British Journal of Pharmacology最新文献

{"title":"Metabolic remodelling in anthracycline cardiotoxicity: mechanisms and therapeutic insights.","authors":"Giulia Guerra, Francesco Niro, Marco Mergiotti, Giovanni Gavatorta, Emilio Hirsch, Alessandra Ghigo","doi":"10.1111/bph.70666","DOIUrl":"https://doi.org/10.1111/bph.70666","url":null,"abstract":"<p><p>Anthracyclines remain a cornerstone of anticancer therapy, but their clinical use is limited by cancer therapy-related cardiac dysfunction, a major contributor to long-term cardiovascular morbidity in cancer survivors. Although traditionally attributed to oxidative stress, DNA damage and mitochondrial toxicity, emerging evidence identifies disruption of metabolism as a central mechanism of anthracycline-induced cardiotoxicity. Anthracycline exposure promotes a distinct metabolic phenotype characterized by impaired mitochondrial oxidative phosphorylation, dysregulated metabolism of fatty acids and glucose, along with decreased metabolic flexibility, ultimately resulting in inefficient myocardial energetics. These changes are modulated by the patient's underlying cardiometabolic status, suggesting that metabolic reserve influences susceptibility to injury. In addition to direct myocardial effects, anthracyclines induce systemic metabolic changes that affect substrate availability and inter-organ communication. This review focuses on cardiotoxicity induced by anthracyclines, particularly by doxorubicin, highlighting mitochondrial dysfunction, altered substrate utilization and metabolic inflexibility in comparison with other cardiac diseases. We also discuss the newly emerging metabolic strategies aimed at improving cardioprotection.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905053","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":"Photodynamic antimicrobial efficacy and mode of action of polypyridyl-based Ru(II) complexes against multidrug-resistant Klebsiella pneumoniae.","authors":"Matías Fabián Cuevas, Scarlet Vallejos-Monroy, Valentina A Iglesias, Angélica R Bravo, Alan R Cabrera, Guadalupe Del C Pizarro, Sebastián Sepúlveda-Salgado, Marcelo Rivas-Astroza, Iván A González, Christian Erick Palavecino","doi":"10.1111/bph.70657","DOIUrl":"https://doi.org/10.1111/bph.70657","url":null,"abstract":"<p><strong>Background and purpose: </strong>The rise of multidrug-resistant (MDR) bacteria poses a significant threat to global health. MDR Klebsiella pneumoniae is of particular concern because of its increasing antibiotic resistance. With limited therapeutic options, antimicrobial photodynamic therapy (aPDT), which employs light-activated photosensitizers to produce reactive oxygen species (ROS), represents a promising alternative.</p><p><strong>Experimental approach: </strong>We assessed the antimicrobial activity of two ruthenium-based photosensitisers, PSRu-379 and PSRu-381, against both susceptible and MDR K. pneumoniae strains and explored their mode of action. Bacterial survival was measured after activation with 61.2 J·cm^-2 of blue light. ROS production was analysed using fluorescent probes; transcriptional responses were examined by RT-qPCR and RNA sequencing; cytotoxicity was tested in human cell lines; and interactions with cefotaxime were evaluated using fractional inhibitory concentration (FIC) analysis.</p><p><strong>Key results: </strong>The minimum effective concentration was 4 μg·ml^-1 for the susceptible strain and 8 μg·ml^-1 for MDR strains. ROS analysis indicated predominant singlet oxygen generation, with minimal contribution from hydrogen peroxide, supporting a predominantly Type II photodynamic mechanism. Transcriptomic analysis revealed upregulation of sulphur metabolism and oxidative stress response pathways, along with downregulation of aminoacid biosynthesis, capsule formation and metal ion transport. The photosensitisers exhibited synergistic interactions with cefotaxime, reducing MIC values and yielding an FIC index of 0.08. Low cytotoxicity was observed in human cell lines under the tested conditions.</p><p><strong>Conclusions and implications: </strong>Ruthenium-based photosensitisers appear to act predominantly through singlet oxygen-mediated oxidative stress, enhancing cefotaxime efficacy while exhibiting low cytotoxicity, and therefore represent promising adjunct therapies against MDR K. pneumoniae.