British Journal of Pharmacology最新文献

{"title":"Scorpion venom heat-resistant synthetic peptide improves cognitive dysfunction of APP/PS1 mice through microglial retromer complex","authors":"Yue Zhang,&nbsp;Yu-Xia Wu,&nbsp;Xiao-Gang Zhang,&nbsp;Song-Yu Guo,&nbsp;Jia He,&nbsp;Na-Na Hu,&nbsp;Yue-Lin Huang,&nbsp;Yue Kong,&nbsp;Qi-Fa Li,&nbsp;Ao-Ran Sui,&nbsp;Bao-Hang Zhu,&nbsp;Hua Piao,&nbsp;Jie Zhao,&nbsp;Shao Li","doi":"10.1111/bph.70124","DOIUrl":"10.1111/bph.70124","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The abnormal accumulation of amyloid-β (Aβ) in the brain is a characteristic pathological change observed in patients with Alzheimer's disease (AD). Microglial phagocytosis, dependent on recycling through the retromer complex and cell membrane-bound receptors, plays a vital role in clearing Aβ from the brain. Previous studies have demonstrated the neurotrophic and neuroprotective effects of Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP); however, its impacts on cognitive function remain unclear. The present study aims to investigate the impact of SVHRSP on cognitive function in APP/PS1 transgenic mice and underlying mechanisms associated with microglial retromer complex.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>SVHRSP and 3-methyladenine (3-MA) were intraperitoneally injected at 7.5 months to investigate their effects on cognitive dysfunction in APP/PS1 mice. Following behavioural testing, brain samples were harvested 24 h later for electrophysiological recordings, analysis of protein and gene expression, and histological assessment. The role of microglial retromer complex was examined using primary microglia cultures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>SVHRSP treatment effectively improved AD-related pathological features, including cognitive impairment, neuronal loss, impaired synaptic plasticity, neuroinflammation, and Aβ deposition in APP/PS1 mice. Both in vivo and in vitro studies revealed that SVHRSP treatment increased expression of retromer complex protein VPS35. 3-MA, a specific class III phosphoinositide 3-kinase (PI3K) inhibitor that prevents autophagosome formation, reduced retromer complex protein expression and hindered the cognitive function improvements of SVHRSP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Our findings suggest that SVHRSP may enhance microglial phagocytosis by modulating retromer complex activity, thereby alleviating Aβ accumulation and improving cognitive dysfunction in AD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 21","pages":"5391-5408"},"PeriodicalIF":7.7,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636261","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":"Correction to “Oroxylin A attenuates psoriasiform skin inflammation by direct targeting p62 (sequestosome 1) via suppressing M1 macrophage polarization”","authors":"","doi":"10.1111/bph.70149","DOIUrl":"10.1111/bph.70149","url":null,"abstract":"<p>\u0000 <span>Ma, Y</span>, <span>Liu, Y</span>, <span>Zhong, Y</span>, <span>Li, X</span>, <span>Xu, Y</span>, <span>Chen, L</span>, <span>Gong, L</span>, <span>Huang, H</span>, <span>Chen, X</span>, <span>He, Y</span>, <span>Qiang, L</span>. <span>Oroxylin A attenuates psoriasiform skin inflammation by direct targeting p62 (sequestosome 1) via suppressing M1 macrophage polarization</span>. <i>Br J Pharmacol.</i> <span>2024 Dec</span>; <span>181</span>(<span>24</span>): <span>5110</span>–<span>5132</span>. https://doi.org/10.1111/bph.17349. Epub 2024 Sep 23. PMID: 39313956.</p><p>​In last line of the “funding information” section, the funding number “AD220359310” was incorrect. This should be corrected to “AD22035191”. Also, the location of this funding number “AD22035191” should be swapped with the first funding number, “2022KY0513”.</p><p>Therefore, the entire content of the funding information section should ultimately be revised as follows: ‘Special Fund for Talents of Guangxi, Grant/Award Number: AD22035191; Natural Science Foundation of Jiangsu Province, Grant/Award Numbers: BK20210419, BK20211578; National Natural Science Foundation of China, Grant/Award Numbers: 81974425, 82002907, 82360718; Basic Ability Enhancement Program for Young and Middle-aged Teachers of Guilin Medical University, Grant/Award Number: 2022KY0513’.</p><p>The entire content of the second sentence in the last paragraph of the Methods section (2.2 Cell culture and primary cell isolation) should ultimately be revised as follows: “All the protocols and procedures were ethically approved and confirmed by 2017-KY-022 from Institute of Dermatology, Chinese Academy of Medical Science, Peking Union Medical College.”</p><p>We apologize for this error.