British Journal of Pharmacology最新文献

{"title":"Inhibition of leucine-rich kinase 2 (LRRK2) promotes peripheral axon regeneration via phosphorylation-network remodelling","authors":"Eun-Hae Jang,&nbsp;Eun Mo Yang,&nbsp;Gil Song,&nbsp;Seung Min Park,&nbsp;Harryn Choi,&nbsp;Jaeyong Kim,&nbsp;Chanil Kim,&nbsp;Yunho Gim,&nbsp;Hyuk-Joo Jeon,&nbsp;Yewon Cho,&nbsp;Jong Bae Park,&nbsp;Eun-Mi Hur","doi":"10.1111/bph.70602","DOIUrl":"10.1111/bph.70602","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>In contrast to neurons in the central nervous system, neurons in the peripheral nervous system can regenerate axons after injury via activation of a pro-regenerative transcriptional programme. Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, and several small-molecule LRRK2 kinase inhibitors have been developed, with some in clinical trials. However, the physiological role of endogenous, non-pathogenic LRRK2 remains largely unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>LRRK2 expression was examined in murine dorsal root ganglia (DRGs) following sciatic nerve crush (SNC) injury. Regenerative axon growth was assessed using cultured adult DRG neurons after genetic or pharmacological inhibition of LRRK2. Axon regeneration after SNC injury was evaluated in vivo following oral administration of the LRRK2 inhibitors, MLi-2 or PF-06447475. Axonal trafficking experiments and phosphoproteomic analyses were performed to investigate mechanisms underlying axon growth promotion induced by LRRK2 inhibitors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>SNC injury reduced LRRK2 expression in DRGs. Genetic and pharmacological inhibition of LRRK2 enhanced regenerative axon growth in culture. Oral administration of MLi-2 or PF-06447475 promoted axon regeneration in vivo after SNC injury. MLi-2 enhanced mitochondrial trafficking, and phosphoproteomic analyses identified cellular processes and kinase-substrate signalling networks associated with a pro-regenerative state triggered by LRRK2 inhibition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>These findings identify endogenous, non-pathogenic LRRK2 as a suppressor of axon regeneration. They also support the potential repositioning of small-molecule LRRK2 inhibitors, including clinically advanced compounds and those in preclinical development, as therapeutic strategies to enhance peripheral nerve regeneration.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6199-6224"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70602","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583682","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":"Rosemary metabolite carnosic acid opens Kv1.1 via its voltage sensor and corrects Kv1.1-linked episodic ataxia in mice","authors":"Rían W. Manville,&nbsp;Ryan F. Yoshimura,&nbsp;Hanh A. Nguyen,&nbsp;Ruiming Zhao,&nbsp;Derk J. Hogenkamp,&nbsp;Steve A. N. Goldstein,&nbsp;Geoffrey W. Abbott","doi":"10.1111/bph.70578","DOIUrl":"10.1111/bph.70578","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder caused primarily by loss-of-function mutations in the voltage-gated potassium channel K_v1.1 (<i>KCNA1</i>). Small molecules that restore K_v1.1 activity hold promise as targeted therapies for EA1, yet current pharmacological strategies remain limited.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Two electrode voltage-clamp electrophysiology and the <i>Xenopus laevis</i> oocyte expression system were used to study effects of carnosic acid, a phenolic diterpene from <i>Salvia rosmarinus</i> (rosemary) leaf extract on K_v1.1-linked EA1 mutant channels. We assessed ataxia therapeutic efficacy by comparing performance of <i>Kcna1</i>^+/+ and <i>Kcna1</i>^E283K/+ mice, a model of human EA1, on a balance beam under isoproterenol challenge in the absence or presence of 0.3-mg·kg⁻¹ carnosic acid.