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890940","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":"Selective excitatory effects of γ-glutamyl-glycine, a glutathione metabolite, on GluN1 NMDA and mGlu5 receptors impacting synaptic plasticity.","authors":"Sandro Andreu, Victoria Gizzi, Ugo Pasco, Fatiha Sebih, Yattou Zitouni, Pablo Jimenez, Valérie Rolland, Alain Chavanieu, Sébastien Estaran, Matthieu Rousset, Thierry Cens, Guillaume Cazals, Pierre Charnet, Janique Guiramand, Catherine Cohen-Solal, Claudine Ménard, Marie-Céleste de Jésus Ferreira, Nathalie Chevallier, Sonia Cantel, Michel Vignes, Julien Roussel","doi":"10.1111/bph.70650","DOIUrl":"https://doi.org/10.1111/bph.70650","url":null,"abstract":"<p><strong>Background and purpose: </strong>Gamma-glutamyl dipeptides are essentially produced after glutathione (GSH) degradation. While several γ-glutamyl dipeptides have been detected in different organs and body fluids, their biological activity remains elusive. This is the case for γ-Glutamyl-Glycine (γ-Glu-Gly) which has been found in different brain areas. γ-Glutamyl-glycine may bind to ionotropic glutamate receptors. Here, we have investigated whether γ-Glu-Gly could exhibit modulatory actions on excitatory synaptic transmission and plasticity by performing its functional characterization on glutamate, GABA and glycine receptors.</p><p><strong>Experimental approach: </strong>Electrophysiological and calcium imaging experiments were performed on cells heterologously expressing either Glutamate, GABA or Glycine receptors and on cultured hippocampal neurons and acute hippocampal slices. The γ-Glu-Gly production by cultured cells and hippocampal slices was measured by LC-MS analysis, following incubation with modulators of the glutathione metabolic cycle.</p><p><strong>Key results: </strong>γ-Glu-Gly exerted partial agonist effects on both NMDA GluN1 and mGlu5 receptors, but without any binding to the glutamate binding domain on both AMPA and NMDA GluN2A receptors. γ-Glu-Gly was devoid of any effect on GABA, glycine and GluN3A receptors. γ-Glu-Gly was able to trigger a long-term increase in synaptic transmission in the CA1 area of mouse hippocampus.</p><p><strong>Conclusion and implications: </strong>γ-Glu-Gly partially retains the excitatory actions of glutamate on specific receptor sub-types and may trigger plastic events in the hippocampus. Its accumulation under pathological conditions associated with oxidative stress and a high GSH consumption could thus interfere with endogenous synaptic transmission and disrupt natural plasticity, which is a hallmark of neurodegenerative diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886360","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":"ATF4–histone 2-hydroxyisobutyrylation feedback loop drives sepsis-induced inflammation","authors":"Liang Zhang,&nbsp;Yongling Lu,&nbsp;Hongmei Qiu,&nbsp;Xinhui Shi,&nbsp;Feng Cao,&nbsp;Ting Yang,&nbsp;Sijia Liu,&nbsp;Qian Chen,&nbsp;Qingsong Jiang,&nbsp;Lin Xia,&nbsp;Wenjun Li,&nbsp;Junxia Yang,&nbsp;Jiang Zheng,&nbsp;Xin Liu,&nbsp;Xiaoli Li,&nbsp;Hong Zhou","doi":"10.1111/bph.70554","DOIUrl":"10.1111/bph.70554","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The role and mechanisms of lysine 2-hydroxyisobutyrylation (Khib) in the acute inflammatory phase of sepsis remain unclear. We investigated the function and underlying mechanisms of histone H4 lysine 5 2-hydroxyisobutyrylation (H4K5-hib) in sepsis-induced inflammation <i>in vivo</i> and <i>in vitro</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Acute sepsis was induced by caecal ligation and puncture (CLP) in mice, and inflammatory responses were modelled in lipopolysaccharide (LPS)-stimulated macrophages. CUT&amp;Tag-seq was used to identify genomic targets associated with H4K5-hib and activating transcription factor 4 (ATF4). Immunofluorescence, Western blotting, qPCR, dual-luciferase assays, and ELISA were performed to investigate the underlying mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>H4K5-hib levels were increased in macrophages during the acute inflammatory phase of sepsis. LPS stimulation enhanced H4K5-hib enrichment at the ATF4 promoter, thereby promoting ATF4 transcription. Inhibition of EP300-mediated 2-hydroxyisobutyrylation or mutation of H4K5 abolished ATF4 activation. Increased H4K5-hib activated the ATF4/NLRP3 signalling axis, promoting inflammasome assembly and amplifying inflammatory responses. ATF4 directly bound to the EP300 promoter and enhanced its transcription, forming a positive feedback loop that further increased H4K5-hib levels. In CLP-induced sepsis, pharmacological inhibition of EP300 or ATF4 reduced H4K5-hib levels and suppressed NLRP3 inflammasome activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>These findings reveal a previously unrecognized epigenetic mechanism underlying sepsis-induced inflammation and identify the EP300/ATF4/H4K5-hib positive feedback loop as a potential therapeutic target for sepsis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 19","pages":"5813-5831"},"PeriodicalIF":7.