British Journal of Pharmacology最新文献

{"title":"A covalent peptide engager approach to equip immunotherapeutic monoclonal and pan IgG serum antibodies with new tumour-targeting function","authors":"Karolina Krygier, Sandra Szu-Wei Hwang, Anthony F. Rullo","doi":"10.1111/bph.70564","DOIUrl":"10.1111/bph.70564","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Site-specific antibody modification is a useful chemical strategy to elaborate antibody therapeutic function. Conventional lysine- or cysteine-based conjugation methods generate heterogeneous products, while protein engineering approaches are resource-intensive. Affinity-guided covalent strategies using antibody binding peptides offer a chemical alternative for selective antibody functionalisation but are limited by challenges with incorporating reactive electrophiles into complex peptide ligands.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We developed covalent peptide engagers (CPEs) that equip antibodies with new tumour-targeting function. CPEs integrate an Fc-binding peptide, SuFEx electrophile and a target-engager moiety. CPEs were synthesised and evaluated in covalent labelling kinetics and selectivity assays using SDS-PAGE gels and biolayer interferometry (BLI). Functional activity was evaluated using tumour cell-immune cell co-culture assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>A first-in-class CPE was synthesised incorporating a latent protein-reactive electrophile within a complex Fc-binding peptide. CPEs demonstrate sufficient selectivity/kinetics for site-selective antibody modifications. We observed SuFEx peptide ligand compatibility is dependent on the presence of internal tyrosine or histidine residues, which can inactivate the covalent peptide and/or enhance hydrolysis rate. Anti-tumour function of IgG-CPE was validated by antibody-dependent cellular phagocytosis, demonstrating robust phagocytosis of urokinase-type plasminogen activator receptor (uPAR)-expressing tumour cells. Herceptin functionalised with uPAR-CPE enabled dual-antigen-targeting via phagocytosis of cells co-expressing HER2 and uPAR, consistent with avidity effects associated with engagement of two tumour antigens.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>CPEs enable covalent reprogramming of endogenous IgG and monoclonal antibodies, offering an alternative to protein engineering for the rapid generation of multi-specific antibodies and therapeutic engagement of humoral immunity across cancer and infectious disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> LINKED ARTICLES</h3>\u0000 \u0000 <p>This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 22","pages":"6685-6703"},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70564","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419005","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":"Expanding the landscape of covalent drug discovery: irreversible targeting of non-cysteine residues","authors":"Bharath Srinivasan,&nbsp;John B. Taylor","doi":"10.1111/bph.70604","DOIUrl":"10.1111/bph.70604","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <p>Covalent inhibitors have re-emerged as a powerful class of therapeutics due to their prolonged target engagement, ability to decouple pharmacokinetic availability from pharmacodynamic outcome, potential for high selectivity and ability to modulate traditionally ‘undruggable’ targets. Historically, cysteine residues have dominated covalent drug discovery owing to their unique nucleophilicity and relative scarcity in the proteome. However, the desire to broaden the chemical scope of covalent therapeutics has driven a surge of interest in irreversibly targeting other amino acid residues, such as lysine, serine, tyrosine, threonine and histidine. This review explores the outstanding questions and challenges in developing covalent inhibitors beyond cysteine, highlighting current warhead chemistries, strategies for achieving selectivity, proteomic mapping advances, assessment of the intrinsic reactivity of the electrophiles targeting non-cysteine residues and opportunities for expanding the druggable proteome. We also discuss future directions and the pharmacological implications of non-cysteine covalent modifications in therapeutic contexts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> LINKED ARTICLES</h3>\u0000 \u0000 <p>This article is part of a themed issue Re-emergence of Covalent Modulation in Drug Discovery. