British Journal of Pharmacology最新文献

{"title":"A novel quinoline and manganese-based carbon monoxide-releasing molecule for intravesical therapy of bladder cancer","authors":"Jing Jin,&nbsp;Yao Jin,&nbsp;Rong Zhang,&nbsp;Ying Li,&nbsp;Zhi-Ying Zhou,&nbsp;Jin-Peng Feng,&nbsp;Yan-Tong Liu,&nbsp;Zhi-Jie Sun,&nbsp;Zhi-Yin Xiao,&nbsp;De-Li Dong","doi":"10.1111/bph.70614","DOIUrl":"10.1111/bph.70614","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Bladder cancer remains a significant burden on public health globally. Carbon monoxide (CO) has emerged as a promising therapeutic agent for cancers because of its key role in inducing mitochondrial dysfunction and metabolic reprogramming in cancer cells; however, its clinical translation has been hindered by systemic toxicity because of its binding to haemoglobin, which is avoided by localised intravesical therapy via the bladder. This study aimed to develop and characterise a novel manganese(I)-based CO releasing molecular MnCORM as a therapeutic agent against bladder cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>A new MnCORM chelate of a quinoline derivative was synthesised and characterised, and its anti-cancer efficacy was assessed using a 2D bladder cancer cell model, a 3D tumour spheroid model, and a murine orthotopic bladder cancer model. Molecular mechanisms were explored via staining assays, transmission electron microscopy (TEM) and western blots.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>MnCORM inhibited cell viability and induced cell death in T24 and RT112 bladder cancer cells. MnCORM activated AMPK, whereas the AMPK inhibitor Compound C mitigated MnCORM-induced cytotoxicity in T24 cancer cells. MnCORM induced AMPK-triggered and Drp1-dependent mitochondrial fission, promoted reactive oxygen species (ROS) accumulation, and induced mitophagy-associated cell death. The inhibitory effect of MnCORM on tumour growth was validated in a 3D tumour spheroid model and further proven in an orthotopic bladder cancer model in nude mice after intravesical instillation of MnCORM (1 mg kg⁻¹).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Our work shows that MnCORM could be potentially applied for bladder cancer therapy through intravesical instillation with less systemic toxicity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 21","pages":"6404-6421"},"PeriodicalIF":7.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618519","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":"TRPV3 drives lung injury by sensing inflammatory signals to disrupt alveolar epithelial barrier and promote inflammation.","authors":"Chuchu Xi, Fang Zhao, Lin Li, Yujing Wang, Hongrong Fu, Xiao Zhang, Heng Zhang, Michael X Zhu, Zhengyu Cao","doi":"10.1111/bph.70706","DOIUrl":"https://doi.org/10.1111/bph.70706","url":null,"abstract":"<p><strong>Background and purpose: </strong>Pulmonary inflammation is a central pathological feature of many respiratory diseases. Transient receptor potential vanilloid 3 (TRPV3), a non-selective cation channel abundantly expressed in the skin, nerve and lung tissues, is involved in itch, skin inflammation and barrier regulation. However, its function in the pulmonary system remains elusive. We aimed to determine whether and how TRPV3 is involved in pulmonary inflammation.</p><p><strong>Experimental approach: </strong>Lipopolysaccharide (LPS) and carvacrol were used to model acute lung injury (ALI) in C57BL/6J mice. Histology, bronchoalveolar lavage fluid analysis, qPCR, Western blotting, immunofluorescence, Ca²⁺ imaging, transepithelial electrical resistance and FITC-dextran permeability assays were used to assess inflammatory cell infiltration, cytokine expression, intracellular Ca²⁺ changes and epithelial barrier integrity.</p><p><strong>Key results: </strong>TRPV3 expression is markedly up-regulated in lung tissues of ALI mice. Pharmacological activation of TRPV3 by carvacrol triggers features of ALI. Genetic deletion or pharmacological inhibition of TRPV3 significantly attenuated LPS- or carvacrol-induced lung injury. Activating TRPV3 in cultured alveolar epithelial cells increased intracellular Ca²⁺, boosted cytokine/chemokine production, disrupted tight junctions, reduced transepithelial electrical resistance and increased epithelial permeability. TNF-α augmented TRPV3 Ca²⁺ responses, and inhibition of TRPV3 activity or suppression of TRPV3 expression abolished TNF-α-induced production of cytokines/chemokines and tight junction disruption.