British Journal of Pharmacology最新文献

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Sculponeatin A induces mitochondrial dysfunction in non-small cell lung cancer through WWP2-mediated degradation of mitochondrial STAT3 Sculponeatin A通过wwp2介导的线粒体STAT3降解诱导非小细胞肺癌的线粒体功能障碍。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-24 DOI: 10.1111/bph.17460
Fang Wan, Chen Qian, Xuewen Liu, Yifan Zhong, Wenkang Peng, Liang Zhang, Xiangrong Zhan, Yongtong Huang, Chengyu Zhang, Jiu Wang, Yuan Si, Ying Liu
{"title":"Sculponeatin A induces mitochondrial dysfunction in non-small cell lung cancer through WWP2-mediated degradation of mitochondrial STAT3","authors":"Fang Wan,&nbsp;Chen Qian,&nbsp;Xuewen Liu,&nbsp;Yifan Zhong,&nbsp;Wenkang Peng,&nbsp;Liang Zhang,&nbsp;Xiangrong Zhan,&nbsp;Yongtong Huang,&nbsp;Chengyu Zhang,&nbsp;Jiu Wang,&nbsp;Yuan Si,&nbsp;Ying Liu","doi":"10.1111/bph.17460","DOIUrl":"10.1111/bph.17460","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The phosphorylation of signal transducer and activator of transcription 3 (STAT3) monomer at S727 promotes its mitochondrial localisation and regulates mitochondrial function, thus exerting a protective effect on tumour cells. However, no inhibitor drugs targeting mitochondrial STAT3 (mitoSTAT3) or S727-STAT3 phosphorylation have been identified. Here, we report a novel diterpenoid extracted from <i>Isodon sculponeatus</i>, sculponeatin A (sptA), induces mitochondrial dysfunction in non-small cell lung cancer (NSCLC) by targeting mitoSTAT3 degradation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>xCELLigence real-time cell analysis assay and high-content analysis were performed to measure cytotoxicity. Mitochondrial function was assessed by transmission electron microscopy, mitochondrial permeability transition pore opening and Seahorse cellular flux assays. The effects of sptA on the upstream signalling pathway of mitochondrial dysfunction were measured by Western blot, gene alterations and other approaches. Immunofluorescence and live cell imaging were performed to visualise the expression and position of mitoSTAT3. Nude mice and zebrafish were modelled with subcutaneous xenografts. Pharmacokinetics of sptA were examined in rats. Drug toxicity was evaluated in zebrafish.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>sptA inhibited mitochondrial respiration in NSCLC cells. sptA induced mitochondrial dysfunction by promoting the degradation of mitoSTAT3. sptA promoted WW domain containing E3 ubiquitin protein ligase 2 (WWP2)-mediated ubiquitination and degradation of mitoSTAT3 through direct binding. sptA inhibited tumour growth in vivo. Evaluation of drug toxicity in zebrafish showed that overdose of sptA may cause heart damage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>These findings suggest that pharmacological targeting the degradation of mitoSTAT3 by sptA may provide therapeutic benefits against NSCLC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 12","pages":"2662-2681"},"PeriodicalIF":6.8,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490765","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}
引用次数: 0
Antibiotic-induced decrease of bacterial load in guinea pig intestine reduces α2-adrenoceptor expression and activity in peristaltic motor inhibition 抗生素诱导的豚鼠肠道细菌负荷的减少可降低α2-肾上腺素能受体的表达和蠕动运动抑制活性。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-23 DOI: 10.1111/bph.70001
Aitak Farzi, Eva Tatzl, Karl Kashofer, Slave Trajanoski, Michael K. Herbert, Peter Holzer