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 17","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70149","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625390","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":"Effects of the P2RX4 antagonist BR11595 in a guinea pig model of chronic asthma","authors":"Dan Li,&nbsp;Hoeke A. Baarsma,&nbsp;Melissa Mol-van der Veen,&nbsp;Vicky Verschut,&nbsp;Kimberley S. Belfor,&nbsp;Tanja de Boer,&nbsp;Harm Maarsingh,&nbsp;Oliver Martin Fischer,&nbsp;Carolin Ebert,&nbsp;Hana Cernecka,&nbsp;Muriel Lizé,&nbsp;Reinoud Gosens,&nbsp;Loes Kistemaker,&nbsp;Martina Schmidt","doi":"10.1111/bph.70127","DOIUrl":"10.1111/bph.70127","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Asthma is characterized by airway hyperresponsiveness (AHR), allergic inflammation, and airway remodelling. Although recent studies have shown that asthma pathophysiology involves P2X4 receptor activation, a potential link with chronic asthma remains to be explored. We investigated the effect of a novel P2X4 receptor antagonist BR11595 on allergen-induced airway responses in a guinea pig model of chronic asthma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Sensitized guinea pigs were exposed to saline or ovalbumin (OVA) once weekly via aerosolization for 12 weeks. BR11595 (10 mg·kg⁻¹) was injected intraperitoneally five times per week, for four different regimens: all 12 weeks, first 6 weeks, last 6 weeks, or last week only. Airway responsiveness to histamine was assessed 24 h before and 6 h after OVA exposure in weeks 1, 6, and 12. Lung tissue inflammation and remodelling were determined 24 h after the last OVA exposure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>OVA induced AHR at weeks 1, 6, and 12 compared with saline-challenged animals. The AHR was less pronounced in week 12 compared with week 1. BR11595 significantly reduced OVA-induced AHR in week 6 in guinea pigs treated with BR11595 for 6 weeks. AHR in week 12 was reduced after BR11595 treatment in week 12 only, next to OVA-induced eosinophilia and Goblet cell hyperplasia, indicating an acute role of P2X4 receptors on chronic inflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>The P2X4-receptor antagonist BR11595 acutely inhibits AHR, eosinophilia, and Goblet cell hyperplasia after 12 weeks, indicating its potential as a therapeutic target for acute intervention of chronic asthma attacks or exacerbations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 21","pages":"5378-5390"},"PeriodicalIF":7.7,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70127","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616295","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":"Blockade of cannabinoid CB1 receptors potentiates the anti-fibrotic effects mediated by SGLT2 inhibition in a mouse model of diabetic nephropathy","authors":"Océane Pointeau,&nbsp;Awa Isma Ba,&nbsp;Audrey Geissler,&nbsp;Romain Barbosa,&nbsp;Abhishek Basu,&nbsp;Arif Muhammad,&nbsp;Marina Nivot,&nbsp;Maéva Loriot,&nbsp;Julia Leemput,&nbsp;Patricia Passilly-Degrace,&nbsp;Sébastien Causse,&nbsp;Laurent Demizieux,&nbsp;Hélène François,&nbsp;Bruno Vergès,&nbsp;Jianmin Duan,&nbsp;Geneviève Gaucher,&nbsp;Michael Harvey,&nbsp;Pascal Degrace,&nbsp;Glenn Crater,&nbsp;Resat Cinar,&nbsp;Tony Jourdan","doi":"10.1111/bph.70118","DOIUrl":"10.1111/bph.70118","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and purpose</h3>\u0000 \u0000 <p>Diabetic nephropathy (DN) is a common complication of diabetes. Current treatments include renin-angiotensin-aldosterone system (RAAS) blockers and sodium-glucose co-transporter 2 (SGLT2) inhibitors. The cannabinoid CB₁ receptor is a potential therapeutic target. We explored combining CB₁ receptor inverse agonism and SGLT2 inhibition for treating DN, to offer better reno-protection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>C57BLKS-Lepr^db/db and control mice were fed a high-protein diet for 9 weeks. After 5 weeks, db/db mice were either exposed to placebo, empagliflozin (SGLT2 inhibitor), monlunabant (CB₁ receptor inverse agonist) or a combination of both compounds (same dose) by daily oral gavage for 28 days. Diagnostic parameters for DN were analysed, along with markers of oxidative stress, inflammation and renal fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key results</h3>\u0000 \u0000 <p>Both single treatments improved albuminuria and albumin-to-creatinine ratios, but the combination was more effective. Similar results were seen for inflammatory oxidative stress markers. The combination showed additive protective effects on glomerular morphology, podocyte loss and proximal tubular cell injury. Dual treatment significantly reduced tubulointerstitial fibrosis compared to monotherapy and vehicle-treated mice. Transcriptomic analysis identified the STAT3 signalling pathway as a key mediator, with decreased STAT3 phosphorylation observed with both treatments. Key mediators involved included angiopoietin 1 and fibroblast growth factor 20, which modulated the STAT3 pathway via CB₁ receptors and SGLT2, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and implications</h3>\u0000 \u0000 <p>Taken together, these data strongly suggest that a poly-pharmacological approach combining both SGLT2 inhibitors and CB₁ receptor inverse agonism represents a promising therapeutic strategy for managing DN, with better reno-protection than mono-therapies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 21","pages":"5355-5377"},"PeriodicalIF":7.