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Rosemary leaf extract and rosemary metabolite carnosic acid are efficacious K_v1.1 openers. Carnosic acid fully or partially corrects heterozygous, heteromeric K_v1.1 EA1 mutant channel activity <i>in vitro</i> and restores normal function in K_v1.1^E283K/+ mice at 0.3 mg·kg⁻¹. Experimental validation of unbiased in silico docking reveals carnosic acid occupies a binding pocket between the S1 and S4 helices of the voltage-sensing domain (VSD) of K_v1.1. Finally, we determined the chemical properties that endow carnosic acid with the ability to open K_v1.1 channels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Our findings uncover a K_v1.1 opener with the potential to reverse EA1 and other K_v1.1-linked disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6179-6198"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70578","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583721","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":"Intermittent cocaine use patterns, not total intake, predict cue-induced drug seeking in rats","authors":"Amélie Mainville-Berthiaume,&nbsp;Hajer Algallal,&nbsp;Salomé Dupuis,&nbsp;Sema Abu Shamleh,&nbsp;Coralie Godbout,&nbsp;Vincent Jacquemet,&nbsp;Anne-Noël Samaha","doi":"10.1111/bph.70596","DOIUrl":"10.1111/bph.70596","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Cocaine-associated cues trigger relapse to drug use in humans and animal models. In rats, long daily cocaine access (4–6 vs. 1–2 h) increases drug self-administration and cue-induced cocaine seeking, suggesting that greater intake promotes relapse. However, prior studies used continuous drug access paradigms, whereas human cocaine use is typically intermittent. Prior studies also used conditioned stimuli (CS), whereas discriminative stimuli (DS) are more effective in triggering drug seeking. Here, we used intermittent access (IntA) self-administration to examine how session length influences CS- and DS-induced cocaine seeking.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Female rats self-administered cocaine intermittently during daily 2- or 4-h IntA sessions (Short-IntA and Long-IntA), with alternating DS+ (cocaine available; 5 min) and DS− (no cocaine; 25 min) periods. Lever pressing during DS+ produced cocaine and a CS+; lever pressing during DS− produced only a CS−. After 4 weeks of abstinence, rats received a test where all cues were presented response-independently, and lever presses—which had no consequence—measured cocaine seeking.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Long-IntA rats took twice more cocaine than did Short-IntA rats. In both groups, DS+ but not CS+ later triggered significant increases in cocaine seeking, with no group differences. Thus, total intake did not predict cue-induced relapse intensity. However, individual cocaine intake patterns did, including hourly consumption, episodes of burst-like self-administration and latency to self-administer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Under intermittent-access conditions, individual cocaine-use patterns, not cumulative intake, predict vulnerability to cue-induced relapse. This highlights the importance of individual drug-taking profiles in relapse risk assessment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6094-6112"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70596","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547960","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":"Tyrosine kinase 2 inhibition by GL-V9 treats psoriasiform dermatitis via macrophage-helper T-cell modulation","authors":"Leyi Chen,&nbsp;Haiyan Tu,&nbsp;Xiaohe Xu,&nbsp;Xiangzheng Li,&nbsp;Shaowen Liu,&nbsp;Rongzhuo Long,&nbsp;He Huang,&nbsp;Qinglong Guo,&nbsp;Xu Chen,&nbsp;Lei Qiang,&nbsp;Yuan He","doi":"10.1111/bph.70603","DOIUrl":"10.1111/bph.70603","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Psoriasis (PsO) is a chronic T lymphocyte-mediated inflammatory disease arising on a polygenic background. GL-V9, a structurally optimized flavonoid with reported anti-inflammatory and anti-fibrotic activities, was investigated as a potential therapeutic agent for PsO.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>The therapeutic and relapse-preventive effects of GL-V9 were evaluated in multiple murine models of psoriasiform inflammation. To define its immunomodulatory actions, we established distinct immune-cell polarization models, including macrophage and T helper cell models, and assessed inflammatory mediator production, immune-cell polarization and intercellular communication within psoriatic lesions. Mechanistic studies further examined the interaction between GL-V9 and tyrosine kinase 2 (TYK2), and the functional relevance of TYK2 using siTYK2-mediated knockdown in bone marrow-derived macrophages and THP-1 cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>GL-V9 effectively alleviated established psoriasiform dermatitis and reduced disease relapse. Mechanistically, preliminary