{"title":"Antibiotic-induced decrease of bacterial load in guinea pig intestine reduces α2-adrenoceptor expression and activity in peristaltic motor inhibition","authors":"Aitak Farzi,&nbsp;Eva Tatzl,&nbsp;Karl Kashofer,&nbsp;Slave Trajanoski,&nbsp;Michael K. Herbert,&nbsp;Peter Holzer","doi":"10.1111/bph.70001","DOIUrl":"10.1111/bph.70001","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The use of analgosedatives in critically ill patients carries the risk of impairing gastrointestinal (GI) propulsion and could thereby lead to sepsis. The gut microbiota can influence GI motility, but whether GI microbial dysbiosis modifies GI peristalsis impairment by analgosedative drugs has not yet been analysed. This question was addressed in the guinea pig small intestine following a decrease of bacterial load by antibiotic pretreatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Guinea pigs were enorally (within the mouth) pretreated with meropenem, neomycin and vancomycin, and antibiotic-induced decrease of bacterial load was confirmed by 16S rDNA sequencing. Peristalsis in the isolated guinea pig small intestine was evaluated by determining the pressure threshold at which a peristaltic wave is triggered. The expression of factors that may be relevant to communication between GI microbiota and the motor system was examined at the mRNA (quantitative (q)PCR]) and/or protein (enzyme-linked immunosorbent assay [ELISA]) level.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Antibiotic treatment disturbed the small intestinal microbiome as shown by decrease of bacterial load and reduced alpha diversity. Microbial dysbiosis did not affect peristalsis at baseline but blunted the ability of α<sub>2</sub> agonists to inhibit peristalsis, while the anti-peristaltic effects of sufentanil, midazolam, neostigmine and propofol were inconsistently affected. These functional alterations were complemented by a decreased expression of α<sub>2</sub>-adrenoceptors, toll-like receptors (TRL) 3, 4 &amp; 7, IFN-γ and iNOS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Antibiotic-induced decrease of bacterial load in the small intestine selectively blunts the ability of α<sub>2</sub> agonists to impair peristalsis. This effect is explained by decreased α<sub>2</sub>-adrenoceptor expression, which may arise from TLR down-regulation in the dysbiotic gut.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 12","pages":"2642-2661"},"PeriodicalIF":6.8,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482187","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}
引用次数: 0
Spontaneous and pharmacologically induced hypothermia protect mice against endotoxic shock 自发和药理学诱导的低温保护小鼠免受内毒素休克。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-23 DOI: 10.1111/bph.70000
Arely Tinajero, Warda Merchant, Adan Khan,  Surbhi, Alexandre Caron, Ryan Reynolds, Lin Jia, Laurent Gautron
{"title":"Spontaneous and pharmacologically induced hypothermia protect mice against endotoxic shock","authors":"Arely Tinajero,&nbsp;Warda Merchant,&nbsp;Adan Khan,&nbsp; Surbhi,&nbsp;Alexandre Caron,&nbsp;Ryan Reynolds,&nbsp;Lin Jia,&nbsp;Laurent Gautron","doi":"10.1111/bph.70000","DOIUrl":"10.1111/bph.70000","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Despite the well-known occurrence of hypothermia during sepsis, its underlying biological nature and adaptive value remain debated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Using indirect calorimetry, telemetry, thermal gradient studies and pharmacological studies, we examined the thermal and metabolic responses of mice treated with a shock-inducing lethal dose of lipopolysaccharide (LPS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We report that LPS-treated mice undergo spontaneous hypothermia, driven by hypometabolism and cold-seeking behaviours, even when animals approach the end of life. Conversely, rewarming LPS-treated mice at 30°C delayed hypothermia but worsened mortality, thus highlighting the adaptive importance of hypothermia. Additionally, we show that LPS-induced hypothermia was partly mediated by peripheral neurotensin expressed in response to vascular toll-like receptor 4 (TLR4) signalling. The administration of a neurotensin analogue (JMV449) induced pharmacological hypothermia and significantly ameliorated the clinical presentation and lethality rates in LPS-treated mice. Moreover, the therapeutic benefits of pharmacological hypothermia were prevented when LPS-treated mice were switched to 30°C. Lastly, these beneficial outcomes were attributed to a reduction in oxygen consumption, metabolic stress and cytopathic hypoxia, rather than the modulation of the cytokine storm.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Collectively, our findings indicate that spontaneous and pharmacologically-induced hypothermia protect against endotoxic shock.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 12","pages":"2621-2641"},"PeriodicalIF":6.8,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482188","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}