</p><p><strong>Conclusions and implications: </strong>TRPV3 senses inflammatory signals to augment inflammation and disrupt tight junctions in alveolar epithelial cells, making it a promising molecular target to develop treatments for pulmonary inflammation.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147286","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":"Association of altered body composition with cardiac wasting in cancer with and without cardiotoxic therapy.","authors":"Sara Hadzibegovic, Jonathan L Hella, Jan Porthun, Alessia Lena, Danara Krug, Iulia Baluta, Ursula Wilkenshoff, Amir A Mahabadi, Matthias Totzeck, Tienush Rassaf, Stefan D Anker, Wolfram Doehner, Ulrich Keller, Lars Bullinger, Dominik P Modest, Barry J A Laird, Richard J E Skipworth, John G F Cleland, Christian Oeing, Stephan von Haehling, Ulf Landmesser, Markus S Anker","doi":"10.1111/bph.70639","DOIUrl":"https://doi.org/10.1111/bph.70639","url":null,"abstract":"<p><strong>Background and purpose: </strong>In advanced cancer, associations among changes in body composition, cardiac wasting and prior cardiotoxic anticancer therapy have not been investigated.</p><p><strong>Experimental approach: </strong>Using bioelectrical impedance analysis (BIA), body composition was measured in 206 patients with mostly advanced cancer without known cardiovascular disease or infection (stage III/IV: 84%, prior cardiotoxic anticancer therapy: 55%). Left ventricular (LV) mass was assessed by transthoracic echocardiography and grouped by presence of cardiac wasting according to previously established sex-specific thresholds for LV mass adjusted for height² (<61 g/m² for women, <57 g/m² for men). BIA measurements (indexed to height²) included fat mass index (FMI), fat-free mass index (FFMI), skeletal muscle mass index (SMMI), visceral fat index (VFI), total body water index (TBWI) and extracellular water index (ECWI).</p><p><strong>Key results: </strong>Patients with cancer and cardiac wasting (n = 88) were younger (57±15 vs 62±13 years) and more often women (68% vs 29%) compared to those without cardiac wasting (n = 118). Patients with cardiac wasting had significantly lower FMI (-12%), FFMI (-14%), SMMI (-16%), VFI (-46%), TBWI (-13%) and ECWI (-14%). For women, FFMI was significantly associated with LV mass/height² (r = 0.41) and VFI for men (r = 0.40). In the multivariable linear regression analysis, FFMI was the strongest significant predictor of cardiac wasting, with no significant interaction by sex or previous cardiotoxic therapy.</p><p><strong>Conclusions and implications: </strong>Cardiac wasting in advanced cancer is associated with lower FFMI and VFI independent of prior cardiotoxic therapy.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126542","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":"Multi-omics and machine learning identify neutrophil annexin A3 as a therapeutic target of ginsenoside Rb1 for comorbidity of ischaemic stroke and ulcerative colitis.","authors":"Jiahao Zhou, Peihong Li, Enze Yu, Jinfen Chen, Manfei Zhou, Yiyang Li, Jiacheng Hu, Siqing Guo, Hongyi Hu, Yi Yuan, Yonghua Zhao","doi":"10.1111/bph.70691","DOIUrl":"https://doi.org/10.1111/bph.70691","url":null,"abstract":"<p><strong>Background and purpose: </strong>Epidemiological evidence suggests a bidirectional relationship between ischaemic stroke (IS) and ulcerative colitis (UC), yet the underlying molecular mechanisms remain poorly understood.</p><p><strong>Experimental approach: </strong>Four IS and three UC datasets from the gene expression omnibus (GEO) database were analysed to identify key comorbidity genes. Two-sample Mendelian randomisation (MR) was conducted to infer causal relationships. Clinical validations utilised peripheral blood neutrophils from UC-IS patients, assessed via western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). The direct binding of ginsenoside Rb1 to annexin A3 (ANXA3) was verified through molecular docking, molecular dynamics simulations and cellular thermal shift assay (CETSA).