evidence indicated that GL-V9 binds to the pseudokinase domain of TYK2 and suppresses JAK/STAT activation, thereby reducing the production of pro-inflammatory cytokines and chemokines. In M1 macrophages and T helper 1 (Th1) cells, GL-V9 disrupted TYK2-dependent signalling, altered pathogenic polarization states and weakened inflammatory communication with neighbouring immune cells, collectively restoring a more balanced immune microenvironment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>GL-V9 ameliorates PsO by targeting TYK2–STAT signalling and reshaping macrophage–T helper cell-driven inflammation. These findings support GL-V9 as a promising therapeutic candidate for PsO and other TYK2-mediated inflammatory diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6154-6178"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148577222","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":"Pharmacogenetic mechanism of cilostazol-induced headaches: Splicing-mediated loss of ABCC5 gene function","authors":"Sung Hee Lee,&nbsp;So Myoung Kim,&nbsp;Dong-Hwan Lee,&nbsp;Md. Hasanuzzaman,&nbsp;Danbi Park,&nbsp;Md. Intazur Rahaman,&nbsp;Seokil Lee,&nbsp;Yongchul Gu,&nbsp;Hye Won Kim,&nbsp;Wonhee Park,&nbsp;Hyunho Kim,&nbsp;Woo-Dae Bang,&nbsp;Joonhee Park,&nbsp;Yejin Park,&nbsp;Hyun June Park,&nbsp;Jinu Lee,&nbsp;Sung Kweon Cho,&nbsp;Kyungsoo Park,&nbsp;Min Goo Lee,&nbsp;Ji Hyun Lee,&nbsp;Eun-Jae Lee,&nbsp;So Won Kim","doi":"10.1111/bph.70597","DOIUrl":"10.1111/bph.70597","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Cilostazol, a phosphodiesterase 3 inhibitor, causes intolerable headaches in over one third of patients, frequently leading to treatment discontinuation. We investigated whether <i>ABCC5</i> variant rs7636910 (NM_005688.4:c.1146A &gt; G) protects against cilostazol-induced headaches through altered cyclic nucleotide signalling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Analysis included 101 healthy Korean volunteers from Phase 1 clinical trials, with independent replication in a multi-ethnic cohort (n = 369) from the All of Us Research Program. Functional consequences of rs7636910 were evaluated through splicing analysis, expression studies, transport assays and cellular models examining cyclic nucleotide dynamics and vascular responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>G allele carriers showed a reduced risk of moderate-to-severe headaches (OR = 0.29, 95% CI 0.12–0.73), replicated in the multi-ethnic cohort (OR = 0.26, dominant model). The variant disrupted canonical splicing, causing a 38-bp deletion, premature termination, and nonsense-mediated decay, reducing <i>ABCC5</i> expression by more than 20% in blood and thyroid tissues. Cilostazol was not an MRP5 substrate, and pharmacokinetics were genotype-independent. In <i>ABCC5</i>-knockdown HCASMCs (Human Coronary Artery Smooth Muscle Cells), baseline cAMP was elevated tonically with paradoxical cGMP accumulation, whereas drug-induced cAMP fold-increases remained comparable to controls. Tonic cAMP elevation desensitised PKA, abolishing PDE3 inhibitor-induced vascular relaxation despite elevated cAMP—a loss recapitulated by PKA inhibition in MRP5-normal cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>The rs7636910 variant reduces cilostazol-induced headaches through a signalling-based mechanism independent of drug pharmacokinetics, suggesting that transporter variants affecting endogenous substrate handling are as clinically important as drug-metabolising enzyme polymorphisms. This variant represents a candidate pharmacogenetic biomarker for identifying cilostazol-tolerant patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6113-6131"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560862","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":"GPER stimulation attenuates mitochondrial dysfunction and cardiac dysfunction in ovariectomized mice with heart failure with preserved ejection fraction (HFpEF).","authors":"Miaomiao Qi, Runmin Sun, Qiongying Wang, Lulu Zhu, Mingze Li, Wenting Wang, Xin Fan, Jing Yu","doi":"10.1111/bph.70661","DOIUrl":"https://doi.org/10.1111/bph.70661","url":null,"abstract":"<p><strong>Background: </strong>Heart failure with preserved ejection fraction (HFpEF) is prevalent among postmenopausal women and is strongly linked to estrogen deficiency. G-protein coupled estrogen receptor (GPER) mediates non-genomic estrogen signalling and exerts cardiovascular protective effects. Its role in the pathogenesis of HFpEF remains unclear. This study aimed to explore whether GPER activation could attenuate mitochondrial dysfunction and cardiac damage in ovariectomized (OVX) mice with HFpEF.