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435168","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":"Muscarinic agonists for schizophrenia: Bridging preclinical evidence and clinical enthusiasm","authors":"Brian J. Morris,&nbsp;Judith A. Pratt","doi":"10.1111/bph.70582","DOIUrl":"10.1111/bph.70582","url":null,"abstract":"<p>Antipsychotic drugs targeting dopamine receptors have been used to treat schizophrenia for decades, primarily alleviating positive symptoms such as hallucinations and delusions. However, they provide limited benefit for cognitive and negative symptoms—major contributors to poor outcomes—and are frequently associated with significant side effects. The recent approval of KarXT, the first muscarinic-targeting antipsychotic drug, marks a potentially important shift in therapeutic strategy. Here, we review the mechanism of action of xanomeline (the centrally active component of KarXT) and related compounds, using a RDoC-informed framework spanning receptor, cellular, systems, network and behavioural level. We interrogate the pharmacological profile of xanomeline at M₁–M₅ receptors, highlighting the role of receptor reserve in conferring partial agonist activity at M₁ and M₄ receptors in vivo. At a systems level, xanomeline is likely to act at M₁/M₄ receptors on glutamatergic afferents and cortical pyramidal neurons; M₂ receptors in the thalamic reticular nucleus; M₄ receptors in the striatum, on glutamatergic afferents and GABAergic direct pathway medium spiny neurons; and M₅ receptors on dopaminergic afferents in the striatum. We consider mechanistic overlap with clozapine, and the evidence that 5-HT_1A receptor partial agonist actions and 5-HT₇ receptor modulation may contribute to xanomeline's broader profile. We propose that combining muscarinic actions with activity at 5-HT receptors may enhance efficacy by restoring disrupted circuits and networks relevant to the full spectrum of symptoms, while reducing dopamine-mediated and metabolic side effects. In conclusion, muscarinic modulation is a promising direction not only for schizophrenia but potentially trans-diagnostically in psychiatry.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 19","pages":"5701-5731"},"PeriodicalIF":7.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70582","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700891","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":"Correction to “Ticagrelor increases its own potency at the P2Y12 receptor by directly changing the plasma membrane lipid order in platelets”","authors":"","doi":"10.1111/bph.70611","DOIUrl":"10.1111/bph.70611","url":null,"abstract":"<p>\u0000 <span>Pyrshev, K.</span>, <span>Allemand, F.</span>, <span>Rabani, V.</span>, <span>Yesylevskyy, S.</span>, <span>Davani, S.</span>, <span>Ramseyer, C.</span>, &amp; <span>Lagoutte-Renosi, J.</span> (<span>2024</span>). <span>Ticagrelor increases its own potency at the P2Y12 receptor by directly changing the plasma membrane lipid order in platelets</span>. <i>British Journal of Pharmacology</i>, <span>181</span>(<span>21</span>), <span>4369</span>–<span>4380</span>. https://doi.org/10.1111/bph.16500</p><p>In “Influence of the lipid order on platelet inhibition by Ticagrelor” section, the reported IC₅₀ values and their confidence intervals (“In the control group, the IC₅₀ value was 0.56 μM (0.55–0.58 μM), while upon addition of cholesterol, it dropped to 0.37 μM (0.36–0.38 μM).”) were calculated from a curve fitted to the pooled data, a more appropriate approach is to fit a curve for each replicate and calculate the geometric mean of the IC₅₀ and its confidence interval across all replicates. This yields 0.56 μM (0.43–0.73 μM) for the control group and 0.36 μM (0.27–0.49 μM) upon addition of cholesterol. To compare these values, an extra sum-of-squares F-test was performed, yielding a p-value of 0.019, confirming the significant difference between these two IC₅₀ values.</p><p>Figure 6 has been updated to show the fitted curves for each replicate, see below.</p><p>To supplement Figures 1B and 2B, the values shown in the graphs are provided as supplementary materials in Tables S1 and S2.</p><p>We apologize for this error.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 19","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70611","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429805","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":"Activation of sigma non-opioid intracellular receptor 1 (S1R) receptor inhibits plexin domain containing 2 (Plxdc2) driven microglial inflammation to ameliorate depressive-like behaviours in mice","authors":"Jing-Ya Wang,&nbsp;Peng Ren,&nbsp;De-Yi Yang,&nbsp;Han Ni,&nbsp;Shuang Zhang,&nbsp;Chen- Xing Yue,&nbsp;Zhi-Rui Zeng,&nbsp;Zeng-Qiang Yuan,&nbsp;Yun-Feng Li","doi":"10.1111/bph.70598","DOIUrl":"10.1111/bph.70598","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Microglia are central regulators of neuroinflammation in depression. Drivers involved remain incompletely understood. Sigma non-opioid intracellular receptor 1 (S1R) is involved in brain inflammation. This study investigates how S1R regulates neuroinflammation associated with