</p><p><strong>Key results: </strong>MR analysis indicated a causal association between ANXA3 expression and increased risk of IS and UC. Immune infiltration analysis demonstrated a strong positive correlation between ANXA3 expression and neutrophil infiltration in both IS and UC. ScRNA-seq confirmed that ANXA3 was expressed in neutrophils within diseased tissues. Circulating neutrophils from UC-IS comorbidity patients showed significantly elevated ANXA3 mRNA and protein levels. Molecular dynamics simulations revealed a stable ginsenoside Rb1-ANXA3 complex with favourable binding free energy. CETSA confirmed the direct binding of ginsenoside Rb1 to ANXA3 in primary human neutrophils. UC-IS serum induced neutrophil hyperactivation, including excessive migration, NETosis, myeloperoxidase (MPO) release and reactive oxygen species (ROS) production, which was significantly attenuated by ginsenoside Rb1 in vitro.</p><p><strong>Conclusions and implications: </strong>ANXA3 is a predominant neutrophil-derived biomarker linking UC-IS comorbidity. Ginsenoside Rb1 mitigates comorbidity-induced neutrophil hyperactivation by directly binding ANXA3, representing a promising therapeutic strategy.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126590","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":"Rifaximin ameliorates memory impairment and Alzheimer's pathological changes in APP/PS1 mice associated with changes in the gut microbiome-bile acids-serum metabolites networks.","authors":"Di Wu, Mei-Tong Nie, Jixian Lin, Yang Liu, Yong Wang, Min Chu, Lan Zheng, Jing Zhao","doi":"10.1111/bph.70643","DOIUrl":"https://doi.org/10.1111/bph.70643","url":null,"abstract":"<p><strong>Background and purpose: </strong>Modifying the brain-gut-microbiota axis has emerged as a promising therapeutic strategy against Alzheimer's disease (AD). Whether rifaximin, a non-absorbed and non-systemic antibiotic, can be applied to the treatment of AD remains unexplored. In this study, we investigated the effects of rifaximin using a APP/PS1 double-transgenic mouse model of AD.</p><p><strong>Experimental approach: </strong>Six-month-old male APP/PS1 mice were administered saline or rifaximin (100 mg·kg^-1) via oral gavage for 2 months. Gut microbiota composition and metabolites were subsequently analysed to elucidate the underlying mechanisms of rifaximin in AD.</p><p><strong>Key results: </strong>Rifaximin modified gut microbiota composition, increasing abundance of Akkermansia muciniphila and Christensenellaceae, while decreasing abundance of Clostridia_UCG-014, Muribaculaceae, Lachnospiraceae, Turicibacter, Eubacterium_xylanophilum_group, Alistipes, Bacteroides_acidifaciens and Eubacterium_brachy groups. Furthermore, rifaximin alleviated memory impairment in APP/PS1 mice, decreased amyloid-β (Aβ) burden and secondary neuroinflammation and attenuated neuronal death and synaptic dysfunction. Metabolomic analysis revealed that rifaximin altered the profile of gut bile acids by decreasing the concentrations of primary (cholic acid and taurocholic acid) and secondary (taurodeoxycholic acid and taurolithocholic acid) bile acids. Additionally, rifaximin enhanced tryptophan metabolism, shown by increased serum 5-HT concentrations. Both microbial and metabolic shifts were closely correlated with gut microbiota composition.</p><p><strong>Conclusions and implications: </strong>Our results showed that rifaximin alleviated spatial working and short-term recognition memory impairment and mitigated Alzheimer's-like pathological changes in APP/PS1 mice, effects accompanied by alterations in the gut microbiota-intestinal bile acid profile-serum metabolites network. Rifaximin could provide a new therapeutic approach to the treatment of AD.