British Journal of Pharmacology最新文献

{"title":"Natural product-derived TRPM7 channel inhibitors in neurological injury: Mechanisms, pharmacological potential and translational challenges.","authors":"Xinyang Zhang, Hio Lam Ho, F David Horgen, Andrea Fleig, Zhong-Ping Feng, Hong-Shuo Sun","doi":"10.1111/bph.70667","DOIUrl":"https://doi.org/10.1111/bph.70667","url":null,"abstract":"<p><p>Disruption of intracellular ionic homeostasis is a convergent pathological feature across diverse neurological injuries and disorders, including ischaemic and haemorrhagic stroke, hypoxic-ischaemic brain injury, traumatic brain injury, epilepsy and brain tumour. Among stress-activated ion channels implicated in these conditions, the transient receptor potential melastatin 7 (TRPM7) channel has emerged as a key mediator linking metabolic stress to sustained dysregulation of Ca²⁺, Mg²⁺ and Zn²⁺ signalling and downstream injury cascades. TRPM7 is a unique bifunctional protein composed of a divalent cation-permeable ion channel fused with a C-terminal α-kinase domain, enabling integration of ionic flux with intracellular signalling. Accumulating evidence from cellular, electrophysiological and in vivo studies demonstrates that TRPM7 contributes causally to neuronal injury, vascular dysfunction, network hyperexcitability and tumour cell malignancy across disease models. Natural products have historically played a central role in ion channel pharmacology, and growing evidence has identified structurally diverse natural product-derived compounds as modulators of TRPM7 channel. In this review, we synthesize mechanistic and pharmacological evidence supporting TRPM7 as a tractable therapeutic target, with particular focus on representative natural product-derived TRPM7 channel inhibitors including carvacrol, waixenicin A and xyloketal B, which span a spectrum of potency, selectivity and mechanistic complexity. We further discuss key translational challenges associated with targeting TRPM7 in neurological injury, including target selectivity, essential physiological roles, CNS exposure and context-dependent disease effects. Collectively, available evidence positions TRPM7 as a pharmacologically actionable target and highlights the potential of natural product scaffolds to guide the development of next-generation TRPM7-directed therapies for neurological injury.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001301","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":"Alamandine/MrgD pathway modulates gut-bone marrow axis in ageing.","authors":"Kishore Chittimalli, Henryata E Rozario, Victor Martinez, Zachary L McAdams, Stephen A Adkins, Aaron C Ericsson, Yagna P R Jarajapu","doi":"10.1111/bph.70656","DOIUrl":"10.1111/bph.70656","url":null,"abstract":"<p><strong>Background and purpose: </strong>Ageing is associated with colon epithelial barrier disruption and up-regulation of myelopoiesis in the bone marrow (BM). Alamandine (Ala) and MrgD are novel members of the renin angiotensin system (RAS). This study tested the hypothesis that Ala restores the colon epithelial barrier integrity in ageing via modulating gut-BM axis.</p><p><strong>Experimental approach: </strong>Mice, 2-3 (Young) or 22-24 months (Old), were treated with saline or Ala by using Osmotic pumps. The intestinal permeability was evaluated using FITC-dextran. Lgr5⁺Olfm4⁺ intestinal stem cells (ISCs), Wnt3a and β-catenin were evaluated by immunohistochemistry or western blotting. Faecal microbiome was analysed by 16S rRNA sequencing. Monocyte-macrophages were characterized by flow cytometry. Caecal or serum bacterial metabolites were analysed and the caecal supernatants (CS) were tested for myelopoietic potential.</p><p><strong>Key results: </strong>MrgD was expressed in ISCs, which was decreased in the Old. Increased intestinal permeability in ageing was reversed by Ala. In the colon organoids, Ala increased Wnt3a levels and this was antagonized by NF449, SQ22536 or 666-15. Ala restored phospho-CREB and active β-catenin levels that were decreased in the Old colon-organoids. Ala increased the richness and β-diversity of the microbiota with decreased Bacillota/Bacteroidota in ageing. Ala decreased the CD80⁺ and increased CX3CR⁺ macrophages in the Old colons. Old-CS induced myelopoiesis in BM cells with higher number of pro-inflammatory macrophages, which was prevented by Ala treatment.</p><p><strong>Conclusions and implications: </strong>Targeting Ala/MrgD pathway is a promising approach for ameliorating the inflammatory stress in ageing by restoring homeostasis in the gut-BM inter-organ communication.