depression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Using integrated machine learning and single-cell transcriptomics, a key gene implicated in microglial dysfunction in depression was identified. Its relevance was examined in a lipopolysaccharide (LPS)-induced mouse model of depression and LPS-stimulated BV-2 cells. Further, targeted knockdown or overexpression of this gene was performed on medial prefrontal cortex (mPFC) microglia, followed by integrated behavioural, cellular and molecular analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p><i>Plxdc2</i> was the key gene up-regulated at both transcriptional and protein levels in blood and depression-susceptible brain regions. Single-cell RNA sequencing confirmed its specific enrichment in microglia, particularly within inflammatory gene sets related to N-linked glycosylation (NLG). LPS-treated mice, depressive-like behaviours were accompanied by elevated expression of Plxdc2 and the glycosylation-related enzyme β-1,4-galactosyltransferase 1 in mPFC microglia. The S1R agonist Hypidone hydrochloride (YL-0919) or conditional knockdown of <i>Plxdc2</i>, reversed these molecular changes, reduced neuroinflammation and alleviated depressive-like behaviours. Analysis demonstrated that overexpressing <i>Plxdc2</i> in mPFC microglia activated the JAK2-STAT1 pathway, enhanced NLG, shifting microglia towards a pro-inflammatory phenotype, worsening deficits in synaptic plasticity and induced depressive-like behaviour. These were reversible by the NLG inhibitor tunicamycin.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Plxdc2 promotes depressive-like behaviours by dysregulating NLG-mediated inflammatory in microglia. S1R activation has a therapeutic effect by inhibiting this pathway, positioning the S1R-Plxdc2 axis as a potential target for modulating microglial function in inflammation-related depression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 19","pages":"5914-5934"},"PeriodicalIF":7.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444430","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":"Transcriptomic and metabolomic analyses reveal that lobeglitazone ameliorates hepatic steatosis in rats concurrent with regulation of mitochondrial pyruvate metabolism","authors":"Hyekyung Yang,&nbsp;Su Young Son,&nbsp;Youngmi Song,&nbsp;Hyewon Choi,&nbsp;In-Gu Do,&nbsp;Choong Hwan Lee,&nbsp;Cheol-Young Park","doi":"10.1111/bph.70601","DOIUrl":"10.1111/bph.70601","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Lobeglitazone is a thiazolidinedione and PPARγ agonist that improves metabolic parameters and hepatic steatosis, but its mechanisms are not fully understood. This study investigated the effects of lobeglitazone on hepatic transcriptomic and metabolic profiles in a rat model of obesity and Type 2 diabetes mellitus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Male Otsuka Long-Evans Tokushima fatty rats were fed a high-fat, high-carbohydrate (HF/HC) diet for 15 weeks and treated with lobeglitazone or vehicle. Metabolic parameters, liver function and histology were assessed. RNA sequencing was conducted to identify changes in hepatic gene expression, and metabolomic profiling was performed on liver and plasma samples. Mechanistic validation was conducted in HepG2 cells using siRNA-mediated PPARγ knockdown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Lobeglitazone treatment improved glucose tolerance and decreased plasma triglyceride and total cholesterol levels. Histological analyses indicated reduced hepatic steatosis, ballooning and lobular inflammation, reflecting protection against hepatic steatosis. RNA sequencing revealed 334 DEGs between the HF/HC-lobeglitazone and HF/HC groups, with pathway enrichment analyses indicating modulation of pathways related to central carbon metabolism. Five pyruvate metabolism–associated genes were down-regulated by lobeglitazone. Quantitative PCR confirmed selected transcriptomic changes, although mitochondrial pyruvate carrier (MPC) 1 and 2 mRNA levels were not significantly altered. In contrast, MPC1 and MPC2 protein levels were markedly reduced. Metabolomics showed increased hepatic and plasma pyruvate, amino acids involved in pyruvate production and hydroxybutyrates, suggesting reduced mitochondrial pyruvate flux. Functional assays demonstrated decreased mitochondrial pyruvate levels following lobeglitazone treatment. PPARγ knockdown abolished lobeglitazone-induced down-regulation of MPC proteins.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Lobeglitazone treatment was associated with improved hepatic steatosis and liver-associated metabolic parameters, accompanied by transcriptional and metabolomic changes related to mitochondrial pyruvate metabolism. These findings are correlative and provide new insights into the hepatic actions of lobeglitazone in metabolic disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 19","pages":"5935-5952"},"PeriodicalIF":7.