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.22/issuetoc</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 22","pages":"6627-6648"},"PeriodicalIF":7.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469204","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":"CRISPR screens identify ACSL4 as a key regulator in macrophage activation and metabolic inflammation.","authors":"Yanting Lin, Dongquan Jing, Yiming Liu, Rui Gao, Qixiang Zhao, Xingyu Jiang, Huijuan Da, Yiming Ren, Qiuhua Cao, Jingwei Jiang, Yuanyuan Sun, Yong Yang, Xinghua Gao","doi":"10.1111/bph.70681","DOIUrl":"https://doi.org/10.1111/bph.70681","url":null,"abstract":"<p><strong>Background and purpose: </strong>Pro-inflammatory macrophages drive obesity-associated metabolic inflammation. Identifying key regulators of their activation is crucial for new therapies. This study aimed to identify novel regulators of pro-inflammatory adipose tissue macrophage (ATM) activation and assess their therapeutic potential.</p><p><strong>Experimental approach: </strong>We combined genome-wide CRISPR-Cas9 screening with scRNA-seq data from human adipose tissue and identified long-chain acyl-CoA synthetase 4 (ACSL4) as critical for pro-inflammatory ATM activation. Validation used myeloid-specific Acsl4 knockout mice (Acsl4^fl/fl Lyz2^Cre) and shRNA-mediated knockdown in macrophage cell lines (RAW264.7, THP-1, and iBMDM). Mechanisms were explored via mutagenesis, immunostaining, co-immunoprecipitation (co-IP), bimolecular fluorescence complementation (BiFC), and transcriptional activity assays. A high-throughput screen of 8,685 DrugBank compounds was performed to identify candidates targeting ACSL4.</p><p><strong>Key results: </strong>ACSL4 deficiency markedly reduced pro-inflammatory factor expression (Tnfα, Il1β, and Il6). Myeloid ACSL4 deletion protected against high-fat diet (HFD)-induced obesity, correlated with reduced pro-inflammatory ATMs and enhanced adipocyte lipolysis and thermogenesis, without affecting food intake, water intake, or locomotor activity in mice. However, glucose tolerance and insulin sensitivity were not significantly affected. Mechanistically, ACSL4 contributed to inflammation independent of its enzymatic/ferroptotic functions (Thr328 mutation, troglitazone insensitivity). Instead, ACSL4 translocated to the nucleus in a karyopherin β1 (KPNB1)-dependent manner. DrugBank screening identified abemaciclib as a potential inhibitor of the ACSL4-KPNB1 interaction. Notably, abemaciclib treatment reduced macrophage inflammation and attenuated HFD-induced obesity in mice.</p><p><strong>Conclusions and implications: </strong>ACSL4 promotes pro-inflammatory macrophage activation through its KPNB1-dependent nuclear translocation and cooperation with IRF5. Targeting the ACSL4-KPNB1 interaction may represent a potential therapeutic strategy for metabolic inflammation.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206430","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":"Investigation of the mechanisms and modulation of irinotecan-induced emesis in Suncus murinus.","authors":"Zengbing Lu, Julia Y H Liu, Yasuhiro Nakagami, Zitong Li, Xiaofei Huang, Man P Ngan, Dexuan Cui, John A Rudd","doi":"10.1111/bph.70702","DOIUrl":"https://doi.org/10.1111/bph.70702","url":null,"abstract":"<p><strong>Background and purpose: </strong>Irinotecan is a widely used chemotherapeutic agent that frequently causes nausea and emesis. Its emetic mechanism of action is poorly understood and the choice of drugs to reduce nausea and emesis is largely empirical.</p><p><strong>Experimental approach: </strong>Using Suncus murinus, we examined (i) the dose-response and temporal profile of irinotecan-induced emesis; (ii) emetic potential of its active metabolite, SN-38; (iii) involvement of vagal and central pathways; (iv) efficacies of classical antiemetics administered alone, or in combinations. Behavioural, respiratory, metabolic and c-Fos immunohistochemical analyses were used to delineate mechanisms involved in emesis control. A microelectrode array (MEA) system assessed the effects of irinotecan and SN-38 on gastrointestinal slow-wave activity.