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982327","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":"Kinase Inhibitor Cardiotoxicity Database (KICDB): a causality-oriented multi-omics database for kinase inhibitor-induced cardiotoxicity","authors":"Jiamin Wei,&nbsp;Yin Liu,&nbsp;Miaoqing Wu,&nbsp;Guoyuan Li,&nbsp;Xinyao Zheng,&nbsp;Huafeng Fu,&nbsp;Jian Zhang,&nbsp;Jijin Lin","doi":"10.1111/bph.70599","DOIUrl":"10.1111/bph.70599","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Kinase inhibitors (KIs) are essential in targeted cancer therapy but frequently cause cardiotoxicity, limiting their clinical utility. A systematic resource to explore the underlying causal mechanisms is urgently needed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We developed the Kinase Inhibitor Cardiotoxicity Database (KICDB ), an interactive web platform integrating large-scale transcriptomic meta-analysis with causal inference to identify molecular determinants of KI-induced cardiotoxicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Meta-analysis of 5291 samples revealed a convergent disruption of the cellular mitotic machinery, specifically chromosome segregation and nuclear division, as a shared mechanism of toxicity across multiple KI classes. Furthermore, Mendelian randomization (MR) analysis identified 26 robust causal associations, linking specific kinase targets (e.g. RING finger protein 13 [RNF13] and tyrosine kinase with immunoglobulin like and EGF like domains 1 [TIE1]) to increased risks of cardiomyopathy and myocardial infarction, while identifying TYRO3 protein tyrosine kinase [Tyro3] and Janus kinase 2 (JAK2) as potential cardioprotective factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>KICDB provides a mechanistic framework linking transcriptomic perturbations with genetically validated causal drivers. By linking transcriptomic perturbations with causal validation, it serves as a resource to advance biomarker discovery, mechanistic exploration and the design of cardioprotective strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6046-6058"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469171","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":"GMP-compliant production, validation and dosimetry of clinical grade [18F]3-(3-fluoropropyl)-2-phenyl-2,3-dihydrobenzo[d]thiazole ([18F]FPBT) for oxidative stress PET imaging","authors":"Hua Zhang,&nbsp;Fangfang Sun,&nbsp;Chun Li,&nbsp;Xin Wang,&nbsp;Yuexuan Song,&nbsp;Lu Jiang,&nbsp;Paul Gape,&nbsp;Samantha Y. A. Terry,&nbsp;Shujun He,&nbsp;Ran Yan,&nbsp;Zhi Lu","doi":"10.1111/bph.70593","DOIUrl":"10.1111/bph.70593","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Oxidative stress plays a critical role in the pathophysiology of various diseases, yet current methods for its non-invasive detection remain limited. This study aimed to systematically validate a superoxide-selective PET tracer, [¹⁸F]FPBT, for the early diagnosis and therapeutic monitoring of oxidative stress-related conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>[¹⁸F]FPBT was synthesised using a GMP-compliant, automated production protocol on the Trasis AllinOne platform. The product underwent comprehensive quality control tests to ensure clinical suitability. Preclinical imaging was conducted using a clinical PET scanner in LPS- and doxorubicin-treated rabbits, to assess tracer uptake in organs subject to oxidative stress. Radiation dosimetry was measured in healthy rabbits to estimate effective human doses. Acute toxicity was evaluated using nonradioactive FPBT in KM mice (1.875 mg·kg⁻¹).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>[¹⁸F]FPBT was successfully produced with batch yields ranging from 2.69 to 4.64 GBq when starting from 19.20–68.45 GBq of fluoride-18. PET imaging demonstrated clear visualisation of cardiac oxidative stress in LPS- and doxorubicin-treated rabbits. Estimated human radiation doses were 0.022 ± 0.004 mSv·MBq⁻¹ for males and 0.028 ± 0.005 mSv·MBq⁻¹ for females, comparable to [¹⁸F]FDG. No treatment-related adverse effects were observed in mice administered FBPT at a dose corresponding to 8896-fold the projected nonradioactive mass dose for a 150-MBq [¹⁸F]FBPT PET scan in humans.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>[¹⁸F]FPBT meets the regulatory and biological safety criteria for human use and shows strong potential for first-in-human PET imaging studies. This tracer could enable early diagnosis, monitoring and treatment evaluation in cardiovascular diseases characterised by elevated oxidative stress.