引用次数: 0
Opportunities of patient-derived organoids in drug development. 患者源性类器官在药物开发中的机遇。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-20 DOI: 10.1111/bph.70010
Antonia Büning, Elena Reckzeh
{"title":"Opportunities of patient-derived organoids in drug development.","authors":"Antonia Büning, Elena Reckzeh","doi":"10.1111/bph.70010","DOIUrl":"https://doi.org/10.1111/bph.70010","url":null,"abstract":"<p><p>Various model systems are utilised during drug development starting from basic research, moving to preclinical research and development for clinical applications in order to identify new drugs to improve human health. However, there are characteristics of humans that are not captured by established models. Such models include homogeneous two-dimensional (2D) cell lines, which lack cellular heterogeneity and physiological relevance, and species differences of animal models. Organoids can mitigate these differences by providing more physiologically relevant three-dimensional (3D) cell models that resemble the molecular state in healthy and pathological tissue. This review presents exemplary approaches using patient-derived organoids (PDOs) that have been developed and the new opportunities that are evolving in drug development with a focus on patient adult stem cell (ASC)-derived organoids. These demonstrate the potential of PDOs used alongside established cell and animal models to improve drug development from basic research to clinical applications such as personalised medicine.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467006","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}
引用次数: 0
Blockade of P2X7 receptors preserves blood retinal barrier integrity by modulating the plasmalemma vesicle-associated protein: Implications for diabetic retinopathy P2X7受体的阻断通过调节质膜囊泡相关蛋白来保持血液视网膜屏障的完整性:对糖尿病视网膜病变的影响。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-20 DOI: 10.1111/bph.70007
Chiara Bianca Maria Platania, Francesca Lazzara, Kenneth Mitton, Naomi Haque, Wendelin Dailey, Federica Conti, Erika Giuffrida, Filippo Drago, Anca Hermenean, Cornel Balta, Hildegard Herman, Alina Ciceu, Maria Consiglia Trotta, Michele D'Amico, Giuseppe Nicosia, Settimio Rossi, Claudio Bucolo
{"title":"Blockade of P2X7 receptors preserves blood retinal barrier integrity by modulating the plasmalemma vesicle-associated protein: Implications for diabetic retinopathy","authors":"Chiara Bianca Maria Platania,&nbsp;Francesca Lazzara,&nbsp;Kenneth Mitton,&nbsp;Naomi Haque,&nbsp;Wendelin Dailey,&nbsp;Federica Conti,&nbsp;Erika Giuffrida,&nbsp;Filippo Drago,&nbsp;Anca Hermenean,&nbsp;Cornel Balta,&nbsp;Hildegard Herman,&nbsp;Alina Ciceu,&nbsp;Maria Consiglia Trotta,&nbsp;Michele D'Amico,&nbsp;Giuseppe Nicosia,&nbsp;Settimio Rossi,&nbsp;Claudio Bucolo","doi":"10.1111/bph.70007","DOIUrl":"10.1111/bph.70007","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Plasmalemma vesicle-associated protein (PLVAP) regulates transcytosis in vascular endothelial cells. PLVAP expression is increased in pathological conditions, such as diabetic retinopathy. P2X7 receptor antagonists have been shown to preserve blood-retinal barrier (BRB) integrity. Here, we have tested the hypothesis that PLVAP expression is tightly linked to P2X7 receptor activity, leading to breakdown of the BRB in an in vitro model of diabetic retinopathy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We integrated network approaches with an in vitro model of diabetic retinopathy using primary human retinal microvascular endothelial cells (HRMECs). Cells were treated with a P2X7 receptor antagonist, JNJ47965567, and expression of several genes predicted to belong to the P2X7 receptor signalling network were assessed. Levels and localisation of