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126588","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":"Inhibition of the MER tyrosine kinase ameliorates pulmonary fibrosis by suppressing macrophage M2 polarisation and osteopontin signalling.","authors":"Juan Li, Xiangsheng Yang, Xiao Xiao Tang","doi":"10.1111/bph.70685","DOIUrl":"10.1111/bph.70685","url":null,"abstract":"<p><strong>Background and purpose: </strong>The MER proto-oncogene tyrosine kinase (MERTK) has been implicated in the pathogenesis of pulmonary fibrosis (PF), and MERTK inhibition has been shown to ameliorate PF. However, the mechanisms remain unclear. Here, we have investigated how MERTK inhibition attenuates bleomycin (BLM)-induced PF in mice and to elucidate the underlying mechanism(s).</p><p><strong>Experimental approach: </strong>We analysed transcriptomic datasets from patients with idiopathic pulmonary fibrosis (IPF) to characterise expression patterns of MERTK and their correlation with clinical parameters. In a BLM-induced murine PF model, a selective MERTK inhibitor UNC5293 was evaluated in both preventive and therapeutic dosing regimens. Given its clinical translation potential, the MERTK/FLT3 inhibitor MRX2843 was evaluated in therapeutic regimen. Fibrosis severity and associated pathological changes were assessed using micro-CT, pulmonary function tests and histopathological analysis. Underlying mechanisms were further investigated in human and mouse-derived macrophages, using flow cytometry and immunofluorescence.</p><p><strong>Key results: </strong>MERTK expression was up-regulated in pulmonary macrophages of patients with IPF and was negatively correlated with lung function parameters. In the BLM-induced PF model, UNC5293 attenuated fibrosis and improved pulmonary compliance and capacity, even when administration was initiated during the fibrotic phase. MRX2843 alleviated histological fibrosis but did not improve pulmonary function. Mechanistically, MERTK inhibition concurrently suppressed macrophage M2 polarisation-involving the PI3K/Akt signalling pathway and efferocytosis-and secretion of a profibrotic mediator osteopontin (SPP-1), thereby synergistically inhibiting the fibrotic process.</p><p><strong>Conclusions and implications: </strong>MERTK inhibition represents a promising therapeutic strategy that ameliorates fibrosis by orchestrating suppression of M2 polarisation and SPP-1 pathogenic pathways, thereby restoring pulmonary function.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104328","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":"Effects of lifelong sulforaphane intake on behavioural, neurochemical and biomolecular dysfunctions in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders.","authors":"Vladyslav Sikora, Maria Bove, Lisa Pia Agosti, Rossella Pia Palmieri, Mohsin Zafar, Paolo Tucci, Maria Grazia Morgese, Stefania Schiavone, Luigia Trabace","doi":"10.1111/bph.70693","DOIUrl":"https://doi.org/10.1111/bph.70693","url":null,"abstract":"<p><strong>Background and purpose: </strong>Autism spectrum disorders (ASD) are multifactorial neurodevelopmental conditions associated with oxidative stress and neuroinflammation across critical developmental periods. Sulforaphane (SFN), a natural compound with antioxidant and anti-inflammatory properties, is a potential therapeutic strategy for ASD-related alterations. Therefore, we investigated the effects of lifelong SFN exposure on behavioural, neurochemical and biomolecular dysfunctions in BTBR T + Itpr3tf/J (BTBR) male and female mice.</p><p><strong>Experimental approach: </strong>Self-Grooming, Marble Burying, Hole Board, Open Field and Social Interaction tests were conducted on C57BL/6 and BTBR male and female mice, fed standard or SFN-enriched diet. Moreover, we quantified cortical levels of neurochemical, redox and neuroinflammatory biomarkers, and plasma proinflammatory cytokines.</p><p><strong>Key results: </strong>Lifelong SFN-enriched diet attenuated stereotyped repertoire, improved exploratory activity and social interactions in both BTBR sexes. SFN decreased cortical serotonergic-, noradrenergic- and kynurenine-pathway-related alterations selectively in BTBR males. SFN supplementation enhanced cortical levels of NRF2, NRF2 DNA-binding activity, haem oxygenase-1 (HO-1) and superoxide dismutase (SOD) 1 in both BTBR sexes, elevated SOD activity in males and glutathione levels in females, reduced reactive oxygen species (ROS) production in males, without affecting NRF2 phosphorylation and kelch-like ECH-associated protein-1 (KEAP1). Furthermore, SFN intake rescued central and peripheral IL-6 and TNF-α levels in BTBR mice of both sexes, while reducing IL-1β and IL-17A levels in males.