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6028-6045"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70593","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469152","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":"Acute anaphylactic and multiorgan inflammatory effects of Comirnaty in pigs: evidence of spike protein mRNA transfection and paralleling inflammatory cytokine upregulation","authors":"László Dézsi,&nbsp;Gábor Kökény,&nbsp;Gábor Szénási,&nbsp;Csaba Révész,&nbsp;Tamás Mészáros,&nbsp;Bálint A. Barta,&nbsp;Réka Facsko,&nbsp;Anna Szilasi,&nbsp;Tamás Bakos,&nbsp;Gergely T. Kozma,&nbsp;Attila B. Dobos,&nbsp;Béla Merkely,&nbsp;Tamás Radovits,&nbsp;János Szebeni","doi":"10.1111/bph.70563","DOIUrl":"10.1111/bph.70563","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Rare but severe adverse events (AEs) associated with mRNA-lipid nanoparticle (LNP) COVID-19 vaccines, such as Comirnaty, include anaphylaxis and inflammatory organ disorders, but their underlying mechanisms are poorly understood. We aimed to develop an animal model to study these phenomena.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Naive and anti-polyethylene (PEG) antibody-sensitised pigs were injected with Comirnaty i.v. Responses were evaluated by haemodynamic monitoring, haematological changes and analysis of inflammatory markers. Inflammatory cytokine gene up-regulation was tested by RT-qPCR at 6 h and at 2 and 6 weeks after vaccination. Vaccine mRNA uptake was followed, and histopathology and spike protein immunohistochemistry were performed in selected organs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Cardiopulmonary distress of varying severity developed within minutes after each Comirnaty injection. Vaccine mRNA accumulation peaked in peripheral mononuclear cells (PBMC) within 15 min and then began to decline within minutes. After 6 h vaccine mRNA was high in liver and spleen, moderate in kidney, lymph nodes, and heart, and low in brain. At the same time expression of mRNA for proinflammatory cytokines (IL-1RA, CXCL10, TNF-α, CCL2) varied in different organs and paralleled with vaccine mRNA uptake, suggesting a close association. Histological abnormalities and spike protein immunopositivity were noted in kidney, heart and brain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>This porcine model revealed systemic anaphylactic reactivity and multiorgan vaccine mRNA uptake following i.v. injection of mRNA-LNPs, with organ-specific inflammatory response at 6 h and thereafter. These findings provide mechanistic insights into rare vaccine-related acute AEs and suggest future efforts to improve the safety of the mRNA-LNP platform.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6225-6239"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70563","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590487","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":"β-Nicotinamide mononucleotide reduces aflatoxin B1 induced liver injury via the gut microbiota-bile acid-farnesoid X receptor (FXR/NR1H4) axis","authors":"Yanyan Wang,&nbsp;Andrea Abreo Medina,&nbsp;Xianjiao Liu,&nbsp;Yongwang Liu,&nbsp;Wenqi Du,&nbsp;Yuhan Wang,&nbsp;Jinxiang Yang,&nbsp;Tianxue Jiang,&nbsp;Xingxiang Chen,&nbsp;Kehe Huang,&nbsp;Yunhuan Liu","doi":"10.1111/bph.70566","DOIUrl":"10.1111/bph.70566","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Aflatoxin B1 (AFB1) is a potent hepatotoxin that poses significant health risks to both livestock and humans. <i>β</i>-Nicotinamide mononucleotide (NMN) has potential therapeutic benefits for liver diseases. However, its mechanism against AFB1-induced liver injury remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study investigates whether NMN supplementation reduces AFB1-induced liver injury through the modulation of the gut-liver axis and elucidates the underlying molecular mechanism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mice were exposed to AFB1 (0.75 mg·kg⁻¹, p.o.) for 2 weeks to induce liver injury, with or without NMN (300 mg·kg⁻¹, p.o.). Changes in gut microbiota were assessed via 16S rRNA sequencing, while bile acids (BAs) profiles were quantified using targeted metabolomics. The farnesoid X receptor (FXR<i>/</i>NR1H4) pathway was analysed using qPCR, western blot and immunofluorescence. To establish causality, antibiotic depletion, faecal microbiota transplantation (FMT) and intestine-specific FXR knockout (<i>FXR</i>^Δ<i>IE</i>) mice were utilized.