PLVAP, VE-cadherin and zonula occludens-1 (ZO-1) in HRMECs were evaluated. In vivo, the effects of JNJ47965567 on PLVAP expression in the retinas of diabetic mice were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>High levels of glucose increased PLVAP expression in HRMECs, which was blocked by JNJ47965567. Furthermore, JNJ47965567 preserved VE-cadherin and ZO-1. In the choroidal vasculature of diabetic mice, PLVAP immunostaining was increased, compared to levels in non-diabetic mice. This increase was significantly attenuated by treatment with JNJ47965567</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>This study showed that P2X7 receptor signalling is an important component of a complex gene regulatory network, including PLVAP, mediating the pathophysiology of diabetic retinopathy. The P2X7 receptor antagonist JNJ47965567 showed a good pharmacodynamic profile, suggesting that this approach could be of value in the treatment of diabetic retinopathy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 12","pages":"2603-2620"},"PeriodicalIF":6.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466985","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}
引用次数: 0
Engineered pulmonary artery tissues for measuring contractility, drug testing and disease modelling 用于测量收缩性、药物测试和疾病建模的工程肺动脉组织。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-20 DOI: 10.1111/bph.17462
Adam L. Fellows, Kate Quigley, Venus Leung, Alexander J. Ainscough, Martin R. Wilkins, Harry Barnett, David Miller, Manuel Mayr, Beata Wojciak-Stothard
{"title":"Engineered pulmonary artery tissues for measuring contractility, drug testing and disease modelling","authors":"Adam L. Fellows,&nbsp;Kate Quigley,&nbsp;Venus Leung,&nbsp;Alexander J. Ainscough,&nbsp;Martin R. Wilkins,&nbsp;Harry Barnett,&nbsp;David Miller,&nbsp;Manuel Mayr,&nbsp;Beata Wojciak-Stothard","doi":"10.1111/bph.17462","DOIUrl":"10.1111/bph.17462","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Vasoreactivity of pulmonary arteries regulates blood flow through the lungs. Excessive constriction of these vessels contributes to pulmonary arterial hypertension (PAH), a progressive and incurable condition, resulting in right heart failure. The search for new and improved drug treatments is hampered by laboratory models that do not reproduce the vasoactive behaviour of healthy and diseased human arteries.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We have developed an innovative technique for producing miniature, three-dimensional arterial structures that allow proxy evaluation of human pulmonary artery contractility. These “engineered pulmonary artery tissues” or “EPATs” are fabricated by suspending human pulmonary artery vascular smooth muscle cells (VSMCs) in fibrin hydrogels between pairs of silicone posts, located on custom-made racks, in 24-well culture plates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>EPATs exhibit rapid, robust and reproducible contraction responses to vasoconstrictors (KCl, ET-1, U46619) as well as relaxation responses to clinically approved PAH vasodilatory drugs that target several signalling pathways, such as bosentan, epoprostenol, selexipag and imatinib. EPATs composed of pulmonary artery VSMCs from PAH patients exhibit enhanced contraction to vasoconstrictors and relaxation in response to vasodilators. We also demonstrate the incorporation of endothelial cells into EPATs for the measurement of endothelium-dependent dilatory responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>We demonstrate the capacity and suitability of EPATs for studying the contractile behaviour of human arterial cells and preclinical drug testing. This novel biomimetic platform has the potential to dramatically improve our understanding and treatment of cardiovascular disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 12","pages":"2585-2602"},"PeriodicalIF":6.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17462","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467004","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}
引用次数: 0