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70601","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444471","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":"Extracellular vesicles in pharmacology: Innovations in drug delivery and therapeutic applications in cancer.","authors":"Evangelia Pantazaka, Georgios Sivvas, Evangelia Papadimitriou, Constantinos M Mikelis","doi":"10.1111/bph.70616","DOIUrl":"https://doi.org/10.1111/bph.70616","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are a diverse population of membrane nanoparticles secreted by nearly all cell types, playing a key role in intercellular communication by transferring bioactive macromolecular cargo. In cancer, EVs shape both the local tumour microenvironment and distant premetastatic niches. They are essential regulators of tumour initiation, progression, immune modulation, angiogenesis and metastatic dissemination. Due to their abundance in biofluids, EVs have attracted attention as diagnostic and prognostic biomarkers for early detection and assessment of therapeutic response. Additionally, EVs represent a promising therapeutic platform for delivering chemotherapeutic agents, nucleic acids and gene-editing tools, with enhanced specificity and reduced systemic toxicity. This review summarises current therapeutic applications of EVs across breast, lung, colorectal, prostate and pancreatic cancers and glioblastoma. Key findings are presented for each formulation, with emphasis on the EV physicochemical properties and engineered modifications, their cargo and mechanisms underlying their biological effects. Although the clinical translation of EV-based advances remains limited and challenging, this review highlights significant preclinical findings and examples of clinical trials where EVs have been used as therapeutic agents.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879132","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":"Therapeutic potential of a Bax inhibitor-1/TMBIM6 antagonist (BIA) and its analogues in Aspergillus fumigatus-induced asthma via dual targeting of AKT and epithelial-derived inflammatory cytokines","authors":"Young-Jin Yu,&nbsp;Ahsan Ullah,&nbsp;Jisun Kim,&nbsp;Mehedi Hasan Bappi,&nbsp;Yerim Heo,&nbsp;Jin Hee Ahn,&nbsp;Hyun-Kyoung Kim,&nbsp;Han-Jung Chae","doi":"10.1111/bph.70579","DOIUrl":"10.1111/bph.70579","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p><i>Aspergillus fumigatus</i> (<i>A. fumigatus</i>) exposure causes of severe allergic asthma, characterized by airway inflammation and epithelial dysfunction. TMBIM6 (Bax inhibitor-1) has been implicated in airway epithelial stress responses and AKT signalling. This study aimed to elucidate the therapeutic potential of the drug called the Bax inhibitor-1 antagonist (BIA) and its structural analogues in a murine model of <i>A. fumigatus</i>-induced allergic asthma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>19 BIA analogues were synthesized and evaluated alongside the original drug BIA in a murine model of <i>A. fumigatus</i>-induced airway inflammation. Inflammatory phenotypes were assessed by analysing bronchoalveolar lavage fluid (BALF), lung histopathology, quantification of T-helper 2 (Th2) and Th17 cytokines. Mechanistic investigations evaluated the AKT/NLRP3 pathway and epithelial-derived cytokines, while TMBIM6-mediated ER Ca²⁺ flux was monitored using a TMBIM6-GCaMP3 reporter system.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>BIA and its analogues significantly attenuated inflammatory cell infiltration, goblet cell hyperplasia, airway remodelling and Th2-associated cytokine expression in the lungs of <i>A. fumigatus</i>-challenged mice. BIA and selected analogues also suppressed Th17-associated cytokine expression. Moreover, BIA analogues preferentially reduced epithelial-derived cytokine expression. Mechanistically, BIA and select analogues markedly suppressed AKT phosphorylation and NLRP3 expression in lungs and airway epithelial cells. Pharmacological inhibition and TMBIM6 knockdown supported the involvement of the TMBIM6/AKT/NLRP3 signalling axis, while BIA and select analogues inhibited TMBIM6-mediated ER calcium leakage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>BIA and its analogues attenuate <i>A. fumigatus</i>-induced allergic lung inflammation by targeting the TMBIM6/calcium/AKT axis, suppressing NLRP3 signalling and epithelial-derived inflammatory cytokines. These findings highlight this axis as a promising therapeutic target for fungal-associated airway inflammation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 19","pages":"5975-5991"},"PeriodicalIF":7.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70579","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469246","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}