</p><p><strong>Methods: </strong>Circulating GPER levels were measured in postmenopausal women with HFpEF and healthy controls. A correlation analysis was performed to assess the associations between GPER and cardiac function. Female C57BL/6J mice underwent ovariectomy and were fed with high-fat diet and l-NAME to induce HFpEF. Mice were treated with the GPER agonist G-1 for 4 weeks. Cardiac function, histological changes, oxidative stress, mitochondrial function and mitophagy were evaluated in vivo and in vitro.</p><p><strong>Results: </strong>Serum GPER levels were significantly higher in postmenopausal women with HFpEF and correlated with NT-proBNP and E/e'. In OVX mice with HFpEF, GPER expression was up-regulated, and G-1 improved diastolic function, reduced myocardial hypertrophy and oxidative stress. Importantly, G-1 restored mitochondrial ATP production, normalized mitochondrial dynamics and promoted mitophagy in vivo and in vitro. These effects were associated with activation of the AMPK/ULK1 pathway. Inhibition of AMPK diminished the protective effects of G-1 in cardiomyocytes.</p><p><strong>Conclusions: </strong>GPER agonist G-1 ameliorated mitochondrial dysfunction, promoted mitophagy and alleviated cardiac diastolic dysfunction in OVX mice with HFpEF, partially through the AMPK/ULK1 pathway, indicating GPER as a therapeutic target for postmenopausal women with HFpEF.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929084","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":"Tetramethylpyrazine ameliorates metabolic dysfunction-associated steatohepatitis by modulating gut microbiota dysbiosis and restoring intestinal barrier integrity.","authors":"Xiaoli He, Linzhang Zhang, Yadi Zhu, Wei Liu, Jiawen You, Wenxuan Chen, Xinyi Fu, Shiyu Yang, Yanting Shao, Yiren Hu, Yunhao Li, Min Zheng, Hongjie Yang, Guangbo Ge, Zheng Yao, Yanming He","doi":"10.1111/bph.70640","DOIUrl":"https://doi.org/10.1111/bph.70640","url":null,"abstract":"<p><strong>Background and purpose: </strong>This study investigated the therapeutic effects and gut-liver axis-related mechanisms of tetramethylpyrazine (TMP) in metabolic dysfunction-associated steatohepatitis (MASH).</p><p><strong>Experimental approach: </strong>Male C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for 6 weeks to establish MASH. TMP or pioglitazone was administered during the final 3 weeks. Hepatic injury, intestinal barrier integrity, gut microbiota, bile acids (BAs), short-chain fatty acids (SCFAs) and faecal metabolomics were assessed using histology, biochemical assays, RT-qPCR, western blotting, 16S rDNA sequencing and metabolomics. Faecal microbiota transplantation (FMT) and lipopolysaccharide (LPS)-stimulated Caco-2 cells were used to evaluate microbiota-dependent and direct intestinal protective effects of TMP.</p><p><strong>Key results: </strong>TMP alleviated hepatic steatosis, inflammation and fibrosis in MCD-fed mice. TMP decreased hepatic macrophage infiltration and inflammatory cytokines, including TNF-α, IL-1β and IL-6. In the intestine, TMP restored epithelial structure, increased faecal sIgA, reduced serum LPS, D-lactate, zonulin and TNF-α and up-regulated Claudin-1, ZO-1 and Occludin. TMP improved gut microbial diversity, suppressed proinflammatory bacteria and enriched beneficial taxa. FMT from TMP-treated donors partially reproduced the hepatoprotective effects in recipient mice. TMP further restored BA and SCFA homeostasis, regulated the FXR/FGF15/CYP7A1 axis and remodelled faecal metabolic profiles associated with lipid peroxidation and inflammation. In Caco-2 cells, TMP attenuated LPS-induced IL-1β and IL-6 expression and restored Occludin expression.</p><p><strong>Conclusion and implications: </strong>TMP exerts protective effects against MCD diet-induced MASH by improving hepatic pathology and restoring gut-liver axis homeostasis, including intestinal barrier integrity, gut microbiota composition, BA and SCFA metabolism and faecal metabolic balance.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929013","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":"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}