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NMN supplementation attenuated AFB1-induced liver injury, inflammation and oxidative stress, while restoring intestinal barrier integrity and reducing hepatic bile acids accumulation. Mechanistically, NMN reshaped the gut microbiota, increased bile salt hydrolase (BSH) activity and lowered intestinal conjugated bile acids, which correlated with activation of intestinal FXR/fibroblast growth factor 15 (FGF-15) signalling and suppression of hepatic Cyp7a1 expression. Importantly, antibiotic depletion of gut microbiota abolished NMN protection, whereas FMT from NMN-treated donors conferred resistance. Importantly, NMN failed to protect <i>FXR</i>^Δ<i>IE</i> mice, demonstrating that intestinal FXR is essential.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>NMN alleviates AFB1-induced liver injury via a gut microbiota-bile acid-FXR axis, highlighting a novel mechanism for its hepatoprotective effects.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6059-6080"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535331","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":"The lung is more than an organ of gas exchange: immunocompetency, platelets and implications for drug discovery","authors":"Simon C. Pitchford","doi":"10.1111/bph.70621","DOIUrl":"10.1111/bph.70621","url":null,"abstract":"<p>The lungs have for a long time been recognised as having pharmacological significance as a specific organ to modulate the pharmacokinetics of endogenous substances needed to maintain homeostasis. The lungs are therefore the site of action of certain drugs that act on these homeostatic processes, resulting in systemic effects on the cardiovascular system and blood. We now understand that the lungs are also a specialised site for haematopoiesis, with integration into the body's immune system. This may have significance given the exposure of the lungs to the environment and their resident microbiota. Within this new understanding, the lungs have also been reported as a significant site of thrombopoiesis, with a reservoir of megakaryocytic precursors that give rise to a megakaryocyte and platelet population with a distinct immunophenotype compared to circulating and bone marrow-derived cells. This article reflects on the potential importance of these discoveries and pharmacological opportunities that may result to control immune/inflammatory responses via selective control of platelet activation in the context of inflammation compared to haemostasis.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"5999-6006"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70621","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590522","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":"Decoding functional specialization in G protein-coupled receptors (GPCRs) through evolution-guided residue profiling","authors":"Berkay Selçuk,&nbsp;Gunnar Schulte,&nbsp;Igor B. Zhulin,&nbsp;Ogün Adebali","doi":"10.1111/bph.70538","DOIUrl":"10.1111/bph.70538","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>G protein-coupled receptors (GPCRs) are integral membrane proteins that mediate physiological processes by enabling cells to detect and respond to diverse stimuli. Although many subfamily-specific functional hotspots have been described, the family-wide determinants of common and subfamily-specific functions remain incomplete.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Here, we developed an evolutionary framework utilizing conservation within orthologs and variation across paralogs to classify positions as common residues (CRs) or selective residues (SRs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Common residues (CRs) cluster in sites linked to structural stability and activation, whereas SRs concentrate at selective interfaces involved in ligand and transducer binding. SR distributions across families revealed that some classes mainly diversify through changes in ligand-recognition sites, whereas others through changes at transducer-binding interfaces. We also uncovered CRs involved in family-specific and cross-family motifs, including conserved disulfide bridges and cholesterol-contact sites.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Together, these findings provide an evolutionary blueprint of family-wide features, reinforce known associations and deliver testable hypotheses that are especially valuable for understudied families.