</p><p><strong>Key results: </strong>Irinotecan induced dose-dependent emesis within 24 h, whereas SN-38 was inactive. Neither compound altered respiration. Bilateral abdominal vagotomy attenuated early-phase (0-4 h) of irinotecan-induced emesis. Palonosetron suppressed emesis and was the most effective monotherapy; olanzapine alone also showed antiemetic efficacy. Notably, olanzapine-containing combinations with palonosetron and aprepitant or dexamethasone provided superior protection compared with monotherapies. Irinotecan increased c-Fos expression in the brainstem, and hypothalamic and limbic regions; palonosetron selectively reduced brainstem activation. Serum metabolomics revealed reduced tyramine levels and associations between emetic episodes and 5-HT-related pathways. MEA recordings showed that irinotecan, but not SN-38, produced selective disruptions of upper-gut rhythmic activity.</p><p><strong>Conclusion and implications: </strong>Irinotecan-induced emesis is mediated predominantly through 5-HT₃-dependent vagal-brainstem pathways with additional activation of hypothalamic and limbic regions. Altered intestinal pacemaker activity and 5-HT metabolism may contribute to gastrointestinal adverse effects.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191398","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 PTPRO inhibitor Pi mitigates endotoxemia-induced encephalopathy-mediated blood-brain barrier disruption through cytoskeletal regulation.","authors":"Fengjiao Wu, Haitao Tang, Qianqian Xiong, Jing Shi, Chang Li, Jun Qian, Haoxuan Jia, Jiwei Hu, Qingqing Yang, Xuemeng Li, Zhengyan Pan, Guiping Liu, Mengjie Tang, Hongtao Wang, Huaxue Wang, Zhongqing Qian, Ting Wang","doi":"10.1111/bph.70682","DOIUrl":"https://doi.org/10.1111/bph.70682","url":null,"abstract":"<p><strong>Background and purpose: </strong>Septic encephalopathy (SE) is closely associated with disruption of blood-brain barrier (BBB), resulting in neurological deficits and poor clinical outcomes. Protein tyrosine phosphatase receptor type O (PTPRO) regulates disease states by dephosphorylating membrane-associated proteins and modulating intracellular signalling. Here we have examined the role of PTPRO in regulating BBB permeability and have assessed a PTPRO inhibitor (Pi) in mitigating BBB disruption during endotoxemia-associated encephalopathy.</p><p><strong>Experimental approach: </strong>Genetic and pharmacological approaches, including PTPRO overexpression, knockdown or deficiency and Pi treatment, were used to evaluate endothelial dysfunction in bEND.3 cells, primary mouse brain microvascular endothelial cells and an LPS-induced murine model of endotoxemia-associated encephalopathy. Barrier dysfunction, cytoskeletal remodelling and signalling events were assessed using permeability assays, immunoblotting, immunofluorescence and in vivo BBB leakage analyses.</p><p><strong>Key results: </strong>LPS increased PTPRO expression in brain tissue from endotoxemic mice and cerebral endothelial cells. Elevated PTPRO promoted F-actin reorganization, stress fibre formation and intercellular gap formation, whereas Pi treatment or PTPRO silencing attenuated these changes. PTPRO overexpression worsened endothelial barrier dysfunction, while Pi reduced thrombin-induced permeability in bEND.3 cells and wild-type primary endothelial cells. Primary endothelial cells from PTPRO-deficient mice were protected. Mechanistically, PTPRO regulated cytoskeletal dynamics through the ErbB2-Rho-MLC2 pathway. In vivo, Pi treatment and PTPRO deficiency reduced BBB leakage, with limited effects on inflammatory cytokines.</p><p><strong>Conclusion and implications: </strong>These findings identify PTPRO as an important regulator of BBB disruption in endotoxemia-associated encephalopathy and support pharmacological targeting of PTPRO as a potential strategy for preserving sepsis-associated BBB injury.