</p><p><strong>Conclusion and implications: </strong>Our findings suggest that lifelong SFN supplementation ameliorates ASD-like behavioural phenotypes in male and female BTBR mice and reveal sex-specific differences in mitigating biomolecular alterations, thereby pointing towards SFN's potential in sex/gender-personalized preventive and therapeutic approaches.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104330","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":"Low-dose LPS and acute restraint stress attenuate behavioural sensitisation in methamphetamine-sensitised male mice.","authors":"Rikuto Christopher Shinohara, Shuhei Ishikawa, Risa Matsumoto, Koki Ito, Mariko Tonosaki, Shiina Matsuyama, Masahiro Ohgidani, Minori Koga, Naoki Hashimoto, Ichiro Kusumi, Takahiro A Kato","doi":"10.1111/bph.70697","DOIUrl":"https://doi.org/10.1111/bph.70697","url":null,"abstract":"<p><strong>Background and purpose: </strong>Clinical observations suggest that acute inflammatory states transiently modulate psychotic symptoms. However, animal models often use relatively strong inflammatory stimuli, and the effects of low-intensity acute inflammation on psychostimulant-induced behavioural sensitisation remain unclear.</p><p><strong>Experimental approach: </strong>We examined whether relatively low-intensity acute inflammatory stimuli attenuate behavioural sensitisation in methamphetamine (METH)-sensitised male mice, a model of psychostimulant-induced psychosis. We used a repeated METH (1 mg·kg^-1)-sensitised model to evaluate the effects of acute inflammation on behavioural sensitisation. Acute inflammation was induced via two methods: lipopolysaccharides (LPS; 1 μg·kg^-1) to mimic peripheral immune activation and restraint stress (RS; single 2-h exposure) to induce an acute stress-related neuroimmune response. LPS doses were adjusted with reference to the magnitude of peripheral cytokine elevation reported in patients, and RS was applied in short single sessions to avoid excessive inflammation.</p><p><strong>Key results: </strong>LPS and RS significantly attenuated behavioural sensitisation, without inducing other detectable behavioural abnormalities. The behavioural effects of both LPS and RS were sensitive to toll-like receptor 4 (TLR4) inhibition. LPS-mediated attenuation was sensitive to cyclooxygenase-2 (COX-2) inhibition, whereas RS-mediated attenuation involved tumour necrosis factor-α (TNF-α). TNF-α expression was increased in brain-isolated microglia following RS, and intrastriatal TNF-α reproduced the attenuation of behavioural sensitisation. RS, but not LPS, significantly reduced the striatal extracellular dopamine levels.</p><p><strong>Conclusions and implications: </strong>Acute inflammation attenuated METH-induced behavioural sensitisation following low-dose LPS and acute RS. These findings suggest that acute inflammation may modulate processes relevant to METH-induced psychosis and highlight TNF-α as a candidate for further investigation.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104458","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":"Targeted delivery of the CB₂ receptor agonist JWH-133 via VCAM-1-functionalised nanoparticles attenuates atherosclerosis and reveals sex-specific therapeutic outcomes.","authors":"Lucía Martín-Navarro, Lucía Martín-Banderas, Josefa Álvarez-Fuentes, María Dolores Herrera-González","doi":"10.1111/bph.70688","DOIUrl":"https://doi.org/10.1111/bph.70688","url":null,"abstract":"<p><strong>Background and purpose: </strong>Atherosclerosis, a chronic inflammatory disease characterised by lipid accumulation and endothelial dysfunction, remains a leading cause of cardiovascular morbidity and mortality. While cannabinoid 2 (CB₂) receptor agonists show therapeutic promise in preclinical studies, their systemic application is hindered by poor bioavailability and off-target effects. Consequently, targeted delivery systems are essential to enhance therapeutic efficacy and mitigate adverse effects.