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6007-6027"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70538","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469177","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":"Paecilomyces cicadae-fermented Radix astragali modulates short-chain fatty acids metabolism in the intestine through gut microbiota and ameliorates hyperuricaemia","authors":"Hong Wang,&nbsp;Jing Xu,&nbsp;Kexin Liang,&nbsp;Yingying Tian,&nbsp;Zhifeng Cui,&nbsp;Jiayu Zhang","doi":"10.1111/bph.70565","DOIUrl":"10.1111/bph.70565","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Hyperuricaemia, a severe metabolic disorder linked to gout, is increasingly prevalent worldwide. <i>Radix astragali</i>, as a drug-food homologous material, has significantly expanded the market for novel functional foods. The solid-state fermentation products of <i>R. astragali</i> and <i>Paecilomyces cicadae</i> (RPF) promise to be candidates for lowering uric acid. Here, we have investigated the effects of RPF, using a model of hyperuricaemia in rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Hyperuricaemia, and damage to liver and kidney, was induced in male Sprague-Dawley rats receiving a high purine diet. Gut microbiota and short-chain fatty acid metabolism were examined by multi-omics analysis of rat faeces. Faecal microbiota transplantation was used to assess the therapeutic potential of gut microbiota and RPF. Effects of <i>Eubacterium siraeum</i> on uric acid and short-chain fatty acid metabolism were examined, in vitro and in hyperuricaemic rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>RPF regulated dysbiosis of gut microbiota and restored the relative abundance of <i>Ruminococcus</i> and <i>Eubacterium</i>, which was associated with normalisation of serum levels of uric acid and short chain fatty acids. In vitro, the <i>E. siraeum</i> DSM15702 strain extensively degraded uric acid. In vivo data from probiotic-treated, hyperuricaemic rats, indicated a reduction of circulating uric acid levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Our study suggests that the gut microbiota–short chain fatty acid axis may play a crucial role in maintaining intestinal homeostasis and in modulating the excretion of uric acid. <i>E. siraeum</i> may serve as a potential adjunct therapy for management of hyperuricaemia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6081-6093"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547905","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":"Cannabinoid CB1 allosteric ligands suppress inflammatory pain in male mice without tolerance, motor impairment, memory deficits or respiratory depression","authors":"Ifeoluwa D. Solomon,&nbsp;Sumanta Garai,&nbsp;Ganesh A. Thakur,&nbsp;Andrea G. Hohmann","doi":"10.1111/bph.70572","DOIUrl":"10.1111/bph.70572","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Positive allosteric modulators (PAMs) engage sites distinct from the orthosteric CB₁ cannabinoid receptor binding site. GAT211, a racemic ligand, contains GAT228 (<i>R</i>) and GAT229 (<i>S</i>) enantiomers. Whether enantiomer-mediated differences in allosteric activation or positive allosteric modulation translate into differences in therapeutic efficacy or unwanted cannabimimetic effects remain unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We evaluated therapeutic efficacy of the pure CB₁ allosteric agonist, GAT228 (<i>R</i>), and the PAM, GAT229 (<i>S</i>), in inflammatory pain induced by complete Freund's adjuvant (CFA) in male mice. We assessed whether these allosteric ligands would spare tolerance, memory deficits, motor impairment and respiratory depression associated with the orthosteric CB₁/CB₂ agonist CP55,940.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>GAT228 and GAT229 attenuated CFA-induced mechanical hypersensitivity in a CB₁-dependent manner without producing tolerance or hypothermia associated with the orthosteric CB₁/CB₂ agonist CP55,940. CP55,940 also produced memory deficits, motor impairment, and robust respiratory depression. GAT228 and GAT229 failed to do so. Unlike CP55,940, allosteric ligands did not produce motor impairment or notable respiratory depression in the presence or absence of CFA-induced inflammation. Allosteric ligands increased novel object recognition memory, whereas CP55,940 decreased time spent exploring the novel object. Intraplantar CFA increased immobility time in the tail suspension test, indicative of pain-related behavioural despair, which was normalized by allosteric ligands and exacerbated by CP55,940.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implication</h3>\u0000 \u0000 <p>CB₁ allosteric ligands represent promising, safer therapeutic strategies for pain management compared to direct CB₁ orthosteric agonists. Overall, this work contributes to offering a novel pathway for pain management that minimizes the risk of adverse effects.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 20","pages":"6132-6153"},"PeriodicalIF":7.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13404072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148577181","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}