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616294","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":"SGLT2 inhibitors and their influence on iron metabolism in the context of inflammation","authors":"Helene G. Meyer,&nbsp;Chiara Tinner,&nbsp;Chloé Sieber,&nbsp;Dirk Lehnick,&nbsp;Balthasar Hug","doi":"10.1111/bph.70136","DOIUrl":"10.1111/bph.70136","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Sodium-glucose linked transporter 2 (SGLT2) inhibitors stimulate erythropoietin, resulting in increased iron utilization. Consequently, patients often have biomarkers indicating iron deficiency. Here we have assessed the relationship between SGLT2 inhibitors and iron biomarkers in anaemic patients with inflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>This retrospective cross-sectional study included patients with anaemia (WHO definition) and inflammation. We performed bivariate analyses (one-way ANOVA) on log-transformed and original values of soluble transferrin-receptor and ferritin index, both markers of iron stores in the presence of inflammation. Three-way ANOVA models assessed the effect of SGLT2 inhibitors on these biomarkers, adjusting for congestive heart failure and diabetes mellitus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Of the 439 participants, 55 were taking SGLT2 inhibitors. One-way ANOVA showed higher log-transformed soluble transferrin-receptor values in SGLT2 inhibitor users. However, when congestive heart failure and diabetes mellitus were controlled for in the three-way ANOVA, the association disappeared. Similar patterns were observed for soluble transferrin-receptor and ferritin index. All models explained only a small proportion of variance in iron biomarkers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Our bivariate analysis showed a clear association between SGLT2 inhibitors and iron biomarkers in the presence of inflammation. However, this association disappeared when the model was controlled for congestive heart failure and diabetes mellitus. The apparent association may be due to factors other than inhibition of SGLT2. Clinicians should prioritize diagnosing and managing iron metabolism disorders in high-risk populations, such as those with heart failure, regardless of SGLT2 inhibitor use.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 17","pages":"3990-3993"},"PeriodicalIF":7.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616296","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":"A system perspective on drug response.","authors":"Vlad Elgart, Joseph Loscalzo","doi":"10.1111/bph.70128","DOIUrl":"https://doi.org/10.1111/bph.70128","url":null,"abstract":"<p><p>The effect of drug perturbation(s) is quantified by measuring a specific phenotype. While drug action occurs on a molecular (microscopic) level, the measured phenotypes typically characterise system-level (macroscopic) variables, such as blood pressure or cell viability. Existing drug perturbation models are designed to infer (dosage-dependent) drug effects on the phenotype by analysis of the drug-induced changes in microscopic variables, such as gene expression or metabolite concentration. These changes are used to establish patterns in observed macroscopic variables. Here, we review conventional analysis of drug response and introduce a simple phenomenological description of drug response directly on a macroscopic level. We demonstrate how this approach can be used to establish a framework for quantifying dose-dependent changes in phenotype induced by low concentrations of a single drug or drug combinations.