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191393","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":"High-resolution pressure myography reveals pressure-dependent local contractile and geometric dynamics in the renal pelvis and ureter.","authors":"Zhugang Chu, Qidi Zhai, Liming Lu, Maik Gollasch, Dmitry Tsvetkov, Rong Dong, S R Wayne Chen, Gang Fan, Guangheng Luo, Mario Kassmann","doi":"10.1111/bph.70695","DOIUrl":"https://doi.org/10.1111/bph.70695","url":null,"abstract":"<p><strong>Background and purpose: </strong>Coordinated peristalsis between the renal pelvis and ureter is critical for effective urine transport. However, intraluminal pressure impact on upper urinary tract (UUT) contractility and pharmacologic responsiveness remains poorly understood due to absence of suitable investigative methods.</p><p><strong>Experimental approach: </strong>This study introduces the first application of high-resolution pressure myography to UUT, establishing a novel ex vivo platform enabling simultaneous, intraluminal pressure-controlled local measurement of renal pelvic contraction frequency and amplitude and ureteral inner diameter, outer diameter, and wall thickness. To define contribution of specific Ca²⁺ signaling pathways, we pharmacologically examined Ca_v1.2 L-type, Ca_v3.x T-type, and ryanodine receptor channels, as well as sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) and neuronal involvement.</p><p><strong>Key results: </strong>Elevating intraluminal pressure from 4 to 20 mmHg increased renal pelvic contraction frequency, while amplitude markedly decreased. Ureteral wall thinning was the main structural adaptation. Nifedipine reduced renal pelvic contraction amplitude and frequency and suppressed ureter peak contraction, all with reduced efficacy under high-pressure conditions. Ni²⁺ affected renal pelvic contractility only at high concentrations and had no effect on ureteral dynamics. Ryanodine did not alter measured parameters, and Na⁺ and N-type Ca²⁺ channels were not involved.</p><p><strong>Conclusions and implications: </strong>High-resolution pressure myography reveals pressure-dependent local contractile and geometric responses in UUT, including altered contraction dynamics, ureteral geometric remodeling, and specific Ca²⁺ channel contributions. Ca_v1.2 channels modulate both amplitude and frequency, with wall thinning as principal acute structural adaptation. Reduced drug efficacy at high pressure highlights necessity to investigate possible pressure-adapted therapies in obstructive uropathy.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164364","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":"Cholinergic inputs to motoneurons in the spinal cord augment focal muscle spasticity in rodents.","authors":"Patrik Meglić, Petra Šoštarić, Eirini Tsape, Melpomeni Galani, Ana Knezović, Laura Restani, Marco Pirazzini, Ornella Rossetto, Gareth B Miles, Laskaro Zagoraiou, Ivica Matak","doi":"10.1111/bph.70708","DOIUrl":"https://doi.org/10.1111/bph.70708","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cholinergic premotor inputs to motoneurons support high levels of motor output when required. However, the possible role of these inputs in pathologically elevated muscle tone has not been characterised. To address this, we examined the modulatory effect of spinal acetylcholine (ACh) on experimental spastic paralysis.</p><p><strong>Experimental approach: </strong>Rats were injected with tetanus neurotoxin (TeNT, 33-100 pg, im) into gastrocnemius to induce sustained rigid hind-paw extension and resistance to passive ankle flexion. The effects of spinal ACh on experimental hypertonia were probed by lumbar intrathecal application of the AChE inhibitor neostigmine (NEO) or a muscarinic M₂ receptor antagonist (AQ-RA 741). Effects of NEO on extracellular ACh were measured in the facial nucleus after TeNT (33 pg) or botulinum toxin A (BoNT/A, 2 U) injection into the rat whisker pad. The intensity of TeNT-evoked hindlimb hypertonia (10 pg, im) was assessed in mice with genetic ablation of cholinergic C bouton source interneurons (V0_C interneurons).