, Ralf P Brandes","doi":"10.1111/bph.17366","DOIUrl":"https://doi.org/10.1111/bph.17366","url":null,"abstract":"<p><strong>Background and purpose: </strong>Endocannabinoids are lipid mediators, which elicit complex biological effects that extend beyond the central nervous system. Tissue concentrations of endocannabinoids increase in atherosclerosis, and for the endocannabinoid N-arachidonoyl-ethanolamine (anandamide, AEA), this has been linked to an anti-inflammatory function. In this study, we set out to determine the anti-inflammatory mechanism of action of AEA, specifically focusing on vascular smooth muscle cells.</p><p><strong>Experimental approach: </strong>RNA-sequencing, RT-qPCR, LC-MS/MS, NanoBit, ChIP, microscale thermophoresis, NMR structural footprinting, Gal4 reporter gene assays and loss of function approaches in cell and ex vivo organ culture were used.</p><p><strong>Key results: </strong>AEA pretreatment attenuated the cytokine-mediated induction of inflammatory gene expression such as CCL2. This effect was also observed in preparations obtained from cannabinoid receptor knockout mice and after pertussis toxin treatment. The anti-inflammatory effect of AEA required preincubation, suggesting an effect through gene induction. AEA increased the expression of the nuclear receptors NR4A1 and NR4A2. Knockdown and knockout of these receptors blocked the AEA-mediated anti-inflammatory effect in cell culture and aortic organ culture, respectively. Conversely, NR4A agonists (CsnB, C-DIM12) attenuated inflammatory gene expression. AEA binds to NR4A, and mutations in NR4A attenuated this effect. The interaction of AEA with NR4A caused recruitment of the nuclear corepressor NCoR1 to the CCL2 promoter, resulting in gene suppression.</p><p><strong>Conclusion and implications: </strong>By binding to NR4A, AEA elicits an anti-inflammatory response in vascular smooth muscle cells. NR4A-binding by AEA analogues may represent novel anti-inflammatory agents.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675211","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":"RETRACTION: Cloricromene, a Coumarine Derivative, Protects Against Collagen-induced Arthritis in Lewis Rats.","authors":"","doi":"10.1111/bph.17417","DOIUrl":"https://doi.org/10.1111/bph.17417","url":null,"abstract":"","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646583","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}