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616288","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":"Novel approaches for the discovery of pharmacogenetic biomarkers of chemotoxicity in patients with colorectal cancer","authors":"Ana Rita Simoes,&nbsp;Silvia Carlés González,&nbsp;María del Carmen Lopez-Doldan,&nbsp;Goretti Duran,&nbsp;Ana Fernández-Montes,&nbsp;Maria Perfecta Fernandez,&nbsp;Mercedes Salgado Fernandez,&nbsp;Jesus Garcia Mata,&nbsp;David Paez,&nbsp;Pau Riera,&nbsp;Elisabeth Guino,&nbsp;Luis Lopez-Fernandez,&nbsp;Belen Garcia de Santiago,&nbsp;Elena López Aspiroz,&nbsp;Augusto Rojas,&nbsp;Antoni Castells,&nbsp;Sergi Castellvi-Bel,&nbsp;Clara Ruiz Ponte,&nbsp;Veronika Vymetalkova,&nbsp;Angel Carracedo,&nbsp;Ceres Fernandez-Rozadilla","doi":"10.1111/bph.70051","DOIUrl":"10.1111/bph.70051","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Chemotherapeutic treatment for colorectal cancer (colorectal cancer) allows for increased patient overall survival. However, current therapeutic regimens are often associated with the development of adverse drug reactions, which represent a morbidity, mortality and economic issue. We propose to identify novel germline markers that allow us to predict adverse drug reactions development after colorectal cancer chemotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>For that purpose, we selected 163 colorectal cancer patients with severe adverse drug reactions (CTCAE grades 3–4) and 52 controls and applied whole-exome sequencing (WES) to discover novel germline toxicity variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We found 13 cases carrying actionable dihydropyrimidine dehydrogenase gene (<i>DPYD</i>) variants and a novel, potentially pathogenic <i>DPYD</i> variant – c.2071G &gt; T, p.(V691L), rs202212118. Moreover, we found 30 novel rare, high-impact variants in 14 reported genes. We also identified seven patients carrying more than one variant in the same gene or pathway, with one patient hinting at a potential digenic inheritance. Using an exome-wide approach, we discovered and independently validated three novel candidate toxicity genes (<i>ALDH9A1</i>, <i>FAM83A</i> and <i>EPX</i>). Gene-based analyses also provided 14 genes significantly associated with neuropathy, skin toxicity and cardiotoxicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Overall, the present work has utilised state-of-the-art approaches to uncover several novel candidate toxicity variants/genes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 21","pages":"5340-5354"},"PeriodicalIF":7.7,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583172","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":"Cannabinoid CB2 receptor-mediated analgesia: mechanism-based insights and therapeutic potential","authors":"Kelsey G. Guenther,&nbsp;Andrea G. Hohmann","doi":"10.1111/bph.70116","DOIUrl":"10.1111/bph.70116","url":null,"abstract":"<p>Agonists of the cannabinoid 2 (CB₂) receptor have shown promise for the treatment of pain in a variety of animal models. However, despite current preclinical evidence supporting the use of CB₂ agonists for pain, successful translation of findings from preclinical models to human patients is lacking. This gap may reflect an incomplete understanding of the types of pain that best respond to CB₂ receptor activation, as well as limited knowledge of mechanisms underlying CB₂-mediated attenuation of pain behaviours. Additionally, how ligand-specific biased signalling impacts CB₂-mediated analgesia in various types of pain has not been well characterized. Here, we review the preclinical literature that has examined the potential therapeutic efficacy of CB₂ agonists in rodent pain models associated with inflammation, traumatic nerve injury, toxic neuropathy (e.g. due to chemotherapy and anti-retroviral treatment), post-surgical pain, visceral pain and disease-associated (e.g. due to cancer, arthritis and diabetes) pain states. We also discuss what is currently known about the mechanisms underlying these effects with an emphasis on insights derived from recently developed CB₂ reporter mice and conditional knockout (cKO) mouse models. These tools compensate for limitations of functional (rather than complete) global knockout (KO) mouse lines and lack of specificity of available CB₂ receptor antibodies to provide a more comprehensive understanding of CB₂-mediated analgesic mechanisms.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 21","pages":"5090-5118"},"PeriodicalIF":7.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70116","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559259","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":"Stabilisation of PRCP by deubiquitinase-targeting chimera (DUBTAC) to replenish autophagy for ameliorating pathological cardiac hypertrophy","authors":"Fangchao Zhou,&nbsp;Jun Xia,&nbsp;Yingjuan Liu,&nbsp;Wenqi He,&nbsp;Hongyuan Zhang,&nbsp;Bernard D. Keavney,&nbsp;Min Zi,&nbsp;Binh Y. Nguyen,&nbsp;Tamer M. A. Mohamed,&nbsp;Jessica M. Miller,&nbsp;Riham R. E. Abouleisa,&nbsp;Susanne S. Hille,&nbsp;Elizabeth J. Cartwright,&nbsp;Oliver J. Müller,&nbsp;Honglin Xu,&nbsp;Sam Butterworth,&nbsp;Xin Wang","doi":"10.1111/bph.70094","DOIUrl":"10.1111/bph.70094","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Autophagy is essential for cellular homeostasis, and its impairment contributes to cardiac hypertrophy. Modulating autophagy has shown potential in treating pathological hypertrophy. Prolylcarboxypeptidase (PRCP), a lysosomal enzyme that hydrolyzes angiotensin II to Ang1-7, has an unclear role in cardiac autophagy and hypertrophy. This study explores PRCP’s function in regulating autophagy under hypertrophic stress and its potential as a therapeutic target.