</p><p><strong>Key results: </strong>NEO augmented the severity of TeNT-evoked hypertonia, whereas AQ-RA 741 attenuated it. Local perfusion of NEO caused a BoNT/A-sensitive increase in extracellular ACh concentration. The involvement of cholinergic C boutons was corroborated by reduced hypertonia following TeNT challenge (10 pg, im) in V0_C-ablated mice.</p><p><strong>Conclusions and implications: </strong>Our results suggest that spinal cholinergic transmission, associated with vesicular ACh release and M₂ signalling at C boutons, exacerbates experimental spastic paralysis. We reveal a new role for endogenous spinal ACh, with implications for developing new therapeutic approaches to treat spasticity and hyperkinetic movement disorders.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179548","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":"Ginsenoside Ra1 alleviates endothelial barrier dysfunction and multi-organ injury in experimental sepsis via NMMHC IIA inhibition.","authors":"Jiahui Tang, Haiyu Chen, Mengchen Xu, Shengpeng Zhang, Boyang Yu, Yuanyuan Zhang, Shuaishuai Gong, Junping Kou","doi":"10.1111/bph.70689","DOIUrl":"https://doi.org/10.1111/bph.70689","url":null,"abstract":"<p><strong>Background and purpose: </strong>Non-muscle myosin heavy chain IIA (NMMHC IIA) has emerged as a significant therapeutic target in vascular diseases and sepsis. However, effective interventions targeting NMMHC IIA in sepsis-induced endothelial dysfunction remain unelucidated. Here, we have assessed ginsenoside Ra1 (Ra1) as a potent NMMHC IIA inhibitor and evaluate its efficacy and underlying mechanisms in sepsis.</p><p><strong>Experimental approach: </strong>We used the caecal ligation and puncture model of polymicrobial sepsis in mice. Survival rate, body temperature, pathological changes, vascular permeability and plasma biochemical indicators were measured to evaluate the effects of Ra1 treatment. Molecular docking technique, cellular thermal shift assay, microscale thermophoresis assay and surface plasmon resonance were performed to confirm the binding of Ra1 with NMMHC IIA. Downstream genes affected by Ra1 were screened via RNA-sequencing and validated using western blotting and immunofluorescence. In vitro, a lipopolysaccharide-induced endothelial barrier injury model in human umbilical vein endothelial cells was established, and endothelial permeability was evaluated.</p><p><strong>Key results: </strong>Ra1 bound strongly to NMMHC IIA, whose knockdown ameliorated sepsis-induced endothelial barrier disruption and multi-organ injury (lung, intestine, liver and kidney). Ra1 attenuated mortality, hypothermia, multi-organ injury, vascular hyperpermeability and endothelial junction disruption in septic mice. Mechanistically, Ra1 inhibited TLR4/NF-κB/NLRP3 signalling to exert its protective effects, which were absent after NMMHC IIA was silenced, demonstrating an NMMHC IIA-dependent mechanism.</p><p><strong>Conclusion and implications: </strong>Our findings identify Ra1 as a potential inhibitor of NMMHC IIA and provide mechanistic insight into therapeutic strategies targeting endothelial dysfunction in sepsis, which warrants further investigation in clinical studies.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178779","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":"BeatVecNet classifies drug-induced contractile phenotypes from beat-gated motion vectors in micropatterned human induced pluripotent stem cell-derived cardiomyocytes.","authors":"Shigeyuki Magi, Yasunari Kanda, Atsuhiko T Naito","doi":"10.1111/bph.70710","DOIUrl":"https://doi.org/10.1111/bph.70710","url":null,"abstract":"<p><strong>Background and purpose: </strong>Assessment of electrophysiological cardiotoxicity in vitro has advanced, yet scalable assays for contractile dysfunction remain limited. BeatVecNet, an interpretable deep-learning framework, classifies drug-induced contractile phenotypes from beat-gated motion vectors in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).