</p><p><strong>Experimental approach: </strong>This study presents a targeted nanotherapeutic strategy for localising the CB₂ receptor agonist directly at atherosclerotic lesions. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), encapsulating the selective agonist JWH-133 and functionalised with a VCAM-1 binding peptide (VBP) for selective binding to vascular cell adhesion molecule-1 (VCAM-1) (VBP-JWH-133-NPs), were developed. In vivo experiments were conducted in both male and female apolipoprotein E-deficient (ApoE^-/-) mice to assess the anti-inflammatory and lipid-modulating effects of the nanotherapy. Serum lipid profiles, aortic plaque burden and key inflammatory markers were analysed.</p><p><strong>Key results: </strong>VBP-JWH-133-NPs significantly reduced foam cell-rich depositions and modulate systemic inflammatory markers in both sexes, demonstrating superior anti-atherogenic efficacy compared with free JWH-133. The therapeutic benefits are notably more pronounced in male mice, which exhibit greater initial plaque area and lipid deposition.</p><p><strong>Conclusion and implications: </strong>These findings underscore the potential of VBP-JWH-133-NPs as an efficient and superior delivery system for cannabinoid therapies in atherosclerosis. By addressing sex as a biological variable, this approach offers a nuanced strategy for developing more effective and precise cardiovascular interventions.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104506","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":"Kininase I drives angiotensin II-induced hypertension through activation of the bradykinin B₁ receptor.","authors":"Acacia White, Drew Theobald, Alexandra Johnston, David A Tulis, Johanna Hannan, Srinivas Sriramula","doi":"10.1111/bph.70692","DOIUrl":"https://doi.org/10.1111/bph.70692","url":null,"abstract":"<p><strong>Background and purpose: </strong>Kininase I, comprising carboxypeptidase N (CPN) and carboxypeptidase M, regulates kinin activity and is up-regulated during injury, inflammation and immune activation. Under these conditions, kininase I converts bradykinin and kallidin into des-Arg kinins, primary endogenous agonists of the bradykinin B₁ receptor (R). B₁R signalling promotes vasoconstriction and inflammatory responses in the pathogenesis of hypertension. The roles of kininase I in regulating kinin-dependent signalling and inter-system interactions that contribute to blood pressure control and hypertensive organ injury remain poorly defined.</p><p><strong>Experimental approach: </strong>CPN knockout (CPNKO) and wild-type (WT) mice underwent chronic Ang II infusion to evaluate the role of CPN, and a separate cohort of WT mice were treated with the kininase I inhibitor Mergetpa alongside angiotensin (Ang) II to assess the effects of kininase I inhibition.</p><p><strong>Key results: </strong>Ang II in WT mice increased blood pressure and was accompanied by sympathetic overactivation, increased B₁R expression, cardiac remodelling, immune cell infiltration and complement activation. CPNKO mice exhibited attenuated Ang II-induced hypertension, reduced B₁ receptor expression, decreased cardiac fibrosis and blunted sympathetic activation. Pharmacologic inhibition of kininase I with Mergetpa reduced Ang II-induced increases in blood pressure, limited B₁R up-regulation and suppressed complement activation and immune cell infiltration.</p><p><strong>Conclusions and implications: </strong>These findings identify kininase I as a critical enzymatic regulator linking the renin angiotensin and kallikrein kinin systems and highlight a mechanism through which cardiovascular and immune signalling pathways interact to drive hypertension. These results position kininase I as a potential therapeutic target for the treatment of hypertension.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104485","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}