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Transverse aortic constriction (TAC) was used to induce hypertrophy in mice. PRCP-knockout (PRCP^KO) mice were generated using CRISPR/Cas9, while PRCP was overexpressed in the heart using adeno-associated virus 9. Cardiac function was evaluated via echocardiography and histological analysis. Autophagy markers were assessed by immunostaining, electron microscopy, and protein expression. In vitro, PRCP expression was manipulated in H9c2 cells. A novel DUBTAC compound was also synthesized to stabilize PRCP, and its protective effects were tested in H9c2 cells and hESC-derived cardiomyocytes under isoprenaline-induced stress.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>PRCP^KO mice developed more severe cardiac hypertrophy, fibrosis, and diastolic dysfunction after TAC. These mice showed reduced autophagosome formation and decreased expression of autophagy-related proteins WDR1 and WIPI1. In contrast, PRCP overexpression mitigated hypertrophy and preserved autophagy. Mechanistically, PRCP regulated autophagy via the interaction of WDR1 with WIPI1. Stabilizing PRCP with DUBTAC prevented its degradation and maintained autophagy under hypertrophic conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>PRCP is a previously unrecognized regulator of autophagy in the heart. Enhancing PRCP expression or stabilizing it pharmacologically via DUBTAC represents a novel and effective therapeutic approach for managing pathological cardiac hypertrophy and improving cardiac health.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 21","pages":"5317-5339"},"PeriodicalIF":7.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70094","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526492","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":"Structure–activity relationship of the allosteric effects of ivermectin at human P2X4 and GABAA receptors","authors":"Jessica L. Meades,&nbsp;Marcella Bassetto,&nbsp;Marius C. Staiculescu,&nbsp;Gayathri Swaminath,&nbsp;Samuel J. Fountain","doi":"10.1111/bph.70121","DOIUrl":"10.1111/bph.70121","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and purpose</h3>\u0000 \u0000 <p>Positive allosteric modulation of the P2X4 receptor is a potential route to providing cardiovascular benefit through enhancing flow-dependent arterial vasodilation and providing cardioprotection. However, ligands that selectively enhance P2X4 activity are absent. The broad-spectrum antiparasitic ivermectin (MK-933) is a known positive allosteric modulator of P2X4, but not selective for P2X4, acting to enhance the activity of other ion channels including the GABA_A receptor through which its neurotoxic and anti-convulsant properties are mediated. Here, we combine complementary methodology to investigate the structure–activity relationship of ivermectin at human P2X4 and GABA_A receptors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach and key results</h3>\u0000 \u0000 <p>Intracellular Ca²⁺ and membrane potential assays in cell lines expressing human P2X4 or human GABA_A α1β3γ2 receptor are used, respectively. A chemical library of ivermectin analogues are pharmacologically characterised at both receptors, and in silico techniques are used to identify ligand binding modes in human P2X4 to interpret pharmacological properties. We identify ivermectin-B1a as a positive allosteric modulation of P2X4, but full agonist at the GABA_A α1β3γ2 receptor. We discover that the large disaccharide moiety of ivermectin-B1a is not required for activity. We identify an intersubunit transmembrane domain binding mode for ivermectin-B1a in P2X4 supported by the structure–activity relationship of ivermectin analogues. A series of novel compounds with selectivity for P2X4 over GABA_A receptor are identified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and implications</h3>\u0000 \u0000 <p>Ivermectin-B1a enhances P2X4 and GABA_A α1β3γ2 receptor activity but through differing pharmacological mechanisms. We identify pharmacophore information for the development of positive allosteric modulators selective for human P2X4 over GABA_A receptors.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 21","pages":"5286-5302"},"PeriodicalIF":7.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70121","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494712","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}