</p><p><strong>Experimental approach: </strong>BeatVecNet was developed and evaluated using beat-gated motion-vector tensors derived from hiPSC-CMs recorded by label-free phase-contrast imaging at 150 fps. hiPSC-CMs were cultured on micropatterned substrates to provide a consistent contraction axis for directional motion analysis. Dense optical flow was used to derive motion vectors, which were retained as beat-gated spatiotemporal tensors rather than reduced to scalar traces. The model uses two convolutional branches to process horizontal and vertical velocity components separately and was evaluated on independent assays containing control, doxorubicin, trastuzumab and sunitinib.</p><p><strong>Key results: </strong>BeatVecNet distinguished drug-induced contractile phenotypes with a macro-F1 of 0.916, outperforming conventional kinematic classifiers (best baseline 0.706), with the largest advantage at low doses. Branch-replacement ablation indicated non-redundant contributions of horizontal and vertical motion components, with trastuzumab classification showing greater sensitivity to horizontal-component replacement and sunitinib classification to vertical-component replacement. Phase-resolved attribution further identified temporal patterns within the beat cycle not explained by peak velocity alone. Micropatterning improved signal consistency and contractile coherence, enabling robust directional motion analysis.</p><p><strong>Conclusion and implications: </strong>BeatVecNet extracts drug-associated contractile signatures not captured by conventional scalar analysis while providing direction- and phase-resolved interpretability at the motion-representation level. This platform complements electrophysiology-centred safety assessment and provides proof of concept for classification of subtle drug-induced contractile phenotypes.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179596","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":"Highly potent, brain-penetrant EP₂ receptor antagonists for the treatment of permanent focal cerebral ischaemia in male and female mice.","authors":"Zhen Jin, Chenyao Jiang, Eun Bee Cho, M Dennis Leo, Jiukuan Hao, Jiawang Liu, Ying Yu, Jianxiong Jiang","doi":"10.1111/bph.70709","DOIUrl":"https://doi.org/10.1111/bph.70709","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cerebral ischaemia is a leading cause of death in older adults and imposes a substantial global economic burden. Recent studies indicate that inhibiting the Gα_s-coupled EP₂ receptor reduces ischaemic brain injury by modulating neuroinflammation. However, these findings derive from the transient middle cerebral artery occlusion (tMCAO) model, which represents only a small subset of large-vessel occlusion (LVO) cases with successful recanalisation.</p><p><strong>Experimental approach: </strong>We characterised the pharmacokinetic parameters of selective EP₂ antagonists CJ-18, CJ-19 and CJ-21 that we recently developed. We evaluated their therapeutic efficacy in mice subjected to permanent MCAO (pMCAO), a model that more accurately reflects the majority of LVO cases, and assessed the impact of EP₂ inhibition on brain injury and inflammation. Finally, we examined the effects of EP₂ inhibition in neuron-glia mixed cultures exposed to oxygen-glucose deprivation (OGD) without reoxygenation.</p><p><strong>Key results: </strong>After systemic administration in mice, new compounds exhibited favourable plasma half-lives and brain penetration. In the pMCAO model, treatment with EP₂ antagonists significantly reduced brain infarction in both male and female mice, in a dose-dependent manner, whilst improving sensorimotor performance without affecting muscle strength. These benefits were accompanied by reduced neuronal death, lowered pro-inflammatory cytokines and attenuated reactive gliosis within the ischaemic penumbra. In addition, EP₂ inhibition by CJ-18 conferred marked neuroprotection in neuron-glia co-cultures exposed to prolonged OGD, preserving neurite integrity and postsynaptic density.</p><p><strong>Conclusions and implications: </strong>This proof-of-concept study supports our drug-like EP₂ receptor antagonists, particularly CJ-18, as potential treatments for permanent focal cerebral ischaemia.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164790","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}