Novel drugs approved by the EMA, the FDA and the MHRA in 2024: A year in review 2024年由EMA、FDA和MHRA批准的新药:一年的审查。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-19 DOI: 10.1111/bph.17458
Stavros Topouzis, Andreas Papapetropoulos, Steve P. H. Alexander, Miriam Cortese-Krott, Dave A. Kendall, Kirill Martemyanov, Claudio Mauro, Nithyanandan Nagercoil, Reynold A. Panettieri Jr, Hemal H. Patel, Rainer Schulz, Barbara Stefanska, Gary J. Stephens, Mauro M. Teixeira, Nathalie Vergnolle, Xin Wang, Péter Ferdinandy
{"title":"Novel drugs approved by the EMA, the FDA and the MHRA in 2024: A year in review","authors":"Stavros Topouzis,&nbsp;Andreas Papapetropoulos,&nbsp;Steve P. H. Alexander,&nbsp;Miriam Cortese-Krott,&nbsp;Dave A. Kendall,&nbsp;Kirill Martemyanov,&nbsp;Claudio Mauro,&nbsp;Nithyanandan Nagercoil,&nbsp;Reynold A. Panettieri Jr,&nbsp;Hemal H. Patel,&nbsp;Rainer Schulz,&nbsp;Barbara Stefanska,&nbsp;Gary J. Stephens,&nbsp;Mauro M. Teixeira,&nbsp;Nathalie Vergnolle,&nbsp;Xin Wang,&nbsp;Péter Ferdinandy","doi":"10.1111/bph.17458","DOIUrl":"10.1111/bph.17458","url":null,"abstract":"<p>In the past year, the European Medicines Agency (EMA), the Food and Drug Administration (FDA) and the Medicines and Healthcare Products Regulatory Agency (MHRA) authorised 53 novel drugs. While the 2024 harvest is not as rich as in 2023, when 70 new chemical entities were approved, the number of ‘orphan’ drug authorisations in 2024 (21) is similar to that of 2023 (24), illustrating the dynamic development of therapeutics in areas of unmet need. The 2024 approvals of novel protein therapeutics (15) and advanced therapy medicinal products (ATMPs, 6) indicate a sustained trend also noticeable in the 2023 new drugs reviewed in this journal last year (16 and 11, respectively). Clearly, the most striking characteristic of the 2024 drug yield is the creative pharmacological design, which allows these medicines to employ a novel approach to target a disease. Some notable examples are the first drug successfully using a ‘dock-and-block’ mechanism of inhibition (zenocutuzumab), the first approved drug for schizophrenia designed as an agonist of M<sub>1</sub>/M<sub>4</sub> muscarinic receptors (xanomeline), the first biparatopic antibody (zanidatamab), binding two distinct epitopes of the <i>same</i> molecule, the first haemophilia therapy that instead of relying on external supplementation of clotting factors, restores Factor Xa activity by inhibiting TFPI (marstacimab), or the first ever authorised direct telomerase inhibitor (imetelstat) that reprogrammes the oncogenic drive of tumour cells. In addition, an impressive percentage of novel drugs were first in class (28 out of 53 or 53% of the total) and a substantial number can be considered disease agnostic, indicating the possibility of future approved extensions of their use for additional indications. The 2024 harvest demonstrates the therapeutic potential of innovative pharmacological design, which allows the effective targeting of intractable disorders and addresses crucial, unmet therapeutic needs.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1416-1445"},"PeriodicalIF":6.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17458","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457095","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}
引用次数: 0
TREM2 activation reduces white matter injury via PI3K/Akt/GSK-3β signalling after intracerebral haemorrhage 脑出血后,TREM2激活通过PI3K/Akt/GSK-3β信号通路减少白质损伤。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-18 DOI: 10.1111/bph.17475
Yuan Zhang, You Shi, Lin Wang, Zhao Li, Yingwen Wang, Jin Yan, Xiaochuan Sun, Qing Luo, Lin Li
{"title":"TREM2 activation reduces white matter injury via PI3K/Akt/GSK-3β signalling after intracerebral haemorrhage","authors":"Yuan Zhang,&nbsp;You Shi,&nbsp;Lin Wang,&nbsp;Zhao Li,&nbsp;Yingwen Wang,&nbsp;Jin Yan,&nbsp;Xiaochuan Sun,&nbsp;Qing Luo,&nbsp;Lin Li","doi":"10.1111/bph.17475","DOIUrl":"10.1111/bph.17475","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>White matter injury (WMI) considerably exacerbates the prognosis following intracerebral haemorrhage (ICH). While the triggering receptor on myeloid cells 2 (TREM2) is recognized for its neuroprotective roles in a range of neurological disorders through the modulation of neuroinflammation, phagocytosis, promoting cell survival, its specific function in WMI after ICH has yet to be fully elucidated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study involved inducing ICH in mice through autologous blood injection. Neurological functions were tested via behavioural assessments and electrophysiological recordings. WMI was examined using immunofluorescence, Luxol fast blue staining, MRI and transmission electron microscopy. Microglia were isolated and analysed using real-time polymerase chain reaction (PCR). Microglia depletion was achieved with PLX3397, primary cultures of microglia and oligodendrocytes were investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The activation of TREM2 resulted in improved neurological outcomes after ICH, correlated with reduced WMI, demonstrated by decreased white matter loss in the corpus striatum, reduced damage to the nodes of Ranvier, and better preservation of myelin and white matter tract integrity. These neuroprotective effects were attributed to changes in microglial states mediated via the PI3K/Akt/GSK-3<i>β</i> signalling pathway. However, the neuroprotective advantages conferred by TREM2 activation were negated in TREM2 KO mice, either through microglia depletion or inhibition of PI3K.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This research is the first to illustrate that TREM2 activation mitigates WMI following ICH through a microglia-dependent mechanism involving the PI3K/Akt/GSK-3<i>β</i> pathway. TREM2 represents a potential therapeutic target for ICH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 11","pages":"2542-2559"},"PeriodicalIF":6.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447903","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}
引用次数: 0
Interactions between ADGRF1 (GPR110) and extracellular matrix proteins govern its effects on tumorigenesis in HER2-positive breast cancer 在her2阳性乳腺癌中,ADGRF1 (GPR110)和细胞外基质蛋白之间的相互作用控制着它对肿瘤发生的影响。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-18 DOI: 10.1111/bph.17463
Noor Mazin Abdulkareem, Raksha Bhat, Micah Castillo, Sung Yun Jung, Suhas Vasaikar, Sarmistha Nanda, Alexis Ruiz, Martin Shea, Wangjia Cao, Jamunarani Veeraraghavan, Hee-Yong Kim, Tasneem Bawa-Khalfe, Tahir Hussain, Xinli Liu, Preethi Gunaratne, Rachel Schiff, Meghana V. Trivedi
{"title":"Interactions between ADGRF1 (GPR110) and extracellular matrix proteins govern its effects on tumorigenesis in HER2-positive breast cancer","authors":"Noor Mazin Abdulkareem,&nbsp;Raksha Bhat,&nbsp;Micah Castillo,&nbsp;Sung Yun Jung,&nbsp;Suhas Vasaikar,&nbsp;Sarmistha Nanda,&nbsp;Alexis Ruiz,&nbsp;Martin Shea,&nbsp;Wangjia Cao,&nbsp;Jamunarani Veeraraghavan,&nbsp;Hee-Yong Kim,&nbsp;Tasneem Bawa-Khalfe,&nbsp;Tahir Hussain,&nbsp;Xinli Liu,&nbsp;Preethi Gunaratne,&nbsp;Rachel Schiff,&nbsp;Meghana V. Trivedi","doi":"10.1111/bph.17463","DOIUrl":"10.1111/bph.17463","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>We and others have previously shown that ADGRF1, an adhesion G protein-coupled receptor, is overexpressed and associated with poor survival in many cancers, including human epidermal growth factor receptor-2 (HER2) breast cancer (BC). Also, we have reported the tumour-promoting function of ADGRF1 using preclinical models of HER2+ BC. In this study, we investigated the effect of ADGRF1 overexpression in an orthotopic in vivo model as well as downstream signalling of ADGRF1 in HER2+ BC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We utilized a doxycycline (Dox)-induced ADGRF1 overexpression system in HER2+ BC cell lines and performed various in vitro and in vivo studies. Following ADGRF1 overexpression in the presence/absence of Matrigel, laminin-111 or collagen-IV, we performed the mammosphere assay to assess the tumorigenicity of breast epithelial cells, as well as cAMP/IP1 assays and RNA-sequencing, to understand the receptor function and pharmacology. We conducted cross-linking-aided immunoprecipitation and mass spectrometry to confirm the physical interaction between ADGRF1 and the extracellular matrix proteins present in Matrigel.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We found that ADGRF1 switched from a tumour-promoting to tumour-suppressive function upon interaction with laminin-111. Interaction of ADGRF1 with laminin-111 resulted in inhibition of Gαs coupling and STAT3 phosphorylation, induction of senescence, increase in HER2 expression, and improvement of sensitivity to anti-HER2 drugs in HER2+ BC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>ADGRF1 switches from a tumour-promoting to tumour-suppressive function upon interaction with laminin-111, leading to improvements in sensitivity to anti-HER2 drugs. Leveraging ADGRF1 interactions with laminin-111 may allow the design of novel therapies against ADGRF1 in HER2+ BC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 11","pages":"2524-2541"},"PeriodicalIF":6.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447640","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}
引用次数: 0
Imatinib aggravates pressure-overload-induced right ventricle failure via JNK/Runx2 pathway 伊马替尼通过JNK/Runx2通路加重压力过载引起的右心室衰竭。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-18 DOI: 10.1111/bph.70006
Xiaohui Zeng, Zhuoji Ma, Shanshan Wen, Liang Zhou, Wanxian Hong, Zhixiong Wu, Chunxian Cen, Qianwen Bai, Shangwei Ding, Xin Chen, Jian Wang, Lingdan Chen, Wenju Lu, Tao Wang
{"title":"Imatinib aggravates pressure-overload-induced right ventricle failure via JNK/Runx2 pathway","authors":"Xiaohui Zeng,&nbsp;Zhuoji Ma,&nbsp;Shanshan Wen,&nbsp;Liang Zhou,&nbsp;Wanxian Hong,&nbsp;Zhixiong Wu,&nbsp;Chunxian Cen,&nbsp;Qianwen Bai,&nbsp;Shangwei Ding,&nbsp;Xin Chen,&nbsp;Jian Wang,&nbsp;Lingdan Chen,&nbsp;Wenju Lu,&nbsp;Tao Wang","doi":"10.1111/bph.70006","DOIUrl":"10.1111/bph.70006","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Right ventricular (RV) function is the key prognostic determinant of pulmonary hypertension (PH). In PH patients, imatinib treatment decreases pulmonary vascular resistance and improves exercise capacity, but does not change mortality or duration to clinical worsening. Imatinib has been reported to be cardiotoxic in the left heart. We hypothesise that imatinib damages the pressure overloaded RV via its direct effects within the heart, which may counteract its therapeutic effects in haemodynamic improvement of PH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>A pulmonary arterial banding (PAB) rat model with fixed pulmonary artery narrowing was performed to avoid changes in RV afterload.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>In PAB rats, imatinib treatment decreased the survival rate and exacerbated RV dysfunction, myocardial hypertrophy, apoptosis and fibrosis. In vitro, imatinib increased cardiomyocyte hypertrophy and did not change cardiac fibroblasts activation; however, imatinib-treated conditioned medium from cardiomyocytes promoted fibroblast activation. Mechanistically, imatinib increased the phosphorylation of c-jun N-terminal kinase (JNK) and the expression of RUNX family transcription factor 2 (Runx2), and subsequently promoted the transcription of thrombospondin 4 (THBS4) and connective tissue growth factor (CTGF) in RV cardiomyocytes. Finally, SP600125, a JNK inhibitor, significantly alleviated imatinib-induced RV failure in PAB rats and enhanced the effects of imatinib on RV function improvement in SU5416 + hypoxia-induced PH rats without affecting pulmonary artery narrowing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>We demonstrate for the first time that imatinib aggravates RV failure under pressure overload through JNK/Runx2 pathway, and JNK inhibition improves the therapeutic effects of imatinib on RV function in PH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 11","pages":"2